Intermediary

Peter A Mayes
Most of

metabolism

of fructose3

ABSTRACT

the

metabolic

effects

of

fructose

arc

terious, sylation tabolism.

eg,

hyperlipidemia,

hyperuricemia,

nonenzymic in copper metabolism

fructomeof

due

to its rapid

utilization regulatory

by the liver step in to carbohydrate

and

it by-passing leading lipid and

the phosto far metabolism.

phofructokinase reaching These ruvate genase, nonesterified long-term tions that triglyceridemia,
nemia. tion ished of Acute inorganic ATP synthesis.

glycolysis,

of proteins, lactacidemia, The paper concentrates concerning Other volume.

is whether

and disturbances on the general

consequences consequences and lactate and a shift fatty absorption increase

loading

include production, in balance acids,

immediate activation from

hepatic increases in pyof pyruvate dehydroto esterification secretion are augmented of by of very-

fructose, particularly and punine metabolism. of other

Of

its impact on carbohydrate, lipid aspects referred to are the subjects

augmented insulin secretion

reviews

in this for some

oxidation in increased effects

further

consideration

resulting (VLDL).

is responsible
Compared an increase with

of the metabolic
fructose insulin (1) feeding whereas

effects
does sucrose

of fructose
not directly feeding

intake.
cause does (2).

low-density-lipoprotein

These

glucose,

Downloaded from ajcn.nutrition.org by guest on April 6, 2013

of fructose, which causes enzyme adaptalipogenesis and VLDL secretion, leading to glucose
liver in with

in plasma

decreased
of the phosphate

tolerance,
fructose

and
causes

hyperinsulisequestraand by Al? diminof the

Thus whenever intake added effect of insulin

only is this the case

of fructose secretion
with sucrose

is accompanied must be taken

itself but some

by glucose, into account.

HFSs
-

the Not
equiv-

are

fructose-l-phosphate the inhibition

alent 50% athletes

to hydrolyzed fructose that contain

sucrose both

because considerations fructose and

they

are apply

50%

glucose

and
for

Consequently,

(3). Similar

to supplements

enzymes
acid

of adenine are of particular

nucleotide
with

degradation
consequent

is removed
hyperuricemia.

and hypertrigly-

uric

glucose.

formation

accelerates

These

effects

significance
individuals.

to potentially

ceridemic

or hyperuricemic

Am

J Clin

Nutr

General
Utilization

metabolism
of blood
consequence

1993;58(suppl):754S-765S.

fructose
of the

and uptake
digestion

into

tissues
and other fructose-

KEY
olism,

WORDS

Fructose,

intermediary

metabolism,

sucrose,

The

of sucrose

immediate
lipid

effects,
metabolism,

long-term

effects,
enzyme

liver,
adaptation,

carbohydrate
lipogenesis,

metabvery-

containing
absorption into through the

foods
and hepatic the liver

such
transport portal

as honey,
of vein. fructose Therefore, Because

fruits,
by all of

and
the

some
intestinal

vegetables,
epithelium absorbed of an flows active

is

low-density

lipoproteins,

insulin,

nonesterified

fatty

acids,

hy-

fructose presence

pertriglyceridemia,

hyperuricemia

initially.

the

hepatic

enzyme

system

for metabolizing accounting for of the fructose rats (4).

fructose, a fractional presented In humans

fructose

readily

Introduction
Virtually due
entry ose

passes into the liver, and 71%, respectively, tube all the unique factors:
after

uptake of 55% to the liver after it was shown that

feeding

fed or starved

metabolic its rapid

or the bypassing

properties uptake
gluconeogenesis

of fructose by the liver, and

at the

are its
tnreg-

to two
to the phosphate

primary
pathway level

the liver metabolized at least half of the fructose injected intravenously (5). In the perfused rat liver we found a value of 40% for the
high

of glycolysis

fractional
rate of

extraction
extraction

of fructose
of fructose

(6).
by

As a consequence
the liver, correspondingly

of the

phosphofructokinase

ulatory creased ose

its

step.

