STEATOHEPATITIS/METABOLIC LIVER DISEASE

Randomized Comparison of Reduced Fat and Reduced

Carbohydrate Hypocaloric Diets on Intrahepatic Fat in
Overweight and Obese Human Subjects
Sven Haufe,1,2 Stefan Engeli,2 Petra Kast,1 Jana Böhnke,1 Wolfgang Utz,3 Verena Haas,1 Mario Hermsdorf,1
Anja Mähler,1 Susanne Wiesner,1 Andreas L. Birkenfeld,4 Henrike Sell,5 Christoph Otto,1 Heidrun Mehling,1
Friedrich C. Luft,1 Juergen Eckel,5 Jeanette Schulz-Menger,3 Michael Boschmann,1 and Jens Jordan2

Obesity-related hepatic steatosis is a major risk factor for metabolic and cardiovascular dis-
ease. Fat reduced hypocaloric diets are able to relieve the liver from ectopically stored lip-
ids. We hypothesized that the widely used low carbohydrate hypocaloric diets are similarly
effective in this regard. A total of 170 overweight and obese, otherwise healthy subjects
were randomized to either reduced carbohydrate (n 5 84) or reduced fat (n 5 86), total
energy restricted diet (230% of energy intake before diet) for 6 months. Body composition
was estimated by bioimpedance analyses and abdominal fat distribution by magnetic reso-
nance tomography. Subjects were also submitted to fat spectroscopy of liver and oral glu-
cose tolerance testing. In all, 102 subjects completed the diet intervention with
measurements of intrahepatic lipid content. Both hypocaloric diets decreased body weight,
total body fat, visceral fat, and intrahepatic lipid content. Subjects with high baseline intra-
hepatic lipids (>5.56%) lost !7-fold more intrahepatic lipids compared with those with
low baseline values (<5.56%) irrespective of diet composition. In contrast, changes in vis-
ceral fat mass and insulin sensitivity were similar between subgroups, with low and high
baseline intrahepatic lipids. Conclusion: A prolonged hypocaloric diet low in carbohydrates
and high in fat has the same beneficial effects on intrahepatic lipid accumulation as the tra-
ditional low-fat hypocaloric diet. The decrease in intrahepatic lipids appears to be inde-
pendent of visceral fat loss and is not tightly coupled with changes in whole body insulin
sensitivity during 6 months of an energy restricted diet. (HEPATOLOGY 2011;53:1504-1514)

E
xcessive hepatic fat content contributes to obe-
sity-associated metabolic disease.1-3 Indeed, the
amount of intrahepatic lipids (IHL) is an im-
portant determinant for whole-body and tissue-insulin
sensitivity,2,4 independent of total body or visceral
fat.5,6 Moreover, excessive hepatic fat accumulation
predisposes to nonalcoholic steatohepatitis, which may
progress to cirrhosis and hepatic cancer.7 Therefore,
interventions reducing hepatic fat content address the
root cause for both obesity-associated metabolic and

Abbreviations: ALT, alanine aminotransferase; C-ISI, composite insulin-sensitivity index; CK-18, cytokeratin 18 fragments; HOMA, homeostasis model
assessment index; IHL, intrahepatic lipids; TGF-b1, transforming growth factor beta 1.
From the 1Franz Volhard Clinical Research Center at the Experimental and Clinical Research Center, Charite´ University Medical School and Max Delbrück Center
for Molecular Medicine, Berlin, Germany; 2Institute of Clinical Pharmacology, Hannover Medical School, Hannover, Germany; 3Franz Volhard Clinic, Charite´
University Medical School and Helios Klinikum, Berlin, Germany; 4Department of Endocrinology, Diabetes and Nutrition, Charite´ University Medical School, Berlin,
Germany, and German Institute of Human Nutrition, Potsdam-Rehbrücke, Germany; 5Institute of Clinical Biochemistry and Pathobiochemistry, German Diabetes
Center, Düsseldorf, Germany.
Received October 26, 2010; accepted February 2, 2011.
This study was part of a joint project between metanomics GmbH (Berlin, Germany) and Charite´ - University Medical School which was supported by the
Federal Ministry of Education and Research (BMBF-0313868) and in part by the Commission of the European Communities (Collaborative Project ADAPT,
Contract No. HEALTH-F2-2008-201100) and the German Obesity Network of Competence (Collaborative Project ADIPOSETARGET, 01 Gl0830) (to S.E. and
J.J). Clinical trial number: ClinicalTrials.gov NCT00956566
Address reprint requests to: Jens Jordan, M.D., Institute for Clinical Pharmacology, Hannover Medical School, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.
E-mail: jordan.jens@mh-hannover.de; fax: þ49-511-532 2750.
Copyright VC 2011 by the American Association for the Study of Liver Diseases.

View this article online at wileyonlinelibrary.com.

DOI 10.1002/hep.24242
Potential conflict of interest: Nothing to report.
Additional Supporting Information may be found in the online version of this article.

