Comparative review of diets for the metabolic syndrome:
implications for nonalcoholic fatty liver disease1–3
Angela M Zivkovic, J Bruce German, and Arun J Sanyal
ABSTRACT
Nonalcoholic fatty liver disease (NAFLD) is a significant health
problem and affects 70 million adults in the United States (30% of the
adult population), and an estimated 20% of these individuals have
the most severe form of NAFLD—nonalcoholic steatohepatitis
(NASH). The mechanisms underlying disease development and pro-
gression are awaiting clarification. Insulin resistance and obesity-
related inflammation, among other possible genetic, dietary, and
lifestyle factors, are thought to play a key role. A program targeting
gradual weight reduction and physical exercise continues to be the
gold standard of treatment for all forms of NAFLD. Even though
weight loss and dietary and lifestyle changes are recommended as
primary treatment for fatty liver, little to no scientific evidence is
available on diet and NAFLD. This article reviews the implications
of current dietary approaches, including national guidelines and
popular weight-loss diets, with a focus on determining the optimal
diet to prescribe for NAFLD and NASH patients. The effects of
macronutrient content (carbohydrate, fat, and protein ratios) and
specific food components, such as soluble fiber, nҀ3 fatty acids, and
fructose, are discussed. The premises, effects, barriers, and issues
related to current dietary guidelines and specific diets are discussed,
and the question, “Will it work for the pathogenesis of NAFLD and
NASH? ”, is addressed. Am J Clin Nutr 2007;86:285–300.
KEY WORDS Nonalcoholic fatty liver disease, NAFLD, non-
alcoholic steatohepatitis, NASH, diet, weight loss
INTRODUCTION
The rising incidence of obesity in today’s environment is as-
sociated with many obesity-related health complications (1), in-
cluding cardiovascular disease, diabetes, hyperlipidemia, hyper-
tension, and nonalcoholic fatty liver disease (NAFLD) (2–5).
This constellation is also recognized as the metabolic syndrome
and is characterized by underlying insulin resistance. NAFLD is
defined as the accumulation of lipid, primarily in the form of
triacylglycerols in individuals who do not consume significant
amounts of alcohol (쏝20 g ethanol/d) and in whom other known
causes of steatosis, such as certain drugs and toxins, have been
excluded (6). The spectrum of NAFLD includes steatosis alone
(type 1), steatosis plus inflammation (type 2), steatosis plus he-
patocyte injury or ballooning degeneration (type 3), and steatosis
plus sinusoidal fibrosis, Mallory bodies (type 4), or both (6 –9).
NASH is considered to be the most severe form of NAFLD (types
3 and 4) and is associated with an array of adverse clinical
Am J Clin Nutr 2007;86:285–300. Printed in USA. © 2007 American Society for Nutrition
outcomes, including cirrhosis (7), hepatocellular carcinoma
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(10 –12), and advanced liver disease, which leads to liver-related
death (7, 13).
Given the close relations between obesity, the metabolic syn-
drome, and the development of NAFLD, it is not surprising that
many NAFLD patients have multiple components of the meta-
bolic syndrome, whether or not they are overweight or obese.
Insulin resistance is present in and is a significant predictor of
NAFLD and NASH in most patients (14), even the 앒10 –15% of
patients who are not overweight (15, 16). NAFLD is a multifac-
torial disease that involves a complex interaction of genetics,
diet, and lifestyle, all of which combine to form the NAFLD
phenotype, as discussed in several recent reviews (17, 18).
A cornerstone of the management strategy in such patients is
the use of diet to decrease body weight, and improve glycemic
control, dyslipidemia, and cardiovascular risks, as well as to treat
fatty liver. There is a bewildering array of diets that have been
recommended for the prevention and treatment of all of the com-
ponents of the metabolic syndrome. Their utility for the treatment
of NAFLD remains mostly unknown. It is also important to note
that cognitive-behavioral approaches, in addition to dietary mod-
ification, are necessary for the long-term success of dietary and
lifestyle interventions; however, this is outside the scope of the
present review.
In this article, we review the current concepts about the patho-
genesis of hepatic steatosis and steatohepatitis and evaluate the
existing diets in the context of this knowledge and the available
literature. The intent is to enable clinicians to evaluate the diets
of NAFLD and NASH patients and make rational decisions
based on this perspective—in the absence of controlled trials—to
help their patients. Finally, a tailored approach for the dietary
1
From the Department of Food Science and Technology, University of
California, Davis, CA (AMZ and JBG); the Nestlé Research Centre, Lau-
sanne, Switzerland (JBG); and the Department of Internal Medicine, Virginia
Commonwealth University, Richmond, VA (AJS).
2
Supported by the University of California at Davis Graduate Group in
Nutrition Block Grant and Jastro Shields Scholarship (to AMZ) and by grant
NIDDK K24 02755-07 (to AJS).
3
Address reprint requests to AJ Sanyal, Virginia Commonwealth Univer-
sity, Department of Internal Medicine, Division of Gastroenterology, Hepa-
tology and Nutrition, PO Box 980341, Richmond, VA 23298-0341. E-mail:
ajsanyal@mail2.vcu.edu. Address correspondence to AM Zivkovic, Depart-
ment of Food Science & Technology, University of California, One Shields
Avenue, Davis, CA 95616. E-mail amzivkovic@ucdavis.edu.
Received December 6, 2006.
Accepted for publication February 13, 2007.
285
286 ZIVKOVIC ET AL

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FIGURE 1. Carbohydrate (CHO) metabolism in peripheral insulin resistance and fatty liver. Excessive or inappropriate intakes of carbohydrates combined
with peripheral insulin resistance (resistance to insulin-stimulated glucose uptake in skeletal muscle and adipose tissue) result in shunting of glucose (Glc) to
the liver, where it is converted to either glycogen (G-G) or free fatty acids (FFA) through insulin-stimulated de novo lipogenesis (DNL), and in the stimulation
of the production of free cholesterol (FC), which leads to an overaccumulation of triacylglycerols (TG) and cholesterol esters (CE) in the liver. The dashed lines
represent impaired pathways, and the bold lines represent enhanced pathways.

treatment of NAFLD is offered as a way to optimize the dietary
management of this condition.
NAFLD PATHOPHYSIOLOGY AND DIET
The pathophysiology of NASH is not fully understood. The
complexities related to disease development and progression are
discussed in detail elsewhere (17–21) and will not be reviewed in
detail here. The main aspects of NAFLD and NASH pathophys-
iology as they relate to diet and nutrition are briefly discussed
below.
Dietary effects on whole-body metabolism and its regulation
via effects on hormones, transcription factors, and lipid meta-
bolic pathways are considered to play a central role in NAFLD.
Insulin resistance is currently thought to be a key factor in the
development of both NAFLD and NASH (22). Many studies
have shown an association of insulin resistance with NAFLD and
NASH on the basis of impaired glucose tolerance or impaired
fasting glucose (23–29). Despite elevated insulin concentrations,
adipose tissue fatty acid flux was not suppressed in NAFLD
patients (29), which indicated the presence of peripheral insulin
resistance.
In most patients, overnutrition or inappropriate diet are
thought to lead to chronically elevated glucose, insulin, and free
fatty acid (FFA) concentrations in the blood. Both excessive
carbohydrate intake (Figure 1) and excessive fat intake (Figure
2) could play a role in increasing blood glucose, FFA, and insulin
concentrations, independently or together. These dietary condi-
tions (Figure 3) contribute to resistance to insulin-stimulated
glucose uptake at the level of the adipose tissue and skeletal
muscle as well as resistance to the insulin-mediated suppression
of TG hydrolysis in adipose tissue (29, 30). Glucose uptake in the
liver is not insulin dependent, and increased glucose concentra-
tions in the blood lead to increased glucose uptake by the liver.
Insulin-mediated stimulation of de novo lipogenesis (DNL)
leads to an increased conversion of glucose to fatty acids (31).
Together, the increased concentrations of both glucose and
FFA in the blood contribute to excessive accumulation of neutral
lipids in the liver. A recent study by Donnelly et al (32), using a
multiple-stable-isotope labeling approach, showed that in
NAFLD patients plasma FFAs were the primary contributor to
the liver triacylglycerol content in the fasted state (50 –70% of
total FA) and to the lipoprotein triacylglycerol content in both the
fed and the fasted state (50 –75% of total FAs). Most of the
plasma FFAs were from adipose tissue, which accounted for
70 –90% of FAs in the fasted state and 50 –70% in the fed state.
The de novo synthesis of FAs from glucose, fructose, and amino
acids was also dysregulated in NAFLD patients. DNL was ele-
vated in the fasting state—accounting for 25% of liver and VLDL
triacylglycerols compared with 5% in healthy individuals (33,
34)—and failed to increase postprandially. Moreover, this study
showed that there were likely 2 distinct pools of FAs in the liver,
which were handled differently. Plasma FFAs—representing
mainly adipose-derived FAs—were thought to be part of a fast-
turnover pool that was preferentially incorporated into VLDLs,
whereas FAs synthesized de novo were thought to enter a hepatic
holding pool. Therefore, especially in the presence of peripheral
insulin resistance, in which the flux of FAs from the adipose is not
suppressed by insulin and plasma FFAs are persistently high,
elevated rates of lipogenesis may be a significant source of ac-
cumulated triacylglycerol in the liver.
In healthy individuals, elevated lipid concentrations in the
liver lead to increased VLDL production and secretion; however,
in NAFLD and NASH patients, this increase in fat export via
VLDL may be impaired or insufficient to prevent fatty liver (35).
Hypertriglyceridemia, low HDL concentrations, and small,
dense LDL particles often result from an increase in the concen-
tration, size, or both of circulating VLDL (36), which together
 DIETS FOR THE METABOLIC SYNDROME AND NAFLD 287

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FIGURE 2. Fat metabolism in peripheral insulin resistance and fatty liver. Excessive or inappropriate dietary fat intake combined with peripheral insulin resistance
(resistance to insulin-inhibited lipolysis in the adipose tissue), continued insulin-stimulated triacylglycerol (TG) hydrolysis via lipoprotein lipase (LpL), and many other
possible genetic alterations in key lipid metabolic pathways tend to result in increased blood free fatty acid (FFA) concentrations. This leads to excessive skeletal muscle
fat accumulation and increased liver concentrations of TG and cholesterol esters (CE). High blood TG concentrations in the form of VLDL tend to accompany this
condition and can induce cholesterol ester transfer protein (CETP) activity, which results in an increased transfer of TG from VLDL to HDL and a subsequent increase
in HDL clearance and decreased HDL concentrations. ␤-ox, fatty acid ␤-oxidation; Chylo, chylomicron; FC, free cholesterol; sm/d, small density.

confer an increased risk of cardiovascular disease (37– 44). In includes high triacylglycerol, low HDL, and increased small,
NAFLD and NASH patients, blood lipid concentrations may be dense LDL (45).
normal or elevated, and many patients have the atherogenic The original “two-hit hypothesis” of NASH asserts that the
dyslipidemia associated with the metabolic syndrome, which accumulation of lipid in the liver (hit one) is followed by a

FIGURE 3. Peripheral insulin resistance and fatty liver. Peripheral insulin resistance (represented by dashed lines) affects carbohydrate and fat metabolism
and causes triacylglycerol (TG) accumulation in the liver. Resistance to insulin’s stimulation of glucose uptake via glucose transporter 4 (GLUT4) by skeletal
muscle and adipose tissue (a), and insulin’s inhibition of lipolysis in the adipose tissue (b) diverts glucose (GLC) to the liver, where insulin continues to stimulate
de novo lipogenesis (DNL), and increases the flux of free fatty acids (FFA) from adipose tissue to the liver (d). In addition, insulin’s continued stimulation of
lipoprotein lipase (LpL)–mediated hydrolysis of fats leads to an increased FFA flux to both adipose tissue and liver (e). As a result, the liver TG concentration
increases (f); however, it is unclear how impairments in lipid export via VLDL secretion (g), ␤-oxidation (␤-ox; h) of FFA, or other metabolic pathways result
in an inability to maintain fat balance, which leads to the development of fatty liver. The bold lines represent enhanced pathways. Chylo, chylomicron.
288 ZIVKOVIC ET AL

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FIGURE 4. Obesity and inflammation. In obesity and overweight, adipocytes secrete the proinflammatory cytokine tumor necrosis factor-␣ (TNF-␣), which
stimulates the secretion of monocyte chemotactic protein-1 (MCP-1) by preadipocytes and which subsequently results in macrophage recruitment. This cascade
of proinflammatory events continues with the further secretion of TNF-␣, interleukin-6 (IL-6), and interleukin-1 ␤ (IL-1␤) by the now-resident and activated
macrophages. These cytokines, in turn, affect both adipocytes and the liver. In the adipocytes the cytokines stimulate the release of nuclear factor ␬B (NF-␬B)
and Jun N-terminal kinase (JNK), which leads to insulin resistance in these cells. In the liver, hepatocytes are stimulated to produce prothrombotic molecules
such as fibrinogen, inflammatory molecules such as C-reactive protein (CRP), the overproduction and secretion of glucose (Glc) into the bloodstream, and the
activation and proliferation of stellate and Kupffer cells, which leads to fibrosis. FFA, free fatty acids.

cascade of prooxidative, hepatotoxic events (hit 2), which are
caused by an as yet unknown mechanism (46). Mitochondrial
dysfunction has been considered to be such a second hit (21).