The (Fig

metabolic

consequence

is the pathways has

food

provision leading arisen based

of infrom tnof
form

substrate interest
use

in all the metabolic

low concentrations vessels after meals

of fructose containing

are found in the fructose or sucrose

systemic blood are consumed is taken would

where

phosphate Current
increased

1).
in fructose metabolism
in the

because
in the

(4, 7, 8). Some 20% of fructose administered intravenously up by the kidney (9). Thus, somewhat less than this amount
be expected to be taken up by this organ after oral feeding

as

a sweetener

industry

of high-fructose
science or not,

corn
fructose

syrup
has

(HFS).
been

Also,
promoted

whether
as

on sound
de-

the

liver

takes fraction

up some would

50% be

of the initial available for

influx. adipose

A considerably tissue (10) and

an

appetite

smaller

pressant, enteral ognized Representing

as a food feeding, for many half

for non-insulin-dependent supplement molecule, largely of the sucrose years as being

diabetics, for endurance fructose responsible

for parathletes.
I

and as a food

has been

red-

From

the Division

of Biochemistry,
College, Heart

Department
University Foundation.

of Veterinary

Basic

for the met-

Sciences, Royal Veterinary 2 Supported by the British

3

of London.

abolic effects of high-sucrose diets. Concern of the realization that fructose, at elevated promote metabolic changes that are actually 754S
Am J C/in

has arisen because concentrations, can or potentially deleNutr 1993;58(suppl):754S-65S.

Address

reprint
of of London,

requests
London

to PA Mayes,
Basic Sciences, NW1 0Th,

Division
Royal UK.

of Biochemistry,
Veterinary College,

Department University

Veterinary

Printed

in USA.

1993

American

Society

for

Clinical

Nutrition

METABOLISM FRUCTSE

OF

FRUCTOSE

755S

I ciucose

6.pase_jcr3I

G1uc::::L,.4

GLUCOSE6-P.....#{216}. Glycogen

[ FRUCTOSE
FRUCTOSE 1-P

1.6- bis.Pe

()
FRUCTOSE

6-P

I 4O6PHOFRUCTOKIP4ASE

FRUCTOSE

1 ,6-bis-P

Glyceraldehyde

Downloaded from ajcn.nutrition.org by guest on April 6, 2013

Co2
FIG phosphatase; 1. Fructose utilization in the liver showing its interrelationship with glucose and fatty acid metabolism. Pase, P, phosphate.

skeletal
tose

muscle

(11).
into which

A recent
exercising is above

study
subjects

(12)

showed

that

when

frucand

with via the which olism

glucose this route

at physiological inhibited that by glucose fructose, is the three particular enzymes

concentrations (10). after in adipose pathway enzymes arc present Nevertheless, from uptake tissue

its phosphorylation it is probably the blood, by Hers enters Of aldolase far (15), muscle.

is infused

to maintain

a concentration concentrations

is largely fruc-

of 5.5 mmol/L, above

tose

physiological

the glucose
oxidation by

concentration,
exercising and

there
resting

is considerably
muscles.

more

metabolic involves (Fig

pathways

and

greater many out using deductions investigaunphymade

significance

discovered

In a previous tions both siological

review

(13)

we pointed

out

that

(fructokinase,

in vivo and concentrations

in vitro had been carried of fructose and that

B, and triokinase),
1). These

two of which

arc specific

for fructose
and

metaband as the are able this

rats (17),

in liver

kidney

from such observations could applied to humans consuming

fructose. centrations Of particular of fructose relevance likely to

be misleading, particularly when normal quantities of sucrose and

to hepatic be attained metabolism in the arc hepatic the conportal

probably in the small intestine of some species-such golden hamster (16), guinea pig (17), and dog (18)-that to convert
not possible

some
in

absorbed
the intestine

fructose
of

into
either

glucose.
humans

However,
(19) or

is

vein.
2.2

In humans
mmol/L have

(14)
been

and

baboons

(8) maximal
after a fructose

concentrations
or sucrose meal.