1504

HEPATOLOGY, Vol. 53, No. 5, 2011
liver disease. Lifestyle interventions including hypo-
caloric diets are a cornerstone for obesity management
because diet-induced weight loss improves insulin
action8,9 and reduces type 2 diabetes mellitus inci-
dence.10 Moreover, weight reduction through caloric
restriction improved hepatic steatosis.11,12 In addition
to energy balance, macronutrient composition may
affect liver fat content. Excessive fat ingestion is a
commonly applied model to induce hepatic steatosis
in laboratory animals.13 Indeed, short-term high-fat
feeding increased hepatic fat content in rodents14 and
in human subjects.15-17 The response involves lipo-
genic transcription factor activation and increased
dietary lipid delivery.14 On the other hand, low-fat
hypocaloric dieting reduced hepatic fat content in
obese subjects.8 Excessive carbohydrate ingestion also
increased hepatic fat in human subjects.18 Yet carbohy-
drate and fat feeding differentially regulates genes
involved in hepatic lipogenesis, fatty acid uptake, and
fat oxidation.19 We determined whether or not a
reduced carbohydrate diet is as effective in reducing
hepatic lipid content in obese individuals as a low-fat
hypocaloric diet. The issue is clinically relevant because
low-carbohydrate hypocaloric diets are popular in the
treatment of obesity.20
Patients and Methods
Patients. We randomized 170 overweight and
obese otherwise healthy subjects (135 women, 35
men) in our study. All subjects completed a compre-
hensive medical evaluation including a dietary record
for 7 consecutive days before study participation.
They ingested no medications. Subjects reporting
more than 2 hours of physical activity per week
assessed with a physical activity record over 7 consec-
utive days were excluded. Physical activity was
defined as any scheduled exercise training performed
by the subjects during the 7 days. We also excluded
subjects consuming >20 g/day of alcohol, with type
2 diabetes, acute or chronic infections, any diseases
requiring treatment, and pregnant or nursing women.
Subjects were advised to continue their current physi-
cal activity level throughout the study. This study
was carried out in accordance with the Declaration of
Helsinki and current guidelines of good clinical prac-
tice. Our Institutional Review Board approved the
study and written informed consent was obtained
before entry.
Study Design. This was a prospective, randomized
study conducted in an academic clinical research center
between March 2007 and June 2010. The data were
15273350, 2011, 5, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.24242 by Jordan Hinari NPL, Wiley Online Library on [20/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
HAUFE ET AL. 1505
generated as part of the B-SMART study (Clinical-
Trials.gov Identifier: NCT00956566), which compared
weight loss and associated metabolic and cardiovascular
markers with reduced carbohydrate and reduced fat
hypocaloric diets. Subjects underwent thorough an-
thropometric, metabolic, and exercise testing before
and after 6 months on a hypocaloric diet with either
reduced carbohydrate or reduced fat content. Except
for the dieticians, study nurses and physicians were
blinded for the treatment assignment. For allocation of
the subjects, a computer-generated list of random
numbers was used. The randomization sequence was
created using SPSS 18 (Chicago, IL) statistical software
and subjects were assigned to reduced carbohydrate or
reduced fat diet with a 1:1 allocation using random
block sizes of 2, 4, and 6. Study nurses and physicians
screening and enrolling volunteers were blinded for the
randomization sequence.
After randomization, subjects provided a baseline 7-
day food protocol, which was analyzed for macro- and
micronutrient content including fatty acid composition
using Optidiet (V3.1.0.004, GOE, Linden, Germany)
a professional analysis software that is based on nutri-
tional content of food as provided by the German
National Food Key. Individual recommendations for
energy intake were calculated as follows: total energy
content of the baseline food protocol was reduced by
30% (to a minimum of 1,200 kcal/day) to ensure sig-
nificant weight reduction. In addition to the reduced
energy intake, nutrition counseling aimed at achieving
a daily macronutrient content !90 g carbohydrates,
0.8 g protein per kg body weight, and a minimum of
30% fat in the reduced carbohydrate group, and a fat
content of !20% of total energy intake, 0.8 g protein
per kg body weight, and the remaining energy content
provided by carbohydrates in the reduced fat group.
All participants attended either reduced carbohydrate
or reduced fat weekly group sessions run by nutrition-
ists throughout the 6-month weight reduction pro-
gram, providing background information on healthy
food choices for each group. Blinding of participants
for the allocated dietary intervention was impossible.
In addition, individual nutritional counseling by a
nutritionist including analysis of a 7-day food protocol
took place every 2 months during the 6-month inter-
vention, to address individual questions, and to moni-
tor adherence to the diet.
Anthropometric and Metabolic Evaluation. After
an overnight fast, we determined body weight, waist
circumference, and height in a standardized fashion.21
During an oral glucose load (75 g glucose/500 mL),
we obtained blood samples at baseline and 15, 30, 45,