There are several other mechanisms being investigated also. The
increased secretion of tumor necrosis factor ␣ (TNF-␣) and other
proinflammatory cytokines by adipocytes and infiltrating mac-
rophages is thought to lead to chronic systemic inflammation
(Figure 4) as well as obesity-linked insulin resistance (47). El-
evated concentrations of circulating TNF-␣ have been docu-
mented in NAFLD patients (48) and have been implicated in the
manifestation of fatty liver disease (49). Small intestinal bacte-
rial overgrowth (50 –52) and deficiencies in various nutrients,
including essential fatty acids (53), choline (54), and amino acids
(55, 56), may also be involved in the development and progres-
sion of this disorder; however, limited evidence exists to support
these mechanisms.
DIETARY TREATMENT OF NAFLD AND NASH
Because of the strong association of obesity and the metabolic
syndrome across the entire spectrum of NAFLD, current recom-
mendations for the treatment of fatty liver disease are aimed at
weight loss and dietary modification (28, 57–59). For unknown
reasons, sudden or quick weight loss achieved through dietary
modification may lead to the progression of liver failure in some
NAFLD patients (60). On the other hand, weight reduction
through surgical methods, even with quick weight-loss after sur-
gery, has been successful in reducing disease progression (58, 59,
61– 63). Despite the fact that weight loss and dietary and lifestyle
changes are recommended as primary treatment for fatty liver, no
specific guidelines exist pertaining to diet. Very few studies of
the effects of different diets on NAFLD have been performed.
The premises, effects, barriers, and issues related to current di-
etary guidelines and specific popular weight-loss diets as they
relate to NAFLD are discussed below.
EFFECT OF INDIVIDUAL DIETARY COMPONENTS ON
THE METABOLIC SYNDROME, INSULIN RESISTANCE,
HEPATIC LIPID METABOLISM, AND
INFLAMMATORY AND FIBROTIC PATHWAYS
Saturated fat
A recent study in a rat model of hepatic steatosis showed that
saturated fatty acids (SFAs) promote endoplasmic reticulum
stress as well as hepatocyte injury (64). Accumulation of SFAs in
the liver due to high-SFA or high-fructose diets led to an increase
in markers associated with endoplasmic reticulum stress and
liver dysfunction. This, along with ample evidence associating
high-SFA intakes with an increased risk of cardiovascular dis-
ease (65– 67), suggests that the intake of dietary saturated fats
should be limited in NAFLD patients. However, what saturated
fat intake should be recommended?
A study comparing 25 overweight (BMI 쏝 30; in kg/m2)
NASH patients and 25 age- and BMI-matched controls collected
7-d food records and assessed dietary patterns (68). NASH pa-
tients had higher intakes of SFA at 14% of total energy, compared
with 10% in controls. Insulin resistance, as measured by the
insulin sensitivity index, was correlated with SFA intake. There-
fore, a SFA intake 쏜10% of total energy may contribute to
insulin resistance and may not be suitable for NASH patients.
A randomized, double-blind, crossover study examined the
effects of 3 diets in 86 free-living healthy men: a control diet
(38% fat with 14% SFAs), the National Cholesterol Education
 DIETS FOR THE METABOLIC SYNDROME AND NAFLD
Program Step I diet (30% fat with 9% SFAs), and the National
Cholesterol Education Program Step II diet (25% fat with 6%
SFAs) (61). Although both reduced-fat diets decreased LDL,
they also decreased HDL and increased plasma triacylglycerol
after 6 wk compared with the control diet. In response to the
6%-SFA diet, subjects who were insulin resistant, who had a
higher percentage of body fat, and/or who had a higher BMI—
characteristics that describe most NAFLD patients— experi-
enced smaller reductions in LDL, larger reductions in HDL, and
increases in triacylglycerol compared with subjects who were
insulin sensitive. On the basis of this evidence, SFA intakes 쏝7%
of total energy may not offer any further improvements in blood
lipids in patients with insulin resistance and may even be detri-
mental.
It is still unclear whether a minimum intake of SFAs in the diet
is beneficial or perhaps even required for optimal health (69). On
the basis of the clinical evidence discussed above, SFA intakes
쏝7% and 쏜10% of energy may be suboptimal for NAFLD
patients.
Monounsaturated fatty acids
Monounsaturated fatty acids (MUFAs) are a class of fatty
acids that are found in foods such as olive oil, nuts, and avoca-
does. The beneficial effects of MUFAs on cardiovascular disease
risk and blood lipid profiles have been extensively studied (65).
In particular, dietary MUFAs decrease oxidized LDL (70), LDL
cholesterol (66), total cholesterol (TC), and triacylglycerol con-
centrations, without the concomitant decrease in HDL typically
seen with low-fat diets (71–73). Additionally, the replacement
of carbohydrate and saturated fat with MUFAs leads to reduc-
tions in glucose and blood pressure and to an increase in HDL
in patients with diabetes (74). A MUFA-rich diet (40% of
energy as fat) also decreased VLDL-cholesterol and VLDL-
triacylglycerol more and was more acceptable to patients with
non-insulin dependent diabetes mellitus (type 2 diabetes) than
was a high-carbohydrate diet (28% of energy as fat) (75). There-
fore, an increase in the intake of MUFAs, particularly as a re-
placement for SFAs and as a higher proportion in the diet in lieu
of carbohydrate, may be beneficial for NAFLD patients.
Polyunsaturated fatty acids
Polyunsaturated fatty acids (PUFAs) are a class of fatty acids
that include nҀ6 and nҀ3 fatty acids. The nҀ3 fatty acid
␣-linolenic acid is a precursor for the long-chain products doco-
sahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). PU-
FAs have been shown to decrease the risk of heart disease when
consumed in lieu of SFAs in both epidemiologic (76, 77) and
clinical (78) studies. The ratio of nҀ6 to nҀ3 fatty acids seems
to be important in determining the effect of PUFAs on various
lipid and nonlipid indexes. Replacement of nҀ6 PUFAs with
␣-linolenic acid improved peripheral insulin sensitivity and low-
ered cholesterol concentrations in rats with fructose-induced in-
sulin resistance (79). An approximate dietary intake of 6% nҀ6
and 1% nҀ3 fatty acids as percentage of energy has been rec-
ommended to maximize the cardiovascular benefits of these es-
sential fatty acids (80).
Several studies have shown a link between essential fatty acid
deficiency and the development of steatosis in animal models
(51, 53, 55, 81– 85), a link that was first observed almost 30 y ago
(86). There is also an indication that essential fatty acids may be
289
essential for VLDL secretion (54). In geese overfed with corn,
liver steatosis is accompanied by a reduced essential fatty acid
content of membrane phospholipids despite an adequate dietary
supply of both linoleic and ␣-linolenic acid (84).
nⴚ3 Fatty acids
The effects of nҀ3 fatty acids on dyslipidemia and insulin
resistance have been extensively reviewed (87) and provide con-
vincing evidence that nҀ3 fatty acids should be an important
dietary component in patients with NAFLD and NASH. Specif-
ically, DHA and EPA induce fatty acid catabolism through the
activation of peroxisome-proliferator activated receptor (PPAR-
)–mediated pathways (88) and down-regulate DNL through ste-
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rol regulatory element binding protein (SREBP) pathways (89).
The effects of dietary fish oil, which is high in DHA and EPA, in
animal models of insulin resistance are impressive. The benefi-
cial effects include 1) decreased plasma triacylglycerol, FFAs,
glucose, and insulin; 2) prevention of peripheral insulin resis-
tance; 3) decreased triacylglycerol concentrations, VLDL secre-
tion, and lipogenesis in the liver; 4): decreased lipid concentra-
tions and utilization and storage of glucose in skeletal muscle;
and 5) decreased adipocyte cell size and visceral fat content and
increased insulin-stimulated glucose transport in the adipose tis-
sue (87).
Walnuts, a good source of ␣-linolenic acid, may also be ben-
eficial. When patients with type 2 diabetes were placed on diets
that included 30 g walnuts/d, plasma HDL and the ratio of HDL
cholesterol to TC increased, and LDL decreased after 8 wk (90).
In another study, hypercholesterolemic men and women who
substituted 32% of their MUFA intake with walnuts had signif-
icant decreases in TC and LDL and improved endothelial func-
tion compared with controls (91).
The first studies to have examined the effects of nҀ3 fatty acid
supplementation in NAFLD patients were recently published.
One such study found that 1 g fish oil/d for 12 mo decreased blood
triacylglycerol concentrations, liver enzymes, fasting glucose,
and steatosis in NAFLD patients (92). Another study also found
decreased blood triacylglycerol, liver enzymes, and TNF-␣ and
regression of steatosis as assessed by ultrasonography after 6 mo
of supplementation with 2 g fish oil/d (93). These preliminary
results, along with the evidence reviewed above, suggest that the
consumption of nҀ3 fatty acids found in fish oils and walnuts is
likely to improve blood lipid profiles and to reduce inflamma-
tion, steatosis, and liver damage in NAFLD patients.
trans Fatty acids
trans Fatty acids occur naturally in foods such as dairy prod-
ucts as a result of bacterial metabolism and in foods such as
margarines as a result of hydrogenation. trans Fatty acids consist
of multiple isomers that have differential effects on human me-
tabolism (94). The bacterially derived cis-9, trans-11 conjugated
linoleic acid and trans-11 oleic acid typically found in dairy
products do not have adverse effects on lipoprotein profiles (95).
Conversely, intake of trans-10, cis-12 conjugated linoleic acid
from hydrogenated oils has been found to increase inflammatory
markers (96), induce endothelial dysfunction (97), and unfavor-
ably alter the blood lipid profile by increasing the LDL:HDL and
TC:HDL ratios (98).
Effective 1 January 2006, after reviewing available scientific
evidence regarding the effect of trans fats on cardiovascular
290 ZIVKOVIC ET AL
health, the Food and Drug Administration ruled that food man-
ufacturers are required to include the content of trans fats on
nutrition labels (99). Although the specific mechanisms of action
are not yet clear, the recommendation to avoid the intake of trans
fatty acids from hydrogenated oils seems well founded for those
at risk of dyslipidemia.
Glycemic index and fiber
Several trials have shown decreases in TC in response to intake
of soluble fiber from sources such as oats (100, 101). This type of
evidence has led the Food and Drug Administration to approve a
claim of cardiovascular disease risk reduction for the labeling of
oat products and foods containing soluble fiber (102). The so-
called “second-meal effect” of low-glycemic index (GI) foods or
slow-release carbohydrates improves the glycemic response to a
subsequent meal and was first described in the early 1980s (103).
The effects of high-fiber, low-GI carbohydrates on glycemic
response and cholesterol concentrations were reviewed recently
in a meta-analysis (104) and provide evidence that these dietary
components may be beneficial to individuals with impaired in-
sulin response.
A breakfast containing a high-fiber indigestible and ferment-
able starch compared with a low-GI starch reduced FFAs in the
blood after a subsequent meal (105). Whereas both breakfasts
lowered glucose concentrations, only the breakfast containing
the low-GI starch decreased insulin concentrations. Although the
results of this study cannot be generalized to long-term effects on
glycemic control or lipid profiles, it seems reasonable to con-
clude that the inclusion of carbohydrates that are high in indi-
gestible and fermentable fiber and low in GI can be helpful in
maintaining glucose, insulin, and FFA concentrations in individ-
uals with insulin resistance and NASH.
Sucrose and fructose
Several studies have shown that high intakes of fructose in-
crease DNL in animal models and in humans (106 –108). One
study of lean and obese women found that 4 d of overfeeding with
either a glucose or sucrose drink increased DNL 2–3-fold (109).
The higher the woman’s baseline lipogenesis rate, the higher the
increase in DNL in response to the 4 d of overfeeding, with a
trend toward a higher increase with sucrose than with glucose.
These data suggest that some individuals may be more sensitive
to fructose-induced stimulation of DNL.
Studies of the effects of fructose consumption on whole-body
energy metabolism were reviewed recently by Havel (110). A
feeding study showed that 2 d of a high fructose intakes (30% of
kcal/d, consumed as a sweetened beverage at every meal) re-
sulted in decreased postprandial glucose concentrations and in-
sulin responses and prolonged alimentary lipemia in women
(111). High glucose intakes with meals, on the other hand, re-
sulted in a suppressed postprandial response of the orexigenic
hormone ghrelin. These data suggest that a high consumption of
fructose and glucose in the form of sweetened beverages may
lead to changes in long-term energy balance regulation at the
level of the central nervous system, which favors increased cal-
orie consumption and weight gain.
Sweetened drinks, such as sodas, are typically consumed as
additional calories and lead to excess intake of as much as 150 –
300 kcal/d (112). It is recommended that intakes of refined sugars
and high-fructose or high-glucose foods and beverages should be
reduced in the NAFLD population. High intakes of fructose and
glucose as simple sugars stimulate the de novo synthesis of fatty
acids, especially in individuals with insulin resistance and in
those who are overweight (32, 109, 113, 114).