of

which
essary

do
for

not

contain

glucose-6-phosphatasc,
glucose. Thus in these two

the during

enzyme
there

necis

recorded

releasing

species

We found
starved (4).
was

values rats were

within the range 1.1-2.2 mmolfL, when fed or given a large fructose meal by gastric intubation a maximum concentration
blood (14).

no conversion respect fructose fructose

ketohexose

of fructose is rapidly

to glucose model

absorption. in the liver

In this to form for only acso

is

the rat is a good 1-phosphate, because

of

of human

fructose

metabolism. of the fructose specific is the

The

In humans
recorded

of 1.0 mmol
Because the

fructoscfL
blood

Fructose

phosphorylated catalyzed (20). This

by AlP enzyme

in peripheral

normal

by the first enzyme is virtually and

in the

fructose fructose maximum Specific tissues

concentration concentrations recorded metabolic

is zero

when

no fructose

is being

absorbed,

pathway-fructokinasc
physiological

in blood will vary from zero up to the above, according to the quantity in the diet. pathways offructose utilization in individual

it is a kctohexokinase,
significance

fructose
diet.

high

tivity much split the phosphorylation However, when of most hexose fructose is present

of fructokinase of the fructose by liver aldolase phosphate,

Aldolase

underlies
passing

the ability
through it.

of the liver
Fructose-i-phosphate

to extract and sequence

in glycolysis

(aldolase
B also

B) into
functions

glyceraldehyde
in the liver

dihyof

Hexokinase will catalyse sugars, including fructose.

droxyacetonc
intermediates.

a member

of the glycolysis

756S
to split fructose-1,6-bisphosphate phosphate. to glyceraldehyde-3-phosphate The third enzyme in the fructose catalyzes the phosphorylation glyceraldehyde-3-phosphate, pathway. fructose stage metabolism of metabolism similar. without catalyzed

MAYES
patocytes strated occurred of anin the and Frucpassing by Effects As on glycolysis, a result of the there glycogenesis, loading of the and gluconeogenesis initial pathways of fructose of glycolysis to using that graded significant concentrations elevations of 0.5 and in vivo whose of of fructose fructose 1 .0 mmol (31) demonwhich meal. may alter 3-phosand in5cc-

and dihydroxyacetone

1-phosphate

pathway is tniokinase (21), which glyceraldehyde by Al? to form other intermediate of the glycolytic Thus, the pathways liver converge at the from tose through this point has arrived the main on, their at this

at concentrations

fructosc/L,

are available in the portal vein Other important intermediates as a result phate, organic tions. fructose phosphate of fructose (Pi). 2,6-bisphosphate, These

after a fructose concentrations include glycerol ATP, lactate,

of glucose and triose phosphate metabolism stage

administration pyruvate, will

is qualitatively in metabolism, step in glycolysis

be discussed

in following

rate-controlling

phosphofructokinase to the liver, is rapidly strate to the metabolic (ie, tose (23). bodies glycolysis,
fatty possibly acid

(22). In this way fructose, phosphorylated, providing pathways leading from gluconeogenesis,
Thus, major estenification).

on presentation increased subtriose phosphate lipogenesis,

products of

glycogenesis, in the quantities

and
fruc-

metabolism

is a tendency

for intermediates

metabolism Smaller

liver are glucose, glycogen, and arc oxidized to carbon dioxide, (13). The general

lactate ketonc dispo-

increase in concentration, the pathway, evidenced blood lactate concentrations reactions tate, the This allostenic metabolite

resulting by increased (36,

in an increased flux through lactate formation and raised 37). In the span of glycolytic and lackinase. because of to pyruvate by pyruvate control

or converted

to tniacylglyccrol

sition of fructose carbon by changes in nutritional esis from ministration Biosynthesis

between its major end products is altered and endocrine status, eg, gluconeogendiabetes, or ad-

from glyceraldehyde-3-phosphate rate-controlling step is catalyzed is normally under feed-forward

enzyme

Downloaded from ajcn.nutrition.org by guest on April 6, 2013

fructose is increased during starvation, of ethanol or glucagon (24). offructose in mammalian tissues

activation by fructosc-1,6-bisphosphatc. may double in concentration when of more significance concentrations, activation of fructose of pyruvate carbon