1506 HAUFE ET AL.
60, 90, and 120 minutes after glucose ingestion to
measure glucose and insulin. We assessed lean body
and fat mass by bioimpedance analysis (BIA 5 series,
Denner, Feldmeilen, Switzerland). After another over-
night fast, subjects underwent imaging studies and
physical fitness testing.
Abdominal and Liver Fat Quantification. Abdo-
minal subcutaneous and visceral fat mass as well as
liver fat content were measured as described.1 For fur-
ther information, see the Supporting Information.
Incremental Exercise Test. Subjects were submitted
to a stepwise incremental exercise test on a bicycle er-
gometer to determine maximal oxygen uptake as out-
lined in the Supporting Information.
Biochemical Measurements and Calculations. Glu-
cose (mmol/L), insulin (lU/mL), lipoproteins, alanine
aminotransferase (ALT [U/L]), and aspartate amino-
transferase (U/L) were determined by standard meth-
ods in a certified clinical chemistry laboratory. Insulin
resistance was estimated by homeostasis model assess-
ment index (HOMA). HOMA was calculated from
fasting insulin and glucose by (insulin [lU/mL] !
glucose [mmol/L])/22.5).22 Impaired glucose tolerance
was defined as 2-hour glucose values during the oral
glucose tolerance test (OGTT) of "140 mg/dL.23
Whole body insulin sensitivity was calculated by the
composite insulin-sensitivity index (C-ISI).24 C-ISI ¼
10,000/H[(FPG!FPI) ! (G!I)], where FPG and FPI
are fasting plasma glucose (mg/dL) and fasting plasma
insulin (lU/mL), respectively, and G (mg/dL) and I
(lU/mL) are the mean glucose and mean insulin con-
centration during the 2-hour OGTT. Hepatic insulin
resistance and b-cell function/secretion (insulinogenic
index) were also estimated.25 The hepatic insulin re-
sistance index was calculated from the OGTT. The
approach has been validated in nondiabetic subjects
against euglycemic insulin clamp testing in combina-
tion with tritiated glucose.26 The insulinogenic index
was computed as the serum insulin increment in the
first 30 minutes of the OGTT divided by the corre-
sponding glucose increment (DI30/DG30), which is
correlated with beta-cell function derived from fre-
quently sampled intravenous glucose tolerance test-
ing.27 Before and after diet serum high sensitive-C-re-
active protein (CRP) (in lg/mL), total and high
molecular weight adiponectin (both lg/mL), and
fetuin-A (in ng/mL), were measured by sandwich
enzyme-linked immunosorbent assay (ELISA) with the
following characteristics: hs-CRP (BioVendor, Heidel-
berg, Germany; #RH961CRP01HR), intraassay coeffi-
cient of variation (CV) 3.8%, and interassay CV
5.2%. Adiponectin (ALPCO Immunoassays, Salem,
15273350, 2011, 5, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.24242 by Jordan Hinari NPL, Wiley Online Library on [20/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
HEPATOLOGY, May 2011
NH; #47-ADPHU-E01), intraassay CV between 5.1%
and 9.8% for the different multimeres and interassay
CV between 4.8% and 6.5%. Fetuin-A (BioVendor,
Heidelberg, Germany; #RD191037100), intraassay
CV 4.9% and interassay CV 5.7%. Transforming
growth factor beta1 (TGF-b1) ELISA kits were pur-
chased from Biovendor and used according to the
manufacturer’s protocol. Samples were measured in
duplicate. The intra- and interassay CVs for the ELISA
were 5.1% and 8.4%, respectively. Soluble human in-
termediate filament protein fragments of cytokeratin
18 were measured with the M30-Apoptosense ELISA
from Peviva AB (Bromma, Sweden) in strict accord-
ance with the manufacturer’s protocol. Intraassay coef-
ficient of variation was 3.1% and interassay coefficient
of variation was 5.2% in a pooled control plasma sam-
ple from our laboratory.
Sample Size and Statistical Analysis. The B-
SMART study had the primary goal to compare
weight loss with reduced fat and reduced carbohydrate
hypocaloric diets. Overall, we expected a 5%-10%
weight loss from baseline within 6 months with a 3%
greater body weight reduction from baseline in the
reduced carbohydrate compared with the reduced fat
group. The secondary goal was to examine associated
cardiovascular and metabolic markers. To allow for a
meaningful analysis of these secondary goals, we
included enough patients to have at least 50 patients
in each group complete the 6-month weight loss
phase. With 50 patients in each group, the study had
a 95% statistical power to show a 3% difference in
weight loss from baseline between groups (alpha ¼
0.05, two-sided). For changes in body weight, meas-
ured every month during diet, we additionally per-
formed an intention to treat with last observation car-
ried forward analysis. Because magnetic resonance
imaging and spectroscopy was only conducted in
patients finishing the 6-month weight loss phase, the
statistical analysis is restricted to completers. No in-
terim analysis was planned.
Differences in the response to dietary interventions
were analyzed using unpaired t tests. For subgroup
analysis at baseline, we applied one-way analysis of
variance (ANOVA) with Bonferroni post-hoc tests. To
test for interactions between diet groups over the 6-
month period (diet ! time), we used a two-way
ANOVA for repeated measures. Univariate associations
between parameters were tested using Pearson’s correla-
tion coefficient. All statistical analyses were performed
with SPSS 18. Significance was accepted at P < 0.05.
Unless otherwise stated, values are given as mean 6
standard deviation (SD).