Protein
There is little information on the effect of protein quantity,
quality, and composition on the pathophysiology of NAFLD and
NASH. It is known that protein deficiency or malnutrition can
cause steatosis (55, 115). Considering that the total protein con-
tent and quality are typically high in the average American diet,
protein deficiency is highly unlikely in NAFLD patients. Con-
versely, an excessive intake of protein may cause glomerular
sclerosis, intrarenal capillary hypertension, and eventually renal
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malfunction in certain vulnerable individuals who have under-
lying renal insufficiency (116 –120). Studies of high protein in-
takes and their possible effects on NAFLD are lacking.
CURRENT DIETARY GUIDELINES
US Department of Agriculture Dietary Guidelines for
Americans
The official dietary recommendations for healthy Americans,
the Dietary Guidelines for Americans, is published every 5 y as
a joint effort of the Department of Health and Human Services,
and the US Department of Agriculture (USDA) (121). The guide-
lines provide advice about dietary habits to promote health and
reduce the risk of major chronic diseases. The USDA guidelines
are meant for health maintenance and are not guidelines for the
treatment of any health condition.
In brief, it is recommended that individuals take in an appro-
priate amount of calories for body size and activity level. They
are encouraged to eat a variety of foods, choose from several food
groups, and include predominantly whole grains and their prod-
ucts in the diet. Nine or more daily servings of fruit and vegeta-
bles are recommended. Servings of meats, fish, vegetable pro-
teins, dairy, and dairy products are based on energy needs, with
fats and sweets to be consumed sparingly as “discretionary cal-
ories.” The most recent version of the guidelines, published in
2005, for the first time recognizes and discusses the notion of
individual differences and customizes the recommendations,
providing sample meal plans, based on height, weight, and ac-
tivity level estimates.
These basic guidelines do not address the special needs of
individuals with various metabolic disorders. NAFLD and
NASH patients are typically overweight, with central adiposity
(122). As such, their primary nutritional focus must be on weight
and body fat reduction rather than on maintenance, for which the
USDA Dietary Guidelines are primarily designed. Evidence
indicates that NAFLD patients may have increased lipogenesis
and that this, in part, contributes to the accumulation of lipid in
the liver (32). A higher carbohydrate intake was also associated
with a greater odds of inflammation in morbidly obese patients
with NAFLD than was a higher fat intake (123). The emphasis of
the USDA Dietary Guidelines on the consumption of carbohy-
drates may therefore be inappropriate for certain patients with
NAFLD and NASH.
American Dietetic Association
The basic dietary recommendation of the American Dietetic
Association for healthy adults is to follow the USDA Dietary
 DIETS FOR THE METABOLIC SYNDROME AND NAFLD
Guidelines, as described above. However, the American Dietetic
Association also maintains an annually updated Manual of Nu-
tritional Therapy for all known metabolic disorders and other
diseases that registered dietitians and other nutrition profession-
als can use to develop diets for their patients. The manual is
available by subscription to nutrition professionals (124).
Although there are no specific recommendations in the manual
for NAFLD, it does include suggestions for patients with the
metabolic syndrome. The first-line therapy for all lipid and non-
lipid risk factors associated with the metabolic syndrome is a
program incorporating weight loss and exercise. Additional rec-
ommendations include a reduction in the intakes of total fat,
SFAs, and trans fat, and, conversely, an increase in the intakes of
PUFAs and MUFAs. There is also a recommendation to include
long-chain nҀ3 fats and plant stanols or sterol esters. The phys-
ical activity goal is based on the America on the Move program
(125), which specifies a goal of increasing the number of steps
per day by 2000 steps above baseline and decreasing energy
intake by 100 kcal/d. It is suggested that the calorie goal be
reached by opting for regular instead of super-size meals, leaving
a few bites on the plate, and drinking water instead of juices and
other beverages. Finally, it is stated that the scientific evidence
does not support any specific generalized nutritional approach
for the metabolic syndrome and, therefore, that interventions
must be individualized.
The recommendations regarding fats and plant stanols and
sterols are well-founded because of the increased risk of cardio-
vascular disease in patients with the metabolic syndrome. The
specific goals for increasing physical activity and specific sug-
gestions for ways to decrease calorie intake are also prudent and
appropriate for NAFLD patients, especially because these ap-
proaches are moderate and would likely lead to gradual, long-
term, sustained weight loss. The American Dietetic Association
recommendations, however, do not address specific approaches
for decreasing insulin resistance and do not provide guidance
regarding carbohydrate and protein intakes.
American Heart Association
Studies have shown associations between fatty liver and hy-
pertension (126) and increased carotid intima-media thickness
(127), both of which are indicators of an increased risk of car-
diovascular disease in NAFLD patients. Several recent investi-
gations have shown associations between insulin resistance, the
metabolic syndrome, and cardiovascular disease (38 – 40, 42,
128); therefore, NAFLD patients having characteristics of the
metabolic syndrome should be treated to reduce their risk of
cardiovascular disease (129).
The position of the American Heart Association (AHA) on
scientific on healthy food habits focuses on the 3 main risk factors
associated with heart disease— high blood cholesterol, high
blood pressure, and excess body weight (130). The same basic
guidelines put forth by the USDA are recommended by the AHA,
with several modifications. These include recommendations to
eat fish twice a week, avoid trans fats, limit SFA intakes to 쏝10%
of total calories, and limit cholesterol to 쏝300 mg/d. The AHA/
National Heart Lung and Blood Institute (NHLBI) joint scientific
statement on the Diagnosis and Management of the Metabolic
Syndrome (130) further recommends decreasing SFA intakes to
쏝7% of total daily calories, maintaining a fat intake of 25–35%
of total calories, reducing overall calorie intake, avoiding simple
291
sugars, and consuming higher amounts of fruit, vegetables, and
whole grains.
The AHA recommendations to decrease SFA, trans fat, and
cholesterol intakes and to avoid simple sugars, while consuming
more low-GI foods and fish, are all reasonable suggestions for
NAFLD and NASH patients. An SFA intake of 10% of daily
calories, which corresponds with the AHA scientific position
statement, rather than the 7% recommendation in the AHA/
NHLBI joint statement, is recommended for reasons already
outlined above.
National Heart, Lung, and Blood Institute
The NHLBI has a set of recommendations that is published on
the NHLBI website (131), which recommends the Therapeutic
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Lifestyle Changes (TLC) diet described below. The Dietary Ap-
proaches to Stop Hypertension (DASH) plan, designed for indi-
viduals with hypertension, and recommendations specifically
pertaining to the dietary management of the metabolic syndrome
are also addressed.
National Cholesterol Education Program
The National Cholesterol Education Program (NCEP) has
been developing guidelines for reducing the incidence of coro-
nary heart disease (CHD) since 1985. The Step I and Step II diets
were created by the Expert Panel on Detection, Evaluation, and
Treatment of High Blood Cholesterol in Adults through 2 guide-
line reports, the Adult Treatment Panel I and II, respectively
(132). The Step I diet is a strategy for the prevention of CHD in
individuals with LDL concentrations 욷160 mg/dL or in those
with a borderline high LDL concentration (130 –159 mg/dL) and
욷2 risk factors, including cigarette smoking, hypertension, low
HDL, family history of premature CHD, and age (men: 45 y;
women: 욷55 y). This diet restricts total fat intake to 울30% of
total daily calories, SFA intake to 쏝10% of total daily calories,
and cholesterol to 쏝300 mg/d.
The Step II diet was created to address the need for further risk
reduction in persons with established CHD and in those who are
already at Step I goals and with a high-risk TC concentration of
욷240 mg/dL. This diet restricts SFA intake further to 쏝7% of
total calories and cholesterol to 쏝200 mg/d. The terms Step I and
Step II are no longer used in the new literature; however, the Step
I diet is still recommended for the general public, whereas the
Step II diet has been updated and renamed the TLC diet.
Therapeutic lifestyle changes
The Adult Treatment Panel III was published in 2001 and
describes the updated TLC diet (131). The TLC recommends
lowering LDL cholesterol with plant sterols and stanols (2 g/d)
and viscous and soluble fiber (20 –30 g/d), weight reduction, and
increased physical activity. The TLC diet guidelines recommend
a decrease in SFA to 7% of daily calories, a reduction in total fat
intake to 25–35% of daily calories, 쏝200 mg cholesterol/d,
쏝2400 mg Na/d, PUFA up to 10% of daily calories, MUFA up
to 20% of total calories, carbohydrate intake of 50 – 60% of
calories, protein at 앒15% of calories, and calorie intakes that
lead to the achievement and maintenance of a healthy weight
(133).
As discussed above, the severe restriction of SFA to 쏝10% of
daily calories recommended by the Step II and TLC diets had less
benefit in terms of LDL reduction, yet was accompanied by a
292 ZIVKOVIC ET AL
further decrease in the HDL:TC ratio, than did a more moderate
9 –10% SFA intake in individuals with insulin resistance (134).
This may be particularly true for patients with fatty liver disease,
especially if the fat calories are replaced with simple carbohy-
drates, which are known to increase DNL. The TLC diet recom-
mends a saturated fat intake that may not be suitable for NAFLD
patients with a high BMI and low insulin sensitivity but that may
be appropriate for patients with established CHD or for those
with LDL concentrations 쏜160 mg/dL and multiple CHD risk
factors.
Dietary Approaches to Stop Hypertension
The DASH eating plan is recommended for lowering blood
pressure and has been found to lower blood cholesterol (135).
DASH is a modification of the USDA Dietary Guidelines, with
specifications related to sodium intake. Studies have shown that
reducing sodium intake to 쏝1500 mg/d as part of the DASH diet,
alone or in conjunction with medication in more severe cases,
effectively lowers blood pressure in prehypertensive patients
(136).
Hypertension is associated with NAFLD (14, 23). African
Americans appear to be especially sensitive to the blood pres-
sure–lowering benefits of low-sodium diets that incorporate re-
ductions in salt intake and increases in potassium intake (136).
One study found particularly favorable results for African Amer-
icans and hypertensive patients with high adherence rates
(앒90%) in the 11-wk period of the clinical study (137). Little to
nothing is known about the pathogenesis of NAFLD in the Af-
rican American population.
The DASH diet plan, however, is not particularly palatable to
many individuals, the menu is rather limiting, and adherence is
low in the long term. Outpatient studies that more closely mimic
free-living conditions, compared with inpatient clinical trials,
have much lower adherence rates (138). Because of its effects in
lowering blood pressure, the DASH diet may be a reasonable and
preferable solution in some NASH patients, particularly in those
who are African American, those who have increased salt sen-
sitivity and high blood pressure, and those who are able to main-
tain this diet in the long term despite lower palatability.
American Diabetes Association
The American Diabetes Association has developed its own
food pyramid, which uses the same basic layout of the USDA
Food Guide Pyramid, to illustrate the dietary recommendations
for patients with diabetes. This food pyramid can be found on the
official American Diabetes Association website, along with
other information pertaining to nutrition, including recommen-
dations on eating out, holiday meal planning, recipes, and ex-
change lists (139). The American Diabetes Association pyramid
groups foods on the basis of their carbohydrate and protein con-
tents rather than on their classifications as foods. For example,
starchy vegetables such as potatoes are placed in the “breads,
grains and other starches category rather than the “vegetables”
category because of their high starch content. Serving sizes for
foods containing high amounts of carbohydrate are smaller in the
American Diabetes Association pyramid than in the USDA pyr-
amid.
The American Diabetes Association position statement on
evidence-based nutritional recommendations for diabetic pa-
tients (140) presents specific goals and recommendations based
on A-, B-, and C-level evidence, depending on the quality and
quantity of scientific evidence collected through clinical trials
and evaluated using the American Diabetes Association evi-
dence grading system. The goals of nutritional therapy for both
type 1 and type 2 diabetes, as outlined in this position statement,
are to attain normal glucose concentrations, improve health
through nutrition and physical activity, and prevent and treat
obesity, dyslipidemia, cardiovascular disease, hypertension, and
nephropathy.
Although the basic nutritional recommendations of the Amer-
ican Diabetes Association are similar to those of the USDA
Dietary Guidelines, the American Diabetes Association recom-
mendations further discuss carbohydrates by subdividing them
into the 3 categories of sugars, starch, and fiber. Specifically, the
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benefits of low-GI diets and the inclusion of fiber and resistant
starch are discussed. According to the American Diabetes Asso-
ciation, clinical trials show no significant differences between
sources or types of carbohydrates on glycemic response if the
total amount of carbohydrate is the same. The American Diabetes
Association also concludes that there are no consistent long-term
benefits with low-GI diets compared with high-GI diets, that the
intake of fiber shows no metabolic benefit unless it is consumed
in very high amounts likely to produce gastrointestinal side ef-
fects and that dietary sucrose does not induce hyperglycemia
more than do equal caloric amounts of starch.
The conclusions of the American Diabetes Association are
surprising in light of trials showing decreases in serum choles-
terol concentrations in response to the intake of soluble fiber
(100, 101) and of the Food and Drug Administration’s approved
claim of cardiovascular disease risk reduction for the labeling of
oat products and foods containing soluble fiber (102). The con-
clusion of the American Diabetes Association that the intake of
simple sugars, such as sucrose, has no adverse effect on patients
with type 2 diabetes is particularly surprising given the evidence
discussed above, which points to the effects of simple sugars,
specifically fructose, on DN, and the resulting increases in cir-
culating FFAs (32, 113) and plasma triacylglycerol (32, 107,
113, 114). The exchange lists, recipes, and other support mate-
rials provided on the American Diabetes Association website
(139) are valuable. However, the lack of recommendation to limit
the intake of simple carbohydrates, especially fructose, and to
include low-GI carbohydrates and fiber in the diet are at odds
with other evidence discussed previously.