Although this fructose is added increases a similar thus falactate.

to hepatocytes (31), in fructose-1-phosphate but more enhanced passage cilitating

are the large which extend kinase (38), and to pyruvate is controlled modification

Although the primary purpose of this paper is to review the effects of exogenously derived fructose, discussion of the metabolism of fructose is not complete without a very brief reference to its synthesis in a few specialized tissues. Free fructose is found in the lens, seminal fluid, and the fetal circulation of ungulates and whales. It is formed by the sorbitol (polyol) pathway (25), which is responsible for fructose formation from glucose. This pathway is present vesicles, and placenta of the groups mentioned in activity as glucose concentrations rise tissues that are not undergoes reduction reductase, followed bitol bitol causing ogenesis aldose version (polyol) and osmotic fructose of diabetic insulin sensitive, such by NADPH to sorbitol, by oxidation of sorbitol in the presence in the Sorbitol human which is probably accumulate damage, cataract. in the lens, seminal above. It increases in diabetics in those as the lens. Glucose catalyzed by aldose to fructose by sonof NAD. lens involved dehydnogenase, Both sonin diabetics, in the pathbut not

Glycogen synthesis and breakdown series of reactions involving covalent phosphorylation ters around and The two

by a complex by protein regulation censynthase

and dephosphorylation. Briefly, rate-controlling enzymes-glycogcn

glycogen phosphorylase. active form of glycogen other whereas hand

(See

ref 25 for a general review.) synthase (synthase a) is the de-

phosphoenzyme, ated. On the phosphoenzymc, lated. Protein phosphatases Both fiers. detail reviewed processes Control from

the inactive synthase b is phosphorylactive glycogen phosphorylase a is the is dephosphoryand protein of these enzymes. allostenic modidiffers in some and has been

whereas the inactive b form kinases carry out phosphorylations carry out dephosphorylations are controlled by hormonal and of glycogen metabolism in liver that of glycogen (39). metabolism

dehydrogenase

in muscle

by Hers

reductase, is found of any exogenously

in liver and is responsible for the conderived sorbitol to fructose.

A study
fructose studies better osition cogen (40, which thase fusions

of the literature

reveals

a disparity

in results

on whether
of is a

promotes liven glycogen deposition, in vivo in the fed condition indicating promoter of glycogenesis than is glucose of glycogen appears to result synthase (40, 41) and inhibition

with the balance that fructose (31). The

net dep-

Effects
Effects

of fructose

on carbohydrate
of important the perfused liven

metabolism
intermediates (23, 26, 27) and cath-

from both activation of glyof glycogen phosphorylase about by several mechanisms. (42-44), Also, carried blood acids, glucosesynout perglycogen fructosc-1-phosphate of fructose. and activates

on the concentrations with both

42).

This

appears

to be brought by after administration

Experiments

Phosphorylase accumulates 6-phosphate and with

a is inhibited increases inhibits the liver

etenized human subjects (9) indicate 66% of a fructose dose is converted is released as lactate. Up to a further (23). venous 1-phosphate liver cent (28-31), investigations After administration there in those kidney tissues (30, using

that in the starved state, to glucose and up to 25% 8% may form glycogen either marked orally increase intestine (33, or by pathway, 34). spectroscopy 1-phosphate of fructose by using with in the (35). Alunphysioisolated heintraie, Rein glucose

in concentration phosphorylase of fed rats, (45).