HEPATOLOGY, Vol. 53, No. 5, 2011
Fig. 1. Patient disposition.
Results
Enrolment began in March 2007 and the study
ended in June 2010. Of 170 randomized subjects, 102
completed the dietary intervention phase and were
included in the statistical analysis (Fig. 1). Similar pro-
portions of subjects in each group completed the study
(65% in the reduced carbohydrate and 60% in the
reduced fat group). In subjects not completing the
study, the time to discontinuation was 3.1 6 1.6
months in the reduced carbohydrate and 3.2 6 1.4
months in the reduced fat group (P ¼ not significant
[n.s.]). Both groups were well matched for gender, age,
body weight, body mass index, blood lipid profiles,
glucose metabolism, and cardiorespiratory fitness.
Table 1 shows baseline characteristics in both interven-
tion groups separately for subjects with normal and
elevated intrahepatic fat content.
As shown in Fig. 2, energy intake was reduced with
both dietary interventions. The estimated reduction in
energy intake was numerically but not significantly
greater in the reduced carbohydrate ("25%) compared
with the reduced fat group ("21%). Figure 2 also
illustrates changes in fat and carbohydrate ingestion
for both groups during dietary intervention. In the
reduced fat group, fat ingestion was decreased
("50%), whereas carbohydrate ("8%) and protein
ingestion ("3%) remained largely unchanged. In the
reduced carbohydrate group we observed a moderate
increase in protein intake (9%) in addition to the car-
bohydrate ("54%) and fat ("9%) changes. Figure 3
shows saturated fatty acid, and n-3 and n-6 polyunsa-
15273350, 2011, 5, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.24242 by Jordan Hinari NPL, Wiley Online Library on [20/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
HAUFE ET AL. 1507
turated fatty acid ingestion before and on diet. Satu-
rated and n-6 polyunsaturated fatty acids were ingested
less during diet with reduced fat compared to reduced
carbohydrate diet.
In an intention to treat analysis with last observa-
tion carried forward analysis, weight loss tended to be
greater with reduced carbohydrates (95.0 6 15.9 to
89.5 6 15.9 kg; P < 0.001) compared to reduced fat
diet (93.6 6 17.3 to 89.4 6 17.0 kg; P < 0.001)
(P ¼ 0.078 between interventions). In completers,
weight loss after 6 months was similar in subjects
assigned to a reduced carbohydrate compared to sub-
jects assigned to a reduced fat diet (Table 2). The time
course of weight loss during the intervention was simi-
lar in both groups (Fig. 4). During 6 months caloric
restriction, intrahepatic fat decreased from 7.6 6 8.2
to 4 6 4.6% ("47%) in the reduced carbohydrate
and from 9.6 6 9.8 to 5.6 6 6.4% ("42%) in the
reduced fat group, (P ¼ n.s. between interventions, P
< 0.001 compared with baseline for both). Abdominal
visceral fat mass decreased from 1.8 6 1.1 to 1.4 6
0.9 kg ("22%) with reduced carbohydrate and from
1.9 6 1 to 1.5 6 0.9 kg ("21%) with reduced fat
diet (P ¼ n.s. between interventions, P < 0.001 com-
pared with baseline for both). Abdominal subcutane-
ous adipose tissue decreased from 10.2 6 3.1 to 8.7
6 3 kg ("15%) with reduced carbohydrate and from
10.1 6 3.3 to 8.6 6 2.9 kg ("15%) with reduced fat
(P ¼ n.s. between interventions, P < 0.001 compared
with baseline for both). Total body fat% estimated by
bioimpedance analysis decreased similarly for both
 15273350, 2011, 5, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.24242 by Jordan Hinari NPL, Wiley Online Library on [20/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1508 HAUFE ET AL. HEPATOLOGY, May 2011

Table 1. Clinical Characteristics of Subjects Randomized to Reduced Carbohydrate or Reduced Fat Diets
and Subdivided by Intrahepatic Lipid Content
Reduced Carbohydrate Reduced Fat

Normal IHL High IHL Normal IHL High IHL

n (men/women) 32 (3/29) 20 (5/15) 23 (2/21) 27 (8/19)