WEIGHT-LOSS DIETS, POPULAR DIETS, AND FAD
DIETS
Mediterranean dietary pattern
The Seven Countries Study, an epidemiologic survey of di-
etary patterns and incidence of CHD published in 1970, first
identified a lower risk of CHD in Mediterranean countries where
the consumption of fruit, vegetables, grains, nuts, legumes, dairy,
olive oil, and small amounts of poultry, fish, red meat, and red
wine were emphasized (140). Since then, clinical trials have
repeatedly shown this Mediterranean dietary pattern to be ben-
eficial. Several recent reviews concluded that adherence to the
Mediterranean dietary pattern leads to improvements in lipopro-
tein indexes, insulin sensitivity, endothelial function, and car-
diovascular mortality (141–145).
 DIETS FOR THE METABOLIC SYNDROME AND NAFLD
It is unclear which specific features of the Mediterranean di-
etary pattern are responsible for the observed beneficial effects.
It has been difficult to define the Mediterranean Diet because the
Mediterranean region represents a large diversity of cultures and
lifestyles. Nonetheless, diets that are higher in MUFAs, have a
lower GI, and are higher in fiber than the average American diet,
which are characteristics of the Mediterranean dietary pattern,
tend to have beneficial effects on insulin sensitivity (146).
A randomized study comparing the effects of a Mediterranean
dietary pattern with a “prudent diet,” consisting of 50 – 60%
carbohydrates, 15–20% protein, and total fat 쏝30%, found that
at 2 y of follow-up, a higher proportion of patients in the Medi-
terranean dietary pattern group (50/90) than in the prudent diet
group (12/90) no longer had features of the metabolic syndrome
(147). In this study of 180 patients, the Mediterranean dietary
pattern was more effective than a low-fat diet at reducing body
weight, BMI, waist circumference, inflammatory markers, glu-
cose, TC, triacylglycerol, and insulin resistance, as well as im-
proving endothelial function and increasing HDL concentra-
tions. Patients also had a lower ratio of plasma nҀ6 to nҀ3 fatty
acids after the Mediterranean dietary intervention (147).
The Mediterranean dietary pattern emphasizes the inclusion of
particular foods rather than the limitation of particular macronu-
trients. Because of this, it may be easier for individuals to un-
derstand and follow the diet. It is also a highly palatable diet that
is well-liked and may lead to a higher adherence among dieters
in the long term. The effectiveness of this diet on multiple factors
of the metabolic syndrome in the 2-y randomized trial discussed
above provides convincing evidence that the combination of high
MUFA and high fiber intakes, a low GI, and the emphasis on lean
protein sources may be a good option for NAFLD patients.
Ornish Diet
The Ornish Diet was developed as a preventive lifestyle ap-
proach for the treatment and management of CHD (148). The
program consists of intensive lifestyle changes incorporating
moderate fat-burning exercise, relaxation and stress-relief tech-
niques, and a low-fat, high-fiber vegetarian diet. The diet allows
the unlimited consumption of fruit, vegetables, grains, beans, and
legumes and suggests moderate consumption of nonfat dairy
products and nonfat or very-low-fat commercially available
products, such as nonfat frozen yogurt bars. The diet restricts the
intake of all meats (including fish), oils and fats, nuts, avocados,
dairy products, sugar and simple carbohydrates, alcohol, and
commercially prepared foods that have 쏜2 g fat per serving.
Several studies have shown the effectiveness of the Ornish
Diet in preventing and even reversing CHD in patients who had
moderate-to-severe artery disease as assessed by coronary arte-
riography (149 –151). In fact, in one study, patients following the
low-fat, vegetarian, Ornish Diet experienced more regression of
atherosclerosis after 5 y than after 1 y, whereas the control group
following a usual care diet experienced progression of athero-
sclerosis at both 1 and 5 y of follow-up (151).
One of the main criticisms of the Ornish Diet for NASH is the
severe restriction of all fats, including nҀ3 fats and MUFAs. As
mentioned above, these fats have been associated with improve-
ments in metabolic measures related to NAFLD, including insu-
lin resistance, inflammation, and blood lipids. Furthermore,
many low-fat and non-fat commercially prepared foods contain
high levels of simple sugars and are high-GI foods, which would
293
tend to exacerbate insulin resistance. Finally, although it is rea-
sonable to suggest higher intakes of fruit, vegetables, legumes,
and whole grains, a vegetarian diet may be too drastic and too
limiting for most patients in the long term. The effects of different
vegetarian diets on NAFLD patients have not been studied. It is
also possible that, with such low fat intakes, phospholipid pro-
duction would be impaired, which would decrease the ability to
synthesize lipoproteins. The Ornish Diet may be an option for a
highly motivated NAFLD patient who has already developed
concomitant CHD and who needs a drastic change to reverse the
progression of atherosclerosis. However, this diet is likely to be
too drastic for most NAFLD patients.
Atkins Diet
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The Atkins Diet focuses on high-protein and high-fat intakes
and drastically low carbohydrate intakes (152). The premise is to
eat as much as one needs to “feel satisfied.” The dieter should
limit carbohydrates and focus on protein, leafy vegetables, and
healthy oils. Specifically, during the 2-wk phase one of the diet,
carbohydrate intake is limited to 20 g/d and should come primar-
ily from salad and other nonstarchy vegetables. During phase 2,
the carbohydrate intake is gradually increased by 5 g/wk until the
desired weight is achieved or the dieter stops losing weight. At
this point, the dieter has found their “carbohydrate equilibrium”
(ranging from 25 to 90 g carbohydrate/d) and should use this
carbohydrate intake for the maintenance of weight in the long
term. The diet accounts for increases in carbohydrate intake
beyond 90 g/d for those who exercise regularly (vigorous exer-
cise 5 d/wk for 45 min).
A recent trial showed that obese men and women lost more
weight with the Atkins Diet than with the conventional low-fat
diet at 3 and 6 mo, but the difference was not significant at 12 mo
(153). Individuals consuming the Atkins Diet had lower triacyl-
glycerol and higher LDL and HDL concentrations throughout the
study than did those consuming the low-fat diet, who experi-
enced the opposite effect. Both diets significantly decreased
blood pressure and the insulin response to an oral glucose load.
Another study in obese, insulin-resistant women found that
those consuming the Atkins Diet had significantly greater
reductions in triacylglycerol, body weight, and waist circum-
ference than did women consuming either the high-
carbohydrate or the high-protein Zone diet after 24 wk (154).
However, 25% of the women consuming the Atkins Diet ex-
perienced a 쏜10% increase in LDL.
The long-term effects of the Atkins Diet and other high-fat,
high-protein diets are still controversial, especially with regard to
increasing the risk of CHD and possible effects on renal function.
The consistent increases in LDL and TC, high intakes of SFAs,
and low intakes of fiber associated with the Atkins Diet are
contraindicated for NAFLD patients because of their proven
effects in increasing CHD risk. The Atkins Diet tends to induce
sudden weight loss and ketosis, especially in the first 3 mo, which
may also be deleterious in NAFLD patients. This diet is unlikely
to be suitable for most NAFLD patients.
Zone Diet
The Zone Diet is designed to modulate macronutrient balance
at each meal for improved glycemic control (155). The dieter is
allowed to eat as much as desired at each meal. The emphasis is
on eating smaller meals throughout the day, preferably 3 meals
294 ZIVKOVIC ET AL
with 2 snacks in between. The proportions of carbohydrate, fat,
and protein are to be kept constant at 앒40%, 30%, and 30%,
respectively. The Zone Diet also emphasizes supplementation
with a high-dose of fish oil (4 g/d).
A recent study in obese women following a diet that had
nutrient ratios similar to those recommended in the Zone Diet
(46% carbohydrate, 20% fat, and 34% protein) compared with a
higher carbohydrate diet (64% carbohydrate, 20% fat, and 17%
protein) found that triacylglycerol decreased more in women
following the Zone-like diet, although weight loss, LDL, HDL,
glucose, insulin, FFAs, and C-reactive protein decreased equally
in both groups and were correlated with the extent of weight loss
(156). Women who had higher baseline triacylglycerol concen-
trations lost more fat mass and had greater decreases in triacyl-
glycerol with the higher-protein Zone-like diet than with the
higher-carbohydrate diet.
Another study in obese adults compared a diet of 40% carbo-
hydrates, 30% fat, and 30% protein, which was termed the non-
ketogenic diet, with an Atkins-like higher-fat diet consisting of
10% carbohydrates, 60% fat, and 30% protein, which was termed
the ketogenic diet (157). The 6-wk trial showed that blood con-
centrations of ␤-hydroxybutyrate in the ketogenic diet group
were almost 4 times those in the nonketogenic diet group and that
LDL was directly correlated with ␤-hydroxybutyrate concentra-
tions. Insulin sensitivity and energy expenditure increased in
both diet groups.
The Zone Diet may be an option for reducing weight, control-
ling insulin resistance, and reducing the risk of CHD in some
NAFLD patients. The emphasis on MUFAs in lieu of saturated
fats, high-dose fish-oil supplements, fruit, vegetables, and high-
fiber, low-GI carbohydrates are all especially relevant for
NAFLD patients. However, the high protein intakes associated
with this diet may not be appropriate for patients with underlying
kidney dysfunction (116 –120). Type 2 diabetes is associated
with higher morbidity and mortality rates linked to kidney dys-
function, especially in youth-onset compared with adult-onset
diabetes (158). Overall, the Zone Diet has favorable elements for
most NAFLD patients, but may be inappropriate for those pa-
tients at risk of renal dysfunction.
South Beach Diet
The South Beach Diet is based on the GI and entails an induc-
tion phase in which very little carbohydrate is consumed. This
phase is followed by the gradual addition of “the right” carbo-
hydrates in the second phase and a maintenance phase (159).
Three daily meals and 2 snacks in between are “mandatory.” The
theory is that eating these snacks, even when not hungry, will
keep the dieter from overeating at the next meal. The dieter
chooses foods from the allowable list for each phase and avoids
foods that are on the “avoid list.” The emphasis is on foods that
have a low GI and are high in MUFAs throughout the diet phases.
In the first phase, all fruit, bread, rice, potatoes, pasta, sugar,
alcohol, and baked goods are eliminated from the diet, whereas
meat, chicken, turkey, fish, eggs, shellfish, vegetables, cheese,
nuts, and salad vegetables are to be eaten at each meal until full.
In phase 2, the dieter gradually re-introduces carbohydrates by
adding one serving of a low-GI, high-fiber carbohydrate to one
meal per day for 1 wk and then another serving and so on.
Supplemental fiber in the form of psyllium husks added to water
is recommended before lunch and dinner to help the dieter reach
a point of satiety more quickly.
One study compared the effects of the South Beach Diet,
which has been described as a modified carbohydrate diet, with
those of the NCEP Step II diet in 60 overweight adults (160).
Individuals in the South Beach group lost more weight, had a
greater decrease in waist-to-hip ratio, and experienced decreases
in triacylglycerol, whereas those following the NCEP diet expe-
rienced decreases in LDL and HDL. In both groups, weight and
TC decreased significantly, whereas there were no changes in
glucose, insulin, or inflammatory markers after 12 wk. However,
exercise and total calorie intake were not monitored in this trial;
therefore, it is impossible to discern whether the observed effects
were due to differences in the effectiveness of the diets, exercise,
or weight loss in and of itself.
The South Beach Diet incorporates some of the main issues
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pertinent to NAFLD patients that have already been discussed
above, including a focus on the consumption of low-GI foods,
fiber, and MUFAs. However, sudden weight loss is often a result
of phase 1 of this diet, and this is not advisable in NAFLD
patients, as mentioned above. The fat content of this diet through-
out the 3 phases is high, ranging from 40% to 60%, which can
lead to an increased risk of CHD. Studies of the long-term effect
of high protein and fat intakes in NAFLD patients are lacking.
Weight Watchers Diet
The Weight Watchers Diet provides 2 options, both of which
focus on reduced calorie consumption within an intensive sup-
port community (161). In one plan, the dieter consumes foods
throughout the day and monitors total intake by making sure not
to exceed a certain number of allowable points. Foods with a
higher nutrient density, such as fruit and vegetables, are worth
fewer points, whereas foods that have a low nutrient density
“cost” more and, therefore, are to be consumed in smaller
amounts or not at all. With the second plan, instead of counting
points, the dieter focuses on the consumption of “wholesome”
foods that are higher in nutrient density and avoids empty calo-
ries, with the exception of an occasional treat consumed in small
amounts.
The true advantage of the Weight Watchers Diet is the built-in
support structure that accompanies the diet. The diet itself does
not go beyond a simple recommendation to eat less to lose weight
and basically adheres to the USDA Dietary Guidelines. Weight
Watchers is known for its strong community support network and
high success rates because dieters attend motivational meetings
regularly. This support strategy may be critical because adher-
ence to modified-calorie diets in the long term is very poor (138,
153, 162–166).