We amino

have

of fructose is a rapid 32), and and containing

using

whole

containing and free fatty

loading

physiological acids into physiological

concentrations which

of glucose,

the fructose small

was infused glucose, rates (46). When either

fructose, or both sugars at sugar was infused alone.

P magnetic-resonance

have confirmed the accumulation of fructose human liver after intravenous administration though logical most of these effects were obtained experiments concentrations of fructose,

there was a net output of glucose from the liver, with no change in glycogen concentration. However, when glucose and fructose were infused together, there was a marked uptake of glucose and an increase without in glycogen. Fructose glucose uptake was the same with or a concomitant infusion.

METABOLISM
Thus, in the sucrose take activation but fructose an increase phosphatase creased which fructose on its own does not seem to be glycogenic but

OF

FRUCTOSE
Generally, it has been a long-term both in animals glucose the case sucrose (53) tolerance that regime and does not glucose humans tolerance with The (54). appear

757S has been a starchreason for

presence of extra glucose, as would be the meal, fructose opens the door for hepatic synthesis of glycogen. synthase This and is achieved, inhibition of glycogen

case after a glucose upby

worse based ficiency insulin

under diet,

compared

and

presumably, of phosphorylase,

the decreased

to be an insufplasma feeding

itself is not able to make in fructose-1,6-bisphosphate (22). It was significant that

use of the facility because inhibits fructose-i,6-bislactate concentrations inthe uptake of lactate pro-

in insulin secretion, concentrations have

rather the reverse. Increased been reported after sucrose

(55-58) response glucose about

and insulin sensitivity, as measured to administered insulin, is less tolerance most likely is due by to increased insulin increased nonestenified

by the hypoglycemic (59). Thus decreased resistance, fatty acid brought (NEFA) or-

only in the presence into the liver could

of a fructose infusion, account for the increased

duction. In the presence was an additional small the fed state, fructose lyzed to lactate rather oral load increases tion from

of a simultaneous glucose infusion, there increment in lactate production. Thus in would appear than converted to be predominantly glycoto glycogen or glucose. An not glucose, in humans and even also leads (47, 48). glucose producthe rates many in vitro, to

concentrations The decreased ganism exhibited accompanied in the liver (62, creased 63). when

and utilization utilization placed

(60, 61). of glucose, as found tissues. However,

in the whole diet, this

on a high-sucrose of individual

or -fructose

is also

in studies

is usually

of fructose or sucrose, but in blood lactate concentration condition gluconcogenesis process. fructose is an active

by an increased there is decreased This is no doubt due

ability to metabolize fructose. Thus, utilization and oxidation of glucose to depressed glucokinase in the liver and after infrucimto

In the starved

exceeding Unfortunately, particularly

activity

of glucose-6-phosphatasc

of gluconeogenesis from studies on gluconcogenesis have sion. many several Two used The

lactate (23, 49). from fructose,

tose-containing mediate effect glycogen

diets are consumed (64). As opposed to the of fructose in facilitating conversion of glucose (46), long-term feeding of fructosc-containing

Downloaded from ajcn.nutrition.org by guest on April 6, 2013

5 mmol/L)

unphysiologically and will not glycolysis and intermediates

high concentrations be considered in the gluconeogenic and enzymes unique the activities pathways to each

of fructose (ic present discusmake pathway use of by (25). and by

in the liver

common pivotal

but arc controlled arc reciprocal

diets reduces the conversion of glucose to liver glycogen (65, 66). However, conversion of fructose to liver glycogen is increased because of enzyme adaptation (64). Consumption of a sucrose diet before crease cose have consumption in blood tissue lactate also of a sucrose compared shows load with did not elicit diet any (67). gluafter animals the utilization to its uptake, extra ina starch ability

nonequilibrium reactions,

enzymes for which

coordinated, dominate phosphofructokinase

tase in gluconeogenesis

these pathways. in glycolysis and

(Fig 1). Their

These arc catalyzed fructose-i,6-bisphosphaactivities arc both induced

Muscle

decreased

to metabolize

and increased ability been fed high