Age, yrs 42 6 9 45 6 8 44 6 9 46 6 9
Bodyweight, kg 89 6 12 99 6 17 88 6 14 96 6 19
Body mass index, kg/m2 32.0 6 3.3 35.6 6 4.7* 31.9 6 3.9 33.9 6 3
Waist circumference, cm 97.7 6 8.7 107.6 6 13.4* 97.2 6 10.0 105.4 6 11.8*
Abdominal obese† (men/women), n 2/21 4/14 1/16 5/17
Blood lipids
Triglycerides, mmol/L 1.01 6 0.39 1.36 6 0.57 1.12 6 0.53 1.27 6 0.71
Cholesterol, mmol/L 4.7 6 0.6 5.1 6 0.7 4.9 6 0.9 4.9 6 1.0
HDL, mmol/L 1.4 6 0.3 1.7 6 1.1 1.6 6 0.7 1.2 6 0.3
LDL, mmol/L 2.8 6 0.5 3.1 6 0.8 3.1 6 0.9 3.2 6 0.9
Rree fatty acids, mmol/L 0.59 6 0.18 0.73 6 0.18* 0.61 6 0.19 0.61 6 0.18
Glucose metabolism
Fasting insulin, lU/mL 6.0 6 3.5 9.4 6 6.3* 6.3 6 3.3 7.4 6 4.1
Fasting glucose, mg/dL 91.5 6 17.1 95.5 6 23.3 94.1 6 8.2 95.9 6 7.8
HOMA, arbitrary unit 1.3 6 0.9 2.3 6 1.9* 1.5 6 0.8 1.8 6 1.0
C-ISI, arbitrary unit 6.1 6 2.6 4.2 6 1.8* 5.9 6 2.4 4.7 6 1.9
Hepatic insulin resistance 969 6 535 1,670 6 1,379* 1,156 6 768 1,813 6 1,405*
Insulinogenic index, lUINS/gGLU 85 6 45 98 6 65 83 6 45 108 6 66
Impaired glucose tolerance,‡ n 12 13 11 14
Biochemical parameters
ALT, U/L 19.3 6 8.4 24 6 9.6 21.6 6 9.3 34.8 6 17.4*
AST, U/L 26.7 6 11.9 24.6 6 6.4 26.8 6 17.7 37.1 6 24.8
Total adiponectin, lg/mL 6.3 6 2.2 5.7 6 1.8 7.1 6 3.6 5.4 6 2.2
Adiponectin (HMW), lg/mL 3.1 6 1.6 2.8 6 1.3 3.7 6 3.2 2.4 6 1.4
Fetuin-A, ng/mL 250 6 64 247 6 91 230 6 68 269 6 76
hs-CRP, lg/mL 1.3 6 1.1 1.7 6 0.9 1.3 6 0.6 1.9 6 1.3
Cytokeratin-18 fragments, U/L 126 6 54 129 6 52 119 6 43 134 6 46
TGF-b1, ng/mL 1.23 6 1.97 1.55 6 2.23 1.04 6 1.38 1.79 6 2.06
Abdominal adipose tissue
Intrahepatic lipids, % 2.9 6 1.1 14.9 6 9.8** 3.0 6 1.1 15.3 6 10.1**
Visceral fat mass, kg 1.3 6 0.6 2.5 6 1.4** 1.4 6 0.7 2.4 6 1.0**
Subcutaneous fat mass, kg 9.4 6 2.8 11.3 6 3.9 9.5 6 3.1 10.5 6 3.5
Cardiorespiratory fitness
VO2max, ml/min/kg 22.9 6 0.9 21.3 6 0.8 23.1 6 1.0 21.4 6 0.9

IHL: intrahepatic lipids, HOMA: homeostasis model assessment index, C-ISI: composite insulin sensitivity index, ALT: alanine aminotransferase, AST: aspartate
aminotransferase, hs-CRP: highly sensitive c-reactive protein, TGF-b1: transforming growth factor beta 1.
*P < 0.05, **P < 0.01: significantly different between normal and high IHL within the same diet group, no significant differences were detected between diets
within the same IHL subgroup, all analyzed by one-way ANOVA with Bonferroni post-hoc tests, data are mean 6 SD.
†Subjects with abdominal obesity (waist circumference: men "102 cm, women "88 cm).21
‡Subjects with impaired glucose tolerance (2-hour value in the OGTT "140 mg/dL).23

interventions (reduced carbohydrate: 35.6 6 6.4%
before and 33.2 6 7.2% after, P < 0.01; reduced fat:
36.4 6 5.5% before and 33.5 6 5.1% after, P <
0.001). Cardiorespiratory fitness expressed as maximum
oxygen uptake did not change with diet in either group.
We observed similar changes in fasting insulin and
glucose concentration as well as HOMA index in both
intervention groups (Table 2). Triglycerides, free fatty
acids, and high-density lipoprotein (HDL)-cholesterol
concentrations were also not significantly different after
diet among groups. However, total- and high-density
lipoprotein (LDL)-cholesterol decreased more in sub-
jects on a reduced fat diet compared to the reduced
carbohydrate diet (Table 2). Liver aminotransferases
decreased numerically but not statistically more in the
reduced fat group. Adiponectin, fetuin-A, and high
sensitive CRP measurements showed similar response
in both dietary groups (Table 2).
We next analyzed subjects according to their intra-
hepatic fat content at baseline. We observed a greater
intrahepatic fat loss along with a greater reduction of
ALT by trend for subgroups with high initial IHL con-
tent, irrespective of dietary macronutrient composition
(Fig. 5, first and second panels). Furthermore, subjects
with high baseline IHL also showed a better relative
reduction in IHL (!50 6 22% versus !31 6 36 on
reduced carbohydrate; !44 6 20 versus !23 6 49%
on reduced fat; P < 0.05 for both). In contrast,
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HEPATOLOGY, Vol. 53, No. 5, 2011 HAUFE ET AL. 1509