SPECIFIC RECOMMENDATIONS AND FUTURE
DIRECTIONS
Taking into account the evidence discussed in this article, the
authors recommend a highly individualized approach for the
dietary treatment of NAFLD and NASH based on a thorough
assessment of individual metabolic, physiologic, and nutritional
status and personal goals and preferences. The effects of each diet
discussed in this article on specific health indexes, such as blood
triacylglycerol concentration and insulin sensitivity, are shown
in Table 1 and are based on a review of the references included
in this article. The composition and the relative macronutrient
content of each diet are shown in Table 2. Most NAFLD patients
would benefit from the guidelines given below.
 DIETS FOR THE METABOLIC SYNDROME AND NAFLD 295
TABLE 1
Effects of diets on selected indexes important to patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH)1

Diet Weight Waist circumference Steatosis Insulin sensitivity2 DNL Inflammation3 TC TG HDL LDL

USDA 2 2 1 2 1 2
AHA 2 2 1 2 2 1 2 2
NCEP Step I 2 2 1 1 2 1 2 2
DASH 2 2 1 1 2 1 2 2
TLC 2 2 1 1 2 1 2 2
American Diabetes Association 2 2 1 2
American Dietetic Association 2 2 1 2
Mediterranean 2 2 2 1 2 2 2 2 1 2
Ornish 2 2 1 1 2 2 1 2 2
Atkins4,5 2 2 1 2 2 1 2 1 1
Zone5 2 2 1 2 2

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South Beach4,5 2 2 2 2 2
Weight Watchers 2 2 1 2 2 2 2 1 2
1
An “up” arrow indicates a likely increase, and a “down” arrow indicates a likely decrease in the index based on studies reviewed in this article. A blank
space indicates that there is not enough evidence to predict outcomes. DNL, de novo lipogenesis; TC, total cholesterol; TG, triacylglycerol; USDA, US
Department of Agriculture; AHA, American Heart Association; NCEP, National Cholesterol Education Program; DASH, Dietary Approaches to Stop
Hypertension; TLC, Therapeutic Lifestyle Changes.
2
Based on the insulin sensitivity index.
3
Determined on the basis of plasma cytokine and C-reactive protein concentrations.
4
This diet may cause rapid or sudden weight loss in the induction period, which may be deleterious in patients with NAFLD and NASH.
5
This diet may be deleterious in patients with hyperuricemia or kidney dysfunction because of its high protein content.

Moderate calorie restriction of 앒100 –500 kcal/d through a
decrease in portion sizes is recommended by the American Di-
etetic Association (124) and the America on the Move program
(125). Evidence of beneficial effects from weight loss through
surgical methods in obese patients with NAFLD (59, 63) sug-
gests that weight reduction through dietary means would also
have positive effects. Specifically, weight loss resulted in a sig-
nificant decrease in the prevalence of the metabolic syndrome
and marked improvements in liver steatosis, inflammation, and
fibrosis (58). However, very few studies examining the effects of
different dietary and lifestyle approaches in achieving weight
loss in NAFLD have been done, and further studies are urgently
needed (60).
NASH patients have a higher postprandial triacylglycerol re-
sponse and an increased production of large VLDL detected by
an oral fat load compared with controls, despite normal fasting
blood lipid concentrations, which suggests that the metabolism
of dietary fat is impaired in these individuals (37). Decreased
total fat consumption could lead to a decrease in postprandial
lipemia and the associated disruptions in lipid metabolism. Fur-
ther studies are needed to ascertain whether the consumption of
smaller meals that are lower in total fat may be helpful in NAFLD
patients.
Regular, moderate exercise is independently associated with a
25–35% decrease in CHD risk over a 20-y period (167), regard-
less of diet and other risk factors. An exercise strategy of walking
a distance of 2 miles, 3 d/wk, at a target heart rate of 60% of heart rate
reserve (as measured by peak oxygen uptake) resulted in increases
in HDL and fitness equivalent to a more rigorous exercise program
of walking 3 miles, 3 d/wk, at 80% of heart rate reserve (168).
Further studies are needed to elucidate the effects of specific exer-
cise strategies in the NAFLD and NASH populations.

TABLE 2
Relative amounts of selected nutrients typical of each diet1
Diet Carbohydrate Fat Protein SFA MUFA PUFA Cholesterol Fiber Sodium

% of daily energy % of daily energy % of daily energy % of daily energy % of daily energy % of daily energy mg/d g/d mg/d
USDA 55–65 20–30 15 쏝 10 쏝 300 20–30 쏝2300
AHA 50–60 25–35 15 쏝7 쏝300 25 쏝2400
NCEP Step I 50–60 25–35 15 쏝10 20 10 쏝300 20–30 쏝2400
DASH 50–60 25–35 15 쏝7 20–30 쏝1500
TLC 50–60 25–35 15 쏝7 쏝200 20–30 쏝2400
American Diabetes Association 55–65 20–30 15 쏝10 쏝300
American Dietetic Association 55–65 20–30 15 쏝10 쏝300
Mediterranean 55 30 15 쏝10 15 5 200 20
Ornish 70–75 10 15–20 쏝1 5
Atkins 쏝20 55–65 25–30 20 10 5 300–600 5
Zone 40 30 30 12 10 5 200–300 15
South Beach 10–28 39–62 28–33 12 10 5 200–300 15
Weight Watchers 55–65 20–30 15 쏝10 쏝300 20–30
1
SFA, saturated fatty acids; MUFA, monounsaturated fatty acids; PUFA, polyunsaturated fatty acids; USDA, US Department of Agriculture; AHA,
American Heart Association; NCEP, National Cholesterol Education Program; DASH, Dietary Approaches to Stop Hypertension; TLC, Therapeutic Lifestyle
Changes.
296 ZIVKOVIC ET AL
nҀ3 Fatty acid intake—specifically DHA and EPA— has
been shown to improve CHD risk by affecting metabolic vari-
ables such as blood triacylglycerol concentrations (80, 169 –171)
and through independent mechanisms related to antiarrhythmic
effects (172–177). ␣-Linolenic acid from walnuts also improves
blood lipid profiles (79, 91, 178). Furthermore, nҀ3 fatty acids
have been found to decrease steatosis in both preliminary trials in
humans (92, 93) and in animal models (85, 87). More studies are
needed to clarify the specific dosages, formulations, and effects
of nҀ3 fatty acids in individuals with NAFLD.
Beneficial effects on both insulin sensitivity and lipid markers
have been found in response to low-GI carbohydrates and high-
fiber intakes from fresh fruit, vegetables, legumes, and grains
(33, 68, 100, 101, 103–105, 146, 147, 171, 179 –182). A reduc-
tion in the amount of total carbohydrates, especially simple sug-
ars, would reduce the total pool of acetyl CoA in the liver and,
therefore, reduce the flux through the DNL pathway. The reduc-
tion in fatty acid synthesis would also result in reduced triacyl-
glycerol synthesis and prevent the excess accumulation of total
fat in the liver. A reduction in the rate at which glucose enters the
bloodstream, via the consumption of lower-GI carbohydrates
and higher amounts of fiber, would also reduce the subsequent
exaggerated insulin excursions and thereby reduce insulin resis-
tance. However, nutritional studies of the specific effects of
modulating carbohydrate type and quantity on insulin resistance
and disease progression in NAFLD patients are needed.
The intake of diets that are lower in carbohydrate, lower in
saturated fat, but higher in protein than the average American
diet—which consists of 앒47% carbohydrate, 38% fat (20%
SFA), and 15% protein—tend to be beneficial for ameliorating
features of the metabolic syndrome, including effects on insulin
sensitivity and blood lipids (85, 115, 123, 134, 140, 141, 153,
154, 156, 160, 183, 184). Certain individuals may be susceptible
to renal malfunction associated with high protein intakes (116);
therefore, an increase in total protein intake may not be appro-
priate in these patients. Studies are needed to examine the effects
of modifying the protein content in NAFLD patients.
An emphasis on MUFAs from foods such as olive oil, in favor
of high-SFA foods such as fatty meats and full-fat dairy products,
is advisable because SFAs have deleterious effects on liver func-
tion (185) and raise blood LDL concentrations (68, 134, 186 –
189), whereas MUFAs are beneficial in reducing the risk of CHD
and type 2 diabetes through effects on blood lipids, endothelial
function, and insulin sensitivity (74, 75, 104, 144, 146, 147, 184,
186, 190, 191).
The recommendation to avoid the intake of sodas and other
sweetened drinks is substantiated by observations that high fruc-
tose intakes, high sucrose intakes, or both can induce DNL,
which leads to higher blood triacylglycerol concentrations and
lower insulin sensitivity (33, 106 –108, 114). Soda consumption
contributes a substantial proportion of the calorie intake in many
overweight and obese individuals (112, 192). A reduction in the
consumption of simple sugars, especially in the form of sweet-
ened beverages, which provide sugar in a very accessible and
easily absorbable form, would help to reduce the exaggerated
glucose and insulin excursions that are associated with insulin
resistance. In addition, a reduction in the consumption of sweet-
ened beverages would lead to a reduction in total calories con-
sumed, which would facilitate weight loss.
Poor adherence in weight loss and lifestyle modification is a
crucial issue in overweight and obese individuals (138, 153, 162,
163, 193–196). Weight loss through diet and exercise tends to be
successful in the first 6 mo, but in the long-term, most individuals
are unable to maintain this weight loss (167). Strategies to im-
prove adherence and long-term behavioral modification are
therefore imperative for the successful treatment of NAFLD
through dietary approaches.
SUMMARY
There is no consensus as to what diet or lifestyle approach is
the right one for NAFLD and NASH patients, largely because of
a lack of scientific evidence. It is likely that there will be no one
correct approach for all NAFLD patients, and diets will therefore
need to be tailored to individual needs. The inclusion of nҀ3 fatty
Downloaded from www.ajcn.org at Swets Blackwell Inc Dir Gen de Biblio/UNAM/Mexico on April 21, 2008
acids, high-MUFA foods, fruit, vegetables, and low-GI, high-
fiber foods and reduced intakes of saturated fats, simple carbo-
hydrates, and sweetened drinks may be universally recom-
mended to NAFLD patients. More studies are needed to clarify
the specific effects of different diets and dietary components on
the health of NAFLD patients. The general recommendations
described in this review may be a useful guide for determining the
appropriate diet for individual patients now, while evidence-
based recommendations from future clinical trials are assembled.
We acknowledge CJ Dillard for her invaluable help with editing.
The authors’ responsibilities were as follows—AMZ: prepared the manu-
script, researched the references, and created the figures and tables; JBG:
provided critical input on content and manuscript development; AJS: pro-
vided critical input on content and manuscript development and had the
original vision for the manuscript, the tables, and the figures. AJS was a
consultant to Oridion, Orphan Therapeutics, Sanofi, and Pfizer but had no
stocks or direct financial interests and no direct conflicts. JBG was a consul-
tant to Nestlé Research Center and Lipomics Technologies, Inc, but had no
direct conflicts.
REFERENCES
1. Pi-Sunyer FX. The obesity epidemic: pathophysiology and conse-
quences of obesity. Obes Res 2002;10(suppl 2):97S–104S.
2. Haynes P, Liangpunsakul S, Chalasani N. Nonalcoholic fatty liver
disease in individuals with severe obesity. Clin Liver Dis 2004;8:535–
47.
3. Abrams GA, Kunde SS, Lazenby AJ, Clements RH. Portal fibrosis and
hepatic steatosis in morbidly obese subjects: a spectrum of nonalco-
holic fatty liver disease. Hepatology 2004;40:475– 83.
4. Chan DF, Li AM, Chu WC, et al. Hepatic steatosis in obese Chinese
children. Int J Obes Relat Metab Disord 2004;28:1257– 63.
5. Boza C, Riquelme A, Ibanez L, et al. Predictors of nonalcoholic ste-
atohepatitis (NASH) in obese patients undergoing gastric bypass. Obes
Surg 2005;15:1148 –53.
6. McCullough AJ. The clinical features, diagnosis and natural history of
nonalcoholic fatty liver disease. Clin Liver Dis 2004;8:521–33.
7. Matteoni CA, Younossi ZM, Gramlich T, Boparai N, Liu YC,
McCullough AJ. Nonalcoholic fatty liver disease: a spectrum of clin-
ical and pathological severity. Gastroenterology 1999;116:1413–9.
8. Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA,
Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and
staging the histological lesions. Am J Gastroenterol 1999;94:2467–74.
9. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a
histological scoring system for nonalcoholic fatty liver disease. Hepa-
tology 2005;41:1313–21.
10. Bugianesi E, Leone N, Vanni E, et al. Expanding the natural history of
nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocel-
lular carcinoma. Gastroenterology 2002;123:134 – 40.
11. Mori S, Yamasaki T, Sakaida I, et al. Hepatocellular carcinoma with
nonalcoholic steatohepatitis. J Gastroenterol 2004;39:391– 6.
12. Smedile A, Bugianesi E. Steatosis and hepatocellular carcinoma risk.
Eur Rev Med Pharmacol Sci 2005;9:291–3.
 DIETS FOR THE METABOLIC SYNDROME AND NAFLD
13. Charlton M, Kasparova P, Weston S, et al. Frequency of nonalcoholic
steatohepatitis as a cause of advanced liver disease. Liver Transpl
2001;7:608 –14.
14. Clark JM. The epidemiology of nonalcoholic fatty liver disease in
adults. J Clin Gastroenterol 2006;40(suppl 1):S5–10.
15. Marchesini G, Brizi M, Morselli-Labate AM, et al. Association of
nonalcoholic fatty liver disease with insulin resistance. Am J Med
1999;107:450 –5.
16. Kim HJ, Kim HJ, Lee KE, et al. Metabolic significance of nonalcoholic
fatty liver disease in nonobese, nondiabetic adults. Arch Intern Med
2004;164:2169 –75.
17. McCullough AJ. Pathophysiology of nonalcoholic steatohepatitis.
J Clin Gastroenterol 2006;40(suppl 1):S17–29.
18. Gaemers IC, Groen AK. New insights in the pathogenesis of non-
alcoholic fatty liver disease. Curr Opin Lipidol 2006;17:268 –273.
19. Marchesini G, Marzocchi R, Agostini F, Bugianesi E. Nonalcoholic
fatty liver disease and the metabolic syndrome. Curr Opin Lipidol
2005;16:421–7.
20. Sass DA, Chang P, Chopra KB. Nonalcoholic fatty liver disease: a
clinical review. Dig Dis Sci 2005;50:171– 80.
21. Fromenty B, Robin MA, Igoudjil A, Mansouri A, Pessayre D. The ins
and outs of mitochondrial dysfunction in NASH. Diabetes Metab 2004;
30:121–38.
22. Choudhury J, Sanyal AJ. Insulin resistance and the pathogenesis of
nonalcoholic fatty liver disease. Clin Liver Dis 2004;8:575–94.
23. Marchesini G, Bugianesi E, Forlani G, et al. Nonalcoholic fatty liver,
steatohepatitis, and the metabolic syndrome. Hepatology
2003;37:917–23.
24. Moon KW, Leem JM, Bae SS, et al. [The prevalence of metabolic
syndrome in patients with nonalcoholic fatty liver disease]. Korean
J Hepatol 2004;10:197–206.
25. Ong JP, Elariny H, Collantes R, et al. Predictors of nonalcoholic ste-
atohepatitis and advanced fibrosis in morbidly obese patients. Obes
Surg 2005;15:310 –5.
26. Liangpunsakul S, Chalasani N. Unexplained elevations in alanine ami-
notransferase in individuals with the metabolic syndrome: results from
the third National Health and Nutrition Survey (NHANES III). Am J
Med Sci 2005;329:111– 6.
27. Marchesini G, Brizi M, Bianchi G, et al. Nonalcoholic fatty liver dis-
ease: a feature of the metabolic syndrome. Diabetes 2001;50:1844 –50.
28. Bugianesi E, Gentilcore E, Manini R, et al. A randomized controlled
trial of metformin versus vitamin E or prescriptive diet in nonalcoholic
fatty liver disease. Am J Gastroenterol 2005;100:1082–90.
29. Sanyal AJ, Campbell-Sargent C, Mirshahi F, et al. Nonalcoholic ste-
atohepatitis: association of insulin resistance and mitochondrial abnor-
malities. Gastroenterology 2001;120:1183–92.
30. Salmenniemi U, Ruotsalainen E, Pihlajamaki J, et al. Multiple abnor-
malities in glucose and energy metabolism and coordinated changes in
levels of adiponectin, cytokines, and adhesion molecules in subjects
with metabolic syndrome. Circulation 2004;110:3842– 8.
31. Timlin MT, Parks EJ. Temporal pattern of de novo lipogenesis in the
postprandial state in healthy men. Am J Clin Nutr 2005;81:35– 42.
32. Donnelly KL, Smith CI, Schwarzenberg SJ, Jessurun J, Boldt MD,
Parks EJ. Sources of fatty acids stored in liver and secreted via lipopro-
teins in patients with nonalcoholic fatty liver disease. J Clin Invest
2005;115:1343–51.
33. Parks EJ. Dietary carbohydrate’s effects on lipogenesis and the rela-
tionship of lipogenesis to blood insulin and glucose concentrations. Br J
Nutr 2002;87(suppl 2):S247–53.
34. Hudgins LC, Hellerstein MK, Seidman CE, Neese RA, Tremaroli JD,
Hirsch J. Relationship between carbohydrate-induced hypertriglycer-
idemia and fatty acid synthesis in lean and obese subjects. J Lipid Res
2000;41:595– 604.
35. Charlton M, Sreekumar R, Rasmussen D, Lindor K, Nair KS. Apoli-
poprotein synthesis in nonalcoholic steatohepatitis. Hepatology 2002;
35:898 –904.
36. Avramoglu RK, Basciano H, Adeli K. Lipid and lipoprotein dysregu-
lation in insulin resistant states. Clin Chim Acta 2006;368:1–19.
37. Cassader M, Gambino R, Musso G, et al. Postprandial triglyceride-rich
lipoprotein metabolism and insulin sensitivity in nonalcoholic steato-
hepatitis patients. Lipids 2001;36:1117–24.
38. Isomaa B, Almgren P, Tuomi T, et al. Cardiovascular morbidity and
mortality associated with the metabolic syndrome. Diabetes Care 2001;
24:683–9.
297
39. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome
and total and cardiovascular disease mortality in middle-aged men.
JAMA 2002;288:2709 –16.
40. Girman CJ, Rhodes T, Mercuri M, et al. The metabolic syndrome and
risk of major coronary events in the Scandinavian Simvastatin Survival
Study (4S) and the Air Force/Texas Coronary Atherosclerosis Preven-
tion Study (AFCAPS/TexCAPS). Am J Cardiol 2004;93:136 – 41.
41. Malik S, Wong ND, Franklin SS, et al. Impact of the metabolic syn-
drome on mortality from coronary heart disease, cardiovascular dis-
ease, and all causes in United States adults. Circulation 2004;110:
1245–50.
42. Olijhoek JK, van der Graaf Y, Banga JD, Algra A, Rabelink TJ, Vis-
seren FL. The metabolic syndrome is associated with advanced vascu-
lar damage in patients with coronary heart disease, stroke, peripheral
arterial disease or abdominal aortic aneurysm. Eur Heart J 2004;25:
342– 8.
43. Alexander CM, Landsman PB, Teutsch SM, Haffner SM. NCEP-
Downloaded from www.ajcn.org at Swets Blackwell Inc Dir Gen de Biblio/UNAM/Mexico on April 21, 2008
defined metabolic syndrome, diabetes, and prevalence of coronary
heart disease among NHANES III participants age 50 years and older.
Diabetes 2003;52:1210 – 4.
44. McNeill AM, Rosamond WD, Girman CJ, et al. The metabolic syn-
drome and 11-year risk of incident cardiovascular disease in the ath-
erosclerosis risk in communities study. Diabetes Care 2005;28:385–90.
45. Koruk M, Savas MC, Yilmaz O, et al. Serum lipids, lipoproteins and
apolipoprotein levels in patients with nonalcoholic steatohepatitis.
J Clin Gastroenterol 2003;37:177– 82.
46. Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenter-
ology 1998;114:842–5.
47. Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of
tumor necrosis factor-alpha: direct role in obesity-linked insulin resis-
tance. Science 1993;259:87–91.
48. Haukeland JW, Damas JK, Konopski Z, et al. Systemic inflammation
in nonalcoholic fatty liver disease is characterized by elevated levels of
CCL2. J Hepatol 2006;44:1167–74.
49. Diehl AM. Tumor necrosis factor and its potential role in insulin re-
sistance and nonalcoholic fatty liver disease. Clin Liver Dis 2004;8:
619 –38.
50. Nardone G, Rocco A. Probiotics: a potential target for the prevention
and treatment of steatohepatitis. J Clin Gastroenterol 2004;38:S121–2.
51. Allard JP. Other disease associations with non-alcoholic fatty liver
disease (NAFLD). Best Pract Res Clin Gastroenterol 2002;16:783–95.
52. Medina J, Fernandez-Salazar LI, Garcia-Buey L, Moreno-Otero R.
Approach to the pathogenesis and treatment of nonalcoholic steato-
hepatitis. Diabetes Care 2004;27:2057– 66.
53. Keim NL, Mares-Perlman JA. Development of hepatic steatosis and
essential fatty acid deficiency in rats with hypercaloric, fat-free paren-
teral nutrition. J Nutr 1984;114:1807–15.
54. Watkins SM, Zhu X, Zeisel SH. Phosphatidylethanolamine-N-
methyltransferase activity and dietary choline regulate liver-plasma
lipid flux and essential fatty acid metabolism in mice. J Nutr 2003;133:
3386 –91.
55. Meghelli-Bouchenak M, Belleville J, Boquillon M. Hepatic steatosis
and serum very low density lipoproteins during two types of protein
malnutrition followed by balanced refeeding. Nutrition 1989;5:321–9.
56. Ip E, Farrell GC, Robertson G, Hall P, Kirsch R, Leclercq I. Central role
of PPAR␣-dependent hepatic lipid turnover in dietary steatohepatitis in
mice. Hepatology 2003;38:123–32.
57. Bugianesi E, Marzocchi R, Villanova N, Marchesini G. Non-alcoholic
fatty liver disease/non-alcoholic steatohepatitis (NAFLD/NASH):
treatment. Best Pract Res Clin Gastroenterol 2004;18:1105–16.
58. Mattar SG, Velcu LM, Rabinovitz M, et al. Surgically-induced weight
loss significantly improves nonalcoholic fatty liver disease and the
metabolic syndrome. Ann Surg 2005;242:610 –7;discussion 618 –20.
59. Clark JM, Alkhuraishi AR, Solga SF, Alli P, Diehl AM, Magnuson TH.
Roux-en-Y gastric bypass improves liver histology in patients with
non-alcoholic fatty liver disease. Obes Res 2005;13:1180 – 6.
60. Clark JM. Weight loss as a treatment for nonalcoholic fatty liver dis-
ease. J Clin Gastroenterol 2006;40:S39 – 43.
61. Oliveira CP, Faintuch J, Rascovski A, et al. Lipid peroxidation in
bariatric candidates with nonalcoholic fatty liver disease (NAFLD)—
preliminary findings. Obes Surg 2005;15:502–5.
62. Jaskiewicz K, Raczynska S, Rzepko R, Sledzinski Z. Nonalcoholic
fatty liver disease treated by gastroplasty. Dig Dis Sci 2006;51:21– 6.
298 ZIVKOVIC ET AL
63. Shaffer EA. Bariatric surgery: a promising solution for nonalcoholic
steatohepatitis in the very obese. J Clin Gastroenterol 2006;40:S44 –50.
64. Wang D, Wei Y, Pagliassotti MJ. Saturated fatty acids promote endo-
plasmic reticulum stress and liver injury in rats with hepatic steatosis.
Endocrinology 2006;147:943–51.
65. Lichtenstein AH. Thematic review series: patient-oriented research.
Dietary fat, carbohydrate, and protein: effects on plasma lipoprotein
patterns. J Lipid Res 2006;47:1661–7.
66. Sacks FM, Katan M. Randomized clinical trials on the effects of dietary
fat and carbohydrate on plasma lipoproteins and cardiovascular dis-
ease. Am J Med 2002;113(suppl 9B):13S–24S.
67. Tanasescu M, Cho E, Manson JE, Hu FB. Dietary fat and cholesterol
and the risk of cardiovascular disease among women with type 2 dia-
betes. Am J Clin Nutr 2004;79:999 –1005.
68. Musso G, Gambino R, De Michieli F, et al. Dietary habits and their
relations to insulin resistance and postprandial lipemia in nonalcoholic
steatohepatitis. Hepatology 2003;37:909 –16.
69. German JB, Dillard CJ. Saturated fats: what dietary intake? Am J Clin
Nutr 2004;80:550 –9.
70. Lapointe A, Couillard C, Lemieux S. Effects of dietary factors on
oxidation of low-density lipoprotein particles. J Nutr Biochem 2006;
17:645–58.
71. Williams CM. Beneficial nutritional properties of olive oil: implica-
tions for postprandial lipoproteins and factor VII. Nutr Metab Cardio-
vasc Dis 2001;11:51– 6.
72. Rajaram S, Burke K, Connell B, Myint T, Sabate J. A monounsaturated
fatty acid-rich pecan-enriched diet favorably alters the serum lipid
profile of healthy men and women. J Nutr 2001;131:2275–9.
73. Kris-Etherton PM, Pearson TA, Wan Y, et al. High-monounsaturated
fatty acid diets lower both plasma cholesterol and triacylglycerol con-
centrations. Am J Clin Nutr 1999;70:1009 –15.
74. Julius U. Fat modification in the diabetes diet. Exp Clin Endocrinol
Diabetes 2003;111:60 –5.
75. Rodriguez-Villar C, Perez-Heras A, Mercade I, Casals E, Ros E. Com-
parison of a high-carbohydrate and a high-monounsaturated fat, olive
oil-rich diet on the susceptibility of LDL to oxidative modification in
subjects with type 2 diabetes mellitus. Diabet Med 2004;21:142–9.
76. Laaksonen DE, Nyyssonen K, Niskanen L, Rissanen TH, Salonen JT.
Prediction of cardiovascular mortality in middle-aged men by dietary
and serum linoleic and polyunsaturated fatty acids. Arch Intern Med
2005;165:193–9.
77. Djousse L, Folsom AR, Province MA, Hunt SC, Ellison RC. Dietary
linolenic acid and carotid atherosclerosis: the National Heart, Lung,
and Blood Institute Family Heart Study. Am J Clin Nutr 2003;77:819 –
25.