Table 2. Changes for Anthropometric and Biochemical

Parameters After 6-Month Diet Compared to Baseline
P-Value
Reduced Reduced Diet 3 Time
Carbohydrates Fat Interaction

n 52 50
D body weight, kg "7.5 6 0.6** "6.5 6 0.7** 0.25
D body mass index, kg/m2 "2.7 6 0.2** "2.4 6 0.2** 0.34
D waist circumference, cm "6.2 6 0.6** "5.6 6 0.7** 0.56
Blood lipids
D triglycerides, mmol/L "0.19 6 0.06** "0.14 6 0.08* 0.53
D free fatty acids, mmol/L 0.03 6 0.03 "0.01 6 0.03 0.62
D total cholesterol, mmol/L "0.08 6 0.09 "0.45 6 0.11** 0.009
D LDL, mmol/L "0.04 6 0.07 "0.33 6 0.08** 0.006
D HDL, mmol/L "0.09 6 0.1 "0.1 6 0.07 0.98
Glucose metabolism
D fasting insulin, lU/mL "2.6 6 0.6** "1.8 6 0.4** 0.27
D fasting glucose, mg/dL "6.1 6 1.3** "5.2 6 1.7** 0.67
D HOMA, arbitrary unit "0.61 6 0.18** "0.43 6 0.11** 0.39
Biochemical parameters
D ALT, U/L "2.5 6 1.3# "6.1 6 2.2** 0.14
D AST, U/L "3.7 6 1.7* "5.1 6 2.7* 0.42
D adiponectin 0.77 6 0.22** 0.34 6 0.19# 0.15
(total), lg/mL
D adiponectin 0.68 6 0.15** 0.33 6 0.12** 0.08
(HMW), lg/mL
D fetuin-A, ng/mL "31 6 12* "36 6 11** 0.76
D hs-CRP, lg/mL "0.34 6 0.19# "0.51 6 0.16** 0.47
D cytokeratin-18 "0.03 6 4.2 "1.5 6 3.8 0.52
fragments, U/L
D TGF-b1, ng/mL "0.89 6 0.26** "0.37 6 0.26 0.17

ALT: alanine aminotransferase, AST: aspartate aminotransferase, hs-CRP:

highly sensitive c-reactive protein, TGF-b1: transforming growth factor beta 1.
#
P < 0.10; *P < 0.05; **P < 0.01: significantly different between baseline
and follow-up within a diet analyzed with Student’s t tests for paired samples;
P-value in third column ¼ diet x time interaction for reduced carbohydrate vs.
reduced fat diet over the 6-month diet by two-way ANOVA.
Data are mean 6 SEM.

Fig. 2. Energy and macronutrient intake. Changes in energy and
macronutrient intake during the 6-month study in response to the die-
tary protocols randomly assigned to subjects (triangles: reduced
carbohydrate diet, circles reduced fat diet). Data are mean 6 SEM,
*P < 0.001 significantly different between reduced carbohydrate and
reduced fat diet.
similar responses occurred for visceral fat mass, insulin
sensitivity (Fig. 5, third panel; Fig. 6, first panel) as
well as fasting insulin, glucose, and HOMA index
between subgroups.
To assess influences of insulin sensitivity on the
response to macronutrient composition, we stratified

Fig. 3. Fatty acid intake. Amount of con-

sumed saturated, polyunsaturated n-3 (n-3),
and polyunsaturated n-6 (n-6) dietary fatty
acids before and at the end of 6 months of
reduced carbohydrate or reduced fat diet.
Data are mean 6 SEM, *P < 0.05, **P <
0.01 significantly different between baseline
and after diet. §Significant time ! group
interaction for diet groups analyzed by two-
way ANOVA. No significant differences were
observed between groups at baseline.
 15273350, 2011, 5, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.24242 by Jordan Hinari NPL, Wiley Online Library on [20/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
1510 HAUFE ET AL. HEPATOLOGY, May 2011

subjects into an insulin-sensitive and an insulin-resistant

Fig. 4. Body weight changes. Changes in body weight in response
to a hypocaloric diet reduced either in carbohydrates (triangles) or fat
(circles) during the 6-month study. Note that body weight reduction
was nearly identical between groups.
group using a predefined C-ISI cutoff of 4.5.28 The insu-
lin-resistant group was heavier (95.9 6 15.8 versus 90.1
6 15.9 kg; P ¼ 0.072) and showed higher IHL values
(12.5 6 11.9 versus 5.8 6 6.3%; P < 0.01) compared
with the insulin-sensitive group. Insulin-resistant sub-
jects lost 7.9 6 4.6 kg on the reduced carbohydrate and
7.8 6 4.9 kg on the reduced fat diet (n.s.). Insulin sensi-
tive subjects lost 7.2 6 4.2 kg on the reduced carbohy-
drate and 5.2 6 4.1 kg on the reduced fat diet (P ¼
0.075). IHL in insulin-resistant subjects decreased 6%
6 6.7% with reduced carbohydrates and 4.9% 6 4.8%
with reduced fat (n.s.). In insulin-sensitive subjects, IHL
decreased 2.1% 6 2.3% with the reduced carbohydrate
and 3.3% 6 5.1% (n.s.) with the reduced fat diet.

Fig. 5. Response to diets in subjects with low and high IHL content. Changes in intrahepatic lipid content (IHL), alanine aminotransferase
(ALT), and visceral adipose tissue (AT) after the 6-month study. Subjects were stratified according to low (<5.6%) and high (>5.6%) baseline
IHL. Data are mean 6 SEM, *P < 0.05, **P < 0.01 significant differences within subgroups from baseline to follow-up analyzed by Student’s
paired t test, and significant time " group interactions between low and high IHL subgroups analyzed by two-way ANOVA, #P < 0.10 different
by trend. No significant changes were observed for subgroups with low or high IHL between diets.
 15273350, 2011, 5, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.24242 by Jordan Hinari NPL, Wiley Online Library on [20/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
HEPATOLOGY, Vol. 53, No. 5, 2011 HAUFE ET AL. 1511

Fig. 6. Changes in insulin sensitivity in subjects with low and high IHL content. Changes in whole body insulin sensitivity (composite insulin
sensitivity index [C-ISI]), hepatic insulin resistance, and pancreatic insulin secretion (insulinogenic index [IGIS]) after the 6-month study. Subjects
were stratified according to low (<5.6%) and high (>5.6%) baseline IHL. Data are mean 6 SEM, *P < 0.05, **P < 0.01 significant differen-
ces within subgroups from baseline to follow up analyzed by Student’s paired t test, and significant time # group interactions between low and
high IHL subgroups analyzed by two-way ANOVA, #P < 0.10 different by trend. No significant changes were observed for subgroups with low or
high IHL between diets.

When stratifying subjects for impaired glucose Discussion

tolerance before diet those with impaired glucose
tolerance had similar bodyweight (94.8 6 15.8
versus 92.5 6 13.7 kg), and higher IHL values
(10.7 6 9.4 versus 7.1 6 6.2%; P ¼ 0.05) com-
pared with subjects with normal glucose tolerance.
Bodyweight loss was similar in both groups regard-
less of the dietary intervention. IHL loss was not
related to diet or glucose tolerance state (impaired
glucose tolerance: reduced carbohydrates: D "4.8
6 6.2%; reduced fat: D "4.0 6 5.9%, both P <
0.01; normal glucose tolerance: reduced carbohy-
drates: D "2.4 6 2.6%; reduced fat: D "3.2 6
4.1%, both P < 0.01). Glucose tolerance improved
only in subjects with impaired glucose tolerance
regardless of diet.
The main finding of our study is that IHL content
decreased similarly in overweight and obese subjects
assigned to moderately reduced carbohydrate or mod-
erately reduced fat hypocaloric diets. The observation
holds true for both subjects with low and subjects with
elevated IHL content at baseline. Our findings provide
insight in mechanisms regulating IHL in human
subjects and may have a bearing on therapeutic
decision-making.
Previous studies compared low-carbohydrate to low-
fat hypocaloric diets. A meta-analysis including earlier
trials revealed that low-carbohydrate diets appear to be
at least as effective as low-fat diets in terms of weight
loss.20 More recent trials showed advantages29 or no