78. Heine RJ, Mulder C, Popp-Snijders C, van der Meer J, van der Veen
EA. Linoleic-acid-enriched diet: long-term effects on serum lipopro-
tein and apolipoprotein concentrations and insulin sensitivity in
noninsulin-dependent diabetic patients. Am J Clin Nutr 1989;49:448 –
56.
79. Ghafoorunissa, Ibrahim A, Natarajan S. Substituting dietary linoleic
acid with alpha-linolenic acid improves insulin sensitivity in sucrose
fed rats. Biochim Biophys Acta 2005;1733:67–75.
80. Wijendran V, Hayes KC. Dietary n-6 and n-3 fatty acid balance and
cardiovascular health. Annu Rev Nutr 2004;24:597– 615.
81. Goheen SC, Larkin EC, Rao GA. Severe fatty liver in rats fed a fat-free
ethanol diet, and its prevention by small amounts of dietary arachido-
nate. Lipids 1983;18:285–90.
82. Werner A, Havinga R, Bos T, Bloks VW, Kuipers F, Verkade HJ.
Essential fatty acid deficiency in mice is associated with hepatic ste-
atosis and secretion of large VLDL particles. Am J Physiol Gastrointest
Liver Physiol 2005;288:G1150 – 8.
83. Alwayn IP, Javid PJ, Gura KM, Nose V, Ollero M, Puder M. Do
polyunsaturated fatty acids ameliorate hepatic steatosis in obese mice
by SREPB-1 suppression or by correcting essential fatty acid defi-
ciency. Hepatology 2004;39:1176 –7; author reply 1177– 8.
84. Cazeils JL, Bouillier-Oudot M, Auvergne A, Candau M, Babile R.
Lipid composition of hepatocyte plasma membranes from geese over-
fed with corn. Lipids 1999;34:937– 42.
85. Bouziane M, Prost J, Belleville J. Dietary protein deficiency affects
nҀ3 and nҀ6 polyunsaturated fatty acids hepatic storage and very low
density lipoprotein transport in rats on different diets. Lipids 1994;29:
265–72.
86. Sheldon GF, Peterson SR, Sanders R. Hepatic dysfunction during hy-
peralimentation. Arch Surg 1978;113:504 – 8.
87. Lombardo YB, Chicco AG. Effects of dietary polyunsaturated nҀ3
fatty acids on dyslipidemia and insulin resistance in rodents and hu-
mans. A review. J Nutr Biochem 2006;17:1–13.
88. Clarke SD, Jump DB. Polyunsaturated fatty acid regulation of hepatic
gene transcription. Lipids 1996;31(suppl):S7–11.
89. Kim HJ, Takahashi M, Ezaki O. Fish oil feeding decreases mature sterol
regulatory element-binding protein 1 (SREBP-1) by down-regulation
of SREBP-1c mRNA in mouse liver. A possible mechanism for down-
regulation of lipogenic enzyme mRNAs. J Biol Chem
1999;274:25892– 8.
90. Tapsell LC, Gillen LJ, Patch CS, et al. Including walnuts in a low-fat/
modified-fat diet improves HDL cholesterol-to-total cholesterol ratios
in patients with type 2 diabetes. Diabetes Care 2004;27:2777– 83.
91. Ros E, Nunez I, Perez-Heras A, et al. A walnut diet improves endothe-
lial function in hypercholesterolemic subjects: a randomized crossover
Downloaded from www.ajcn.org at Swets Blackwell Inc Dir Gen de Biblio/UNAM/Mexico on April 21, 2008
trial. Circulation 2004;109:1609 –14.
92. Capanni M, Calella F, Biagini MR, et al. Prolonged nҀ3 polyunsatu-
rated fatty acid supplementation ameliorates hepatic steatosis in pa-
tients with non-alcoholic fatty liver disease: a pilot study. Aliment
Pharmacol Ther 2006;23:1143–51.
93. Spadaro L, Magliocco O, Spampinato D, et al. 738 Omega-3 polyun-
saturated fatty acids: a pilot trial in non-alcoholic fatty liver disease.
J Hepatol 2006;44:S264 –S264.
94. Mensink RP. Metabolic and health effects of isomeric fatty acids. Curr
Opin Lipidol 2005;16:27–30.
95. Tricon S, Burdge GC, Jones EL, et al. Effects of dairy products natu-
rally enriched with cis-9,trans-11 conjugated linoleic acid on the blood
lipid profile in healthy middle-aged men. Am J Clin Nutr 2006;83:
744 –53.
96. Lopez-Garcia E, Schulze MB, Meigs JB, et al. Consumption of trans
fatty acids is related to plasma biomarkers of inflammation and endo-
thelial dysfunction. J Nutr 2005;135:562– 6.
97. Mozaffarian D. Trans fatty acids— effects on systemic inflammation
and endothelial function. Atheroscler Suppl 2006;7:29 –32.
98. Tricon S, Burdge GC, Kew S, et al. Opposing effects of cis-9,trans-11
and trans-10,cis-12 conjugated linoleic acid on blood lipids in healthy
humans. Am J Clin Nutr 2004;80:614 –20.
99. US Food and Drug Administration CfFSaAN. Food labeling; trans fatty
acids in nutrition labeling; consumer research to consider nutrient con-
tent and health claims and possible footnote or disclosure statements;
final rule and proposed rule. 2006. Internet: http://www.cfsan.fda.gov/
앑acrobat/fr03711a.pdf (accessed 3 June 2007).
100. Jenkins DJ, Kendall CW, Vuksan V, et al. Soluble fiber intake at a dose
approved by the US Food and Drug Administration for a claim of health
benefits: serum lipid risk factors for cardiovascular disease assessed in
a randomized controlled crossover trial. Am J Clin Nutr
2002;75:834 –9.
101. Naumann E, van Rees AB, Onning G, Oste R, Wydra M, Mensink RP.
Beta-glucan incorporated into a fruit drink effectively lowers serum
LDL-cholesterol concentrations. Am J Clin Nutr 2006;83:601–5.
102. US Food and Drug Administration CfFSaAN. A food labeling guide–
appendix C–approved health claims. 1994. Internet: http://
www.cfsan.fda.gov/앑dms/flg-6c.html (accessed 3 June 2007).
103. Jenkins DJ, Wolever TM, Taylor RH, et al. Slow release dietary car-
bohydrate improves second meal tolerance. Am J Clin Nutr 1982;35:
1339 – 46.
104. Anderson JW, Randles KM, Kendall CW, Jenkins DJ. Carbohydrate
and fiber recommendations for individuals with diabetes: a quantitative
assessment and meta-analysis of the evidence. J Am Coll Nutr 2004;
23:5–17.
105. Brighenti F, Benini L, Del Rio D, et al. Colonic fermentation of indi-
gestible carbohydrates contributes to the second-meal effect. Am J Clin
Nutr 2006;83:817–22.
106. Basciano H, Federico L, Adeli K. Fructose, insulin resistance, and
metabolic dyslipidemia. Nutr Metab (Lond) 2005;2:5.
107. Faeh D, Minehira K, Schwarz JM, Periasamy R, Park S, Tappy L. Effect
of fructose overfeeding and fish oil administration on hepatic de novo
lipogenesis and insulin sensitivity in healthy men. Diabetes 2005;54:
1907–13.
108. Haidari M, Leung N, Mahbub F, et al. Fasting and postprandial over-
production of intestinally derived lipoproteins in an animal model of
insulin resistance. Evidence that chronic fructose feeding in the hamster
 DIETS FOR THE METABOLIC SYNDROME AND NAFLD
is accompanied by enhanced intestinal de novo lipogenesis and
ApoB48-containing lipoprotein overproduction. J Biol Chem 2002;
277:31646 –55.
109. McDevitt RM, Bott SJ, Harding M, Coward WA, Bluck LJ, Prentice
AM. De novo lipogenesis during controlled overfeeding with sucrose
or glucose in lean and obese women. Am J Clin Nutr 2001;74:737– 46.
110. Havel PJ. Dietary fructose: implications for dysregulation of energy
homeostasis and lipid/carbohydrate metabolism. Nutr Rev 2005;63:
133–57.
111. Teff KL, Elliott SS, Tschop M, et al. Dietary fructose reduces circu-
lating insulin and leptin, attenuates postprandial suppression of ghrelin,
and increases triglycerides in women. J Clin Endocrinol Metab 2004;
89:2963–72.
112. Popkin BM, Armstrong LE, Bray GM, Caballero B, Frei B, Willett WC.
A new proposed guidance system for beverage consumption in the
United States. Am J Clin Nutr 2006;83:529 – 42.
113. Diraison F, Moulin P, Beylot M. Contribution of hepatic de novo
lipogenesis and reesterification of plasma non esterified fatty acids to
plasma triglyceride synthesis during non-alcoholic fatty liver disease.
Diabetes Metab 2003;29:478 – 85.
114. Schwarz JM, Linfoot P, Dare D, Aghajanian K. Hepatic de novo lipo-
genesis in normoinsulinemic and hyperinsulinemic subjects consum-
ing high-fat, low-carbohydrate and low-fat, high-carbohydrate isoen-
ergetic diets. Am J Clin Nutr 2003;77:43–50.
115. Lockwood DH, Amatruda JM, Moxley RT, Pozefsky T, Boitnott JK.
Effect of oral amino acid supplementation on liver disease after jeju-
noileal bypass for morbid obesity. Am J Clin Nutr 1977;30:58 – 63.
116. Ahmed FE. Effect of diet on progression of chronic renal disease. J Am
Diet Assoc 1991;91:1266 –70.
117. Meyer TW, Anderson S, Brenner BM. Dietary protein intake and pro-
gressive glomerular sclerosis: the role of capillary hypertension and
hyperperfusion in the progression of renal disease. Ann Intern Med
1983;98:832– 8.
118. Blachley JD. The role of dietary protein in the progression and symp-
tomatology of chronic renal failure. Am J Med Sci 1984;288:228 –34.
119. Levey AS, Greene T, Beck GJ, et al. Dietary protein restriction and the
progression of chronic renal disease: what have all of the results of the
MDRD study shown? Modification of Diet in Renal Disease Study
group. J Am Soc Nephrol 1999;10:2426 –39.
120. Klahr S, Levey AS, Beck GJ, et al. The effects of dietary protein
restriction and blood-pressure control on the progression of chronic
renal disease. Modification of Diet in Renal Disease Study Group.
N Engl J Med 1994;330:877– 84.
121. USDA. Dietary guidelines for Americans. US Department of Agricul-
ture, Health and Human Services, 2005.
122. Farrell GC, Larter CZ. Nonalcoholic fatty liver disease: from steatosis
to cirrhosis. Hepatology 2006;43(suppl):S99 –112.
123. Solga S, Alkhuraishe AR, Clark JM, et al. Dietary composition and
nonalcoholic fatty liver disease. Dig Dis Sci 2004;49:1578 – 83.
124. ADA. American Dietetic Association (ADA) nutrition care manual.
2006. Internet: www.nutritioncaremanual.org (accessed 3 June 2007).
125. AmericaOnTheMove. 2003. Internet: http://aom.americaonthemove.
org (accessed 3 June 2007).
126. Donati G, Stagni B, Piscaglia F, et al. Increased prevalence of fatty liver
in arterial hypertensive patients with normal liver enzymes: role of
insulin resistance. Gut 2004;53:1020 –3.
127. Brea A, Mosquera D, Martin E, Arizti A, Cordero JL, Ros E. Nonal-
coholic fatty liver disease is associated with carotid atherosclerosis: a
case-control study. Arterioscler Thromb Vasc Biol 2005;25:1045–50.
128. Turhan H, Yasar AS, Basar N, Bicer A, Erbay AR, Yetkin E. High
prevalence of metabolic syndrome among young women with prema-
ture coronary artery disease. Coron Artery Dis 2005;16:37– 40.
129. AHA. Dietary guidelines for healthy American adults. Dallas, TX:
American Heart Association, 2005.
130. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management
of the metabolic syndrome: an American Heart Association/National
Heart, Lung, and Blood Institute Scientific Statement. Circulation
2005;112:2735–52.
131. NHLBI. Third report of the National Cholesterol Education Program
(NCEP) Expert Panel on Detection, Evaluation, and Treatment of High
Blood Cholesterol in Adults (Adult Treatment Panel III) Executive
Summary. Bethesda, MD: National Institutes of Health, 2001.
132. NHLBI. National Cholesterol Education Program Description. 2006.
299
Internet: http://www.nhlbi.nih.gov/about/ncep/ncep_pd.htm (ac-
cessed 3 June 2007).
133. NHLBI. Therapeutic Lifestyle Changes (TLC) diet guidelines. 2006.
Internet: http://www.nhlbi.nih.gov (accessed 3 June 2007).
134. Lefevre M, Champagne CM, Tulley RT, Rood JC, Most MM. Individ-
ual variability in cardiovascular disease risk factor responses to low-fat
and low-saturated-fat diets in men: body mass index, adiposity, and
insulin resistance predict changes in LDL cholesterol. Am J Clin Nutr
2005;82:957– 63; quiz 1145– 6.
135. NIH-HHS-NHLBI. The DASH diet action plan. Bethesda, MD: Na-
tional Institutes of Health, Department of Health and Human Services,
National Heart, Lung and Blood Institute, 2006.