1512 HAUFE ET AL.
differences15 for reduced carbohydrate diets. However,
most of these trials assessed changes in overall adiposity
rather than fat distribution between adipose tissue depots
and ectopic fat storage in the liver. The issue is relevant
given the central role of intrahepatic fat in the pathogene-
sis of obesity-associated disease, such as insulin resistance
and type 2 diabetes. Indeed, animal and human studies
show that increasing dietary fat content predisposes to
IHL accumulation and insulin resistance.13,30
We observed virtually identical weight loss with
reduced carbohydrate and reduced fat diets. Both
groups adhered to their assigned interventions in terms
of macronutrient content. Physical fitness is negatively
correlated with IHL content.1 Dieticians reminded
participants to keep physical activity constant through-
out the study. Moreover, cardiorespiratory fitness did
not change during either intervention. Thus, differen-
ces in fat distribution, lipoprotein metabolism, or glu-
cose metabolism between interventions are mainly
explained by macronutrient composition rather than
differences in weight loss or physical fitness between
groups. Abdominal visceral, abdominal subcutaneous,
and IHL loss was similar with low-fat and low-carbo-
hydrate diets. These observations suggest that over a
6-month period, success in losing visceral fat and IHL
is primarily related to caloric restriction rather than
macronutrient composition.
IHL is associated with metabolic disease including
insulin resistance2,4 independently of visceral fat.5,6
Although the initial cellular signal in inducing hepatic
lipid accumulation differs between excessive fat or car-
bohydrate ingestion, once insulin resistance develops,
hyperinsulinemia promotes increased hepatic sterol reg-
ulatory element binding protein-1c (SREBP-1c) expres-
sion. SREBP-1c coordinately regulates transcription of
key enzymes involved in lipogenesis.31 Moreover, insu-
lin resistance in rodents and in human subjects changes
the disposition of ingested carbohydrate away from
skeletal muscle glycogen synthesis towards hepatic
de novo lipogenesis.32 Thus, the beneficial effects of
hypocaloric diets on IHL fat could be mediated in part
through improved peripheral insulin resistance. Yet,
whereas insulin-resistant subjects tended to lose more
IHL compared with insulin-sensitive subjects, we did
not observe a relevant interaction between insulin sensi-
tivity and the response to macronutrient composition
of the diet. We obtained similar results when we strati-
fied our subjects for glucose tolerance. A recent clinical
study in obese insulin-resistance subjects reported simi-
lar reductions in body weight and IHL after 11 weeks
on a hypocaloric diet with either high or low carbohy-
drate content. However, the low carbohydrate diet was
15273350, 2011, 5, Downloaded from https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/hep.24242 by Jordan Hinari NPL, Wiley Online Library on [20/11/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
HEPATOLOGY, May 2011
superior in improving hepatic insulin sensitivity.15 In
our subjects an OGTT-derived index of hepatic insulin
resistance, which has to be interpreted with caution,
showed no significant interaction between macronu-
trient composition and improvements in hepatic insulin
sensitivity during the 6-month intervention.
Approximately half of our subjects had an IHL con-
tent >5.6%, a value reported as ‘‘the upper limit of
normal’’ for IHL with an increased risk of hepatic stea-
tosis.33 Subjects exceeding this cutoff showed an !7-
fold greater absolute reduction in IHL compared with
subjects with normal IHL content. Remarkably, sub-
jects with normal and with elevated IHL content
showed similar improvements in glucose metabolism,
even though the absolute reduction in IHL was much
greater in the latter group. The observation may sug-
gest that the improvement in glucose metabolism with
dietary weight loss is not directly related to the quan-
tity of mobilized IHL. The dynamics of fat mobiliza-
tion may be more important in this regard. Possibly
other mechanisms, such as reductions in abdominal
visceral or subcutaneous adipose tissue, mediated the
beneficial effect of dietary weight loss on glucose
metabolism.34 Indeed, subjects with normal and with
elevated IHL showed similar reductions in abdominal
visceral adipose tissue.
We observed larger reductions in total- and LDL-cho-
lesterol in the reduced fat compared with the reduced
carbohydrate group. Yet triglycerides, HDL-cholesterol,
and measures of insulin resistance responded similarly
or improved more with reduced carbohydrate diets.20
Similar to another dietary intervention study,29 circulat-
ing total and high molecular weight adiponectin tended
to increase more with reduced carbohydrate diet. These
findings fuel the concern that macronutrient composi-
tion of hypocaloric diets could adversely affect cardio-
vascular and metabolic risk. However, the issue can only
be sufficiently addressed in long-term studies with hard
cardiovascular endpoints.
TGF-b1, which plays a critical role in the pathogene-
sis of liver fibrosis and hepatocellular carcinoma,35 was
reduced 2-fold after reduced carbohydrate diet com-
pared to reduced fat diet, which could indicate a poten-
tial advantage of carbohydrate-restricted diets on fibro-
genesis. In our subjects, cytokeratin-18 fragments,
which are markers of hepatocyte apoptosis,36 were in
the normal range and did not change with either diet.
The observation suggests that in most subjects obesity-
associated IHL accumulation was not yet associated
with ongoing hepatocyte apoptosis. Our results cannot
be simply extrapolated to patients with more advanced
liver disease.

HEPATOLOGY, Vol. 53, No. 5, 2011
The main limitation of our study is that a 6-month
weight loss period may not be sufficiently long to
observe influences of macronutrient content on IHL.
An influence of macronutrient composition could be
unmasked during weight stabilization or regain. Fur-
thermore, our study does not exclude that more
extreme changes in dietary fat and/or carbohydrate
affect IHL in a weight-independent fashion. However,
we suggest that the changes in macronutrient content
in our study reflect typical Western dietary patterns.
We controlled for fatty acid composition, which may
affect IHL deposition. For example, transgenic restora-
tion of omega-3 fatty acid tissue levels improved he-
patic insulin sensitivity in mice fed a high-fat diet.37
We observed no changes for n-3 fatty acids during ei-
ther diet. A reduction in n-6 fatty acid and more so
saturated fatty acid ingestion in the reduced fat diet
was unavoidable. Because we did not measure physical
activity throughout the study, we cannot completely
rule out an influence of an unrecognized change in
physical activity on our outcomes.
We conclude that over a 6-month period, caloric
restriction through reductions in dietary fat or carbo-
hydrates achieved similar reduction in IHL content in
nondiabetic overweight or obese subjects. Patients with
elevated intrahepatic fat content showed a particularly
large response. The improvement in IHL content was
associated with a reduction in ALT. Thus, both types
of diets are similarly useful in the prevention of
obesity-associated hepatic fat accumulation, which is a
major risk factor for metabolic disease, such as insulin
resistance and type 2 diabetes, and nonalcoholic
steatohepatitis.
Acknowledgment: We thank Gritt Stoffels, Anke
Strauss, and Elke Nickel-Sczcech for technical help
with patient recruitment and study procedures. We
also thank Andreas Busjahn for statistical advice.
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