136. Appel LJ, Brands MW, Daniels SR, Karanja N, Elmer PJ, Sacks FM.
Dietary approaches to prevent and treat hypertension: a scientific state-
ment from the American Heart Association. Hypertension 2006;47:
296 –308.
137. Conlin PR. The dietary approaches to stop hypertension (DASH) clin-
Downloaded from www.ajcn.org at Swets Blackwell Inc Dir Gen de Biblio/UNAM/Mexico on April 21, 2008
ical trial: implications for lifestyle modifications in the treatment of
hypertensive patients. Cardiol Rev 1999;7:284 – 8.
138. Windhauser MM, Evans MA, McCullough ML, et al. Dietary adher-
ence in the Dietary Approaches to Stop Hypertension trial. DASH
Collaborative Research Group. J Am Diet Assoc 1999;99(suppl):S76 –
83.
139. ADA. Using the diabetes food pyramid. 2006. Internet: http://www.
diabetes.org (accessed 3 June 2007).
140. ADA. American Diabetes Association position statement: evidence-
based nutrition principles and recommendations for the treatment and
prevention of diabetes and related complications. J Am Diet Assoc
2002;102:109 –18.
141. Serra-Majem L, Roman B, Estruch R. Scientific evidence of interven-
tions using the Mediterranean diet: a systematic review. Nutr Rev
2006;64(suppl):S27– 47.
142. Meydani M. A Mediterranean-style diet and metabolic syndrome. Nutr
Rev 2005;63:312– 4.
143. Aude YW, Mego P, Mehta JL. Metabolic syndrome: dietary interven-
tions. Curr Opin Cardiol 2004;19:473–9.
144. Grundy SM, Abate N, Chandalia M. Diet composition and the meta-
bolic syndrome: what is the optimal fat intake? Am J Med 2002;
113(suppl 9B):25S–29S.
145. Panagiotakos DB, Polychronopoulos E. The role of Mediterranean diet
in the epidemiology of metabolic syndrome; converting epidemiology
to clinical practice. Lipids Health Dis 2005;4:7.
146. Hung T, Sievenpiper JL, Marchie A, Kendall CW, Jenkins DJ. Fat
versus carbohydrate in insulin resistance, obesity, diabetes and cardio-
vascular disease. Curr Opin Clin Nutr Metab Care 2003;6:165–76.
147. Esposito K, Marfella R, Ciotola M, et al. Effect of a Mediterranean-
style diet on endothelial dysfunction and markers of vascular inflam-
mation in the metabolic syndrome: a randomized trial. JAMA 2004;
292:1440 – 6.
148. Ornish D. Dr. Dean Ornish’s program for reversing heart disease: the
only system scientifically proven to reverse heart disease without drugs
or surgery. 1st ed. New York, NY: Random House, 1990.
149. Gould KL, Ornish D, Kirkeeide R, et al. Improved stenosis geometry by
quantitative coronary arteriography after vigorous risk factor modifi-
cation. Am J Cardiol 1992;69:845–53.
150. Ornish D, Brown SE, Billings JH, et al. Can lifestyle changes reverse
coronary heart disease? The Lifestyle Heart Trial. Lancet 1990;336:
129 –33.
151. Ornish D, Scherwitz LW, Billings JH, et al. Intensive lifestyle changes
for reversal of coronary heart disease. JAMA 1998;280:2001–7.
152. Atkins RC. Dr. Atkins’ new diet revolution. Revised ed. New York,
NY: Avon Books, 1998.
153. Foster GD, Wyatt HR, Hill JO, et al. A randomized trial of a low-
carbohydrate diet for obesity. N Engl J Med 2003;348:2082–90.
154. McAuley KA, Hopkins CM, Smith KJ, et al. Comparison of high-fat
and high-protein diets with a high-carbohydrate diet in insulin-resistant
obese women. Diabetologia 2005;48:8 –16.
155. Sears B. The Zone: a Dietary road map. New York, NY: HarperCollins
Publishers, 1995.
156. Noakes M, Keogh JB, Foster PR, Clifton PM. Effect of an energy-
restricted, high-protein, low-fat diet relative to a conventional high-
carbohydrate, low-fat diet on weight loss, body composition, nutri-
tional status, and markers of cardiovascular health in obese women.
Am J Clin Nutr 2005;81:1298 –306.
300 ZIVKOVIC ET AL
157. Johnston CS, Tjonn SL, Swan PD, White A, Hutchins H, Sears B.
Ketogenic low-carbohydrate diets have no metabolic advantage over
nonketogenic low-carbohydrate diets. Am J Clin Nutr 2006;83:1055–
61.
158. Pavkov ME, Bennett PH, Knowler WC, Krakoff J, Sievers ML, Nelson
RG. Effect of youth-onset type 2 diabetes mellitus on incidence of
end-stage renal disease and mortality in young and middle-aged Pima
Indians. JAMA 2006;296:421– 6.
159. Agatston A. The South Beach diet: the delicious, doctor-designed,
foolproof plan for fast and healthy weight loss. New York, NY: Ran-
dom House, 2003.
160. Aude YW, Agatston AS, Lopez-Jimenez F, et al. The national choles-
terol education program diet vs a diet lower in carbohydrates and higher
in protein and monounsaturated fat: a randomized trial. Arch Intern
Med 2004;164:2141– 6.
161. Weight Watchers. 2006. Internet: http://www.weightwatchers.com/
plan/turnaround/index.aspx (accessed 3 June 2007).
162. Dansinger ML, Gleason JA, Griffith JL, Selker HP, Schaefer EJ. Com-
parison of the Atkins, Ornish, Weight Watchers, and Zone diets for
weight loss and heart disease risk reduction: a randomized trial. JAMA
2005;293:43–53.
163. Franklin TL, Kolasa KM, Griffin K, Mayo C, Badenhop DT. Adher-
ence to very-low-fat diet by a group of cardiac rehabilitation patients in
the rural southeastern United States. Arch Fam Med 1995;4:551– 4.
164. Twardella D, Merx H, Hahmann H, Wusten B, Rothenbacher D,
Brenner H. Long term adherence to dietary recommendations after
inpatient rehabilitation: prospective follow up study of patients with
coronary heart disease. Heart 2006;92:635– 40.
165. Noakes M, Clifton P. Weight loss, diet composition and cardiovascular
risk. Curr Opin Lipidol 2004;15:31–5.
166. Brinkworth GD, Noakes M, Keogh JB, Luscombe ND, Wittert GA,
Clifton PM. Long-term effects of a high-protein, low-carbohydrate diet
on weight control and cardiovascular risk markers in obese hyperinsu-
linemic subjects. Int J Obes Relat Metab Disord 2004;28:661–70.
167. Byberg L, Zethelius B, McKeigue PM, Lithell HO. Changes in physical
activity are associated with changes in metabolic cardiovascular risk
factors. Diabetologia 2001;44:2134 –9.
168. Spate-Douglas T, Keyser RE. Exercise intensity: its effect on the high-
density lipoprotein profile. Arch Phys Med Rehabil 1999;80:691–5.
169. Deckelbaum RJ, Akabas SR. nҀ3 Fatty acids and cardiovascular dis-
ease: navigating toward recommendations. Am J Clin Nutr 2006;84:
1–2.
170. Wang C, Harris WS, Chung M, et al. nҀ3 Fatty acids from fish or
fish-oil supplements, but not ␣-linolenic acid, benefit cardiovascular
disease outcomes in primary- and secondary-prevention studies: a sys-
tematic review. Am J Clin Nutr 2006;84:5–17.
171. Castro IA, Barroso LP, Sinnecker P. Functional foods for coronary
heart disease risk reduction: a meta-analysis using a multivariate ap-
proach. Am J Clin Nutr 2005;82:32– 40.
172. Albert CM, Campos H, Stampfer MJ, et al. Blood levels of long-chain
nҀ3 fatty acids and the risk of sudden death. N Engl J Med 2002;346:
1113– 8.
173. Marchioli R, Barzi F, Bomba E, et al. Early protection against sudden
death by nҀ3 polyunsaturated fatty acids after myocardial infarction:
time-course analysis of the results of the Gruppo Italiano per lo Studio
della Sopravvivenza nell’Infarto Miocardico (GISSI)-Prevenzione.
Circulation 2002;105:1897–903.
174. Leaf A, Kang JX, Xiao YF, Billman GE, Voskuyl RA. Experimental
studies on antiarrhythmic and antiseizure effects of polyunsaturated
fatty acids in excitable tissues. J Nutr Biochem 1999;10:440 – 8.
175. Leaf A, Kang JX, Xiao YF, Billman GE, Voskuyl RA. Functional and
electrophysiologic effects of polyunsaturated fatty acids on excitable
tissues: heart and brain. Prostaglandins Leukot Essent Fatty Acids
1999;60:307–12.
176. Leaf A, Kang JX, Xiao YF, Billman GE. nҀ3 fatty acids in the pre-
vention of cardiac arrhythmias. Lipids 1999;34(suppl):S187–9.
177. Billman GE, Kang JX, Leaf A. Prevention of ischemia-induced cardiac
sudden death by nҀ3 polyunsaturated fatty acids in dogs. Lipids 1997;
32:1161– 8.
178. Renaud S, de Lorgeril M, Delaye J, et al. Cretan Mediterranean diet for
prevention of coronary heart disease. Am J Clin Nutr 1995;61(suppl):
1360S–7S.
179. Jenkins DJ, Josse AR, Labelle R, Marchie A, Augustin LS, Kendall
CW. Nonalcoholic fatty liver, nonalcoholic steatohepatitis, ectopic fat,
and the glycemic index. Am J Clin Nutr 2006;84:3– 4.
180. Valtuena S, Pellegrini N, Ardigo D, et al. Dietary glycemic index and
liver steatosis. Am J Clin Nutr 2006;84:136 – 42.
181. Laaksonen DE, Toppinen LK, Juntunen KS, et al. Dietary carbohydrate
modification enhances insulin secretion in persons with the metabolic
syndrome. Am J Clin Nutr 2005;82:1218 –27.
182. Brynes AE, Mark Edwards C, Ghatei MA, et al. A randomised four-
Downloaded from www.ajcn.org at Swets Blackwell Inc Dir Gen de Biblio/UNAM/Mexico on April 21, 2008
intervention crossover study investigating the effect of carbohydrates
on daytime profiles of insulin, glucose, non-esterified fatty acids and
triacylglycerols in middle-aged men. Br J Nutr 2003;89:207–18.
183. Bianchi G, Marzocchi R, Agostini F, Marchesini G. Update on
branched-chain amino acid supplementation in liver diseases. Curr
Opin Gastroenterol 2005;21:197–200.
184. Luscombe-Marsh ND, Noakes M, Wittert GA, Keogh JB, Foster P,
Clifton PM. Carbohydrate-restricted diets high in either monounsatu-
rated fat or protein are equally effective at promoting fat loss and
improving blood lipids. Am J Clin Nutr 2005;81:762–72.
185. Wei Y, Wang D, Topczewski F, Pagliassotti MJ. Saturated fatty acids
induce endoplasmic reticulum stress and apoptosis independently of
ceramide in liver cells. Am J Physiol Endocrinol Metab 2006;291:
E275– 81.
186. Sarkkinen E, Schwab U, Niskanen L, et al. The effects of
monounsaturated-fat enriched diet and polyunsaturated-fat enriched
diet on lipid and glucose metabolism in subjects with impaired glucose
tolerance. Eur J Clin Nutr 1996;50:592– 8.
187. Cox C, Mann J, Sutherland W, Ball M. Individual variation in plasma
cholesterol response to dietary saturated fat. BMJ 1995;311:1260 – 4.
188. Biddinger SB, Almind K, Miyazaki M, Kokkotou E, Ntambi JM, Kahn
CR. Effects of diet and genetic background on sterol regulatory
element-binding protein-1c, stearoyl-CoA desaturase 1, and the devel-
opment of the metabolic syndrome. Diabetes 2005;54:1314 –23.
189. Lin J, Yang R, Tarr PT, et al. Hyperlipidemic effects of dietary saturated
fats mediated through PGC-1beta coactivation of SREBP. Cell 2005;
120:261–73.
190. Malhi H, Bronk SF, Werneburg NW, Gores GJ. Free fatty acids induce
JNK-dependent hepatocyte lipoapoptosis. J Biol Chem
2006;281:12093–101.
191. Keys A, Menotti A, Karvonen MJ, et al. The diet and 15-year death rate
in the seven countries study. Am J Epidemiol 1986;124:903–15.
192. Levy AS, Heaton AW. Weight control practices of U.S. adults trying to
lose weight. Ann Intern Med 1993;119:661– 6.
193. Winett RA, Tate DF, Anderson ES, Wojcik JR, Winett SG. Long-term
weight gain prevention: a theoretically based Internet approach. Prev
Med 2005;41:629 – 41.
194. Fletcher B, Berra K, Ades P, et al. Managing abnormal blood lipids: a
collaborative approach. Circulation 2005;112:3184 –209.
195. Wing RR, Venditti E, Jakicic JM, Polley BA, Lang W. Lifestyle inter-
vention in overweight individuals with a family history of diabetes.
Diabetes Care 1998;21:350 –9.
196. Becker DM, Raqueno JV, Yook RM, et al. Nurse-mediated cholesterol
management compared with enhanced primary care in siblings of in-
dividuals with premature coronary disease. Arch Intern Med 1998;158:
1533–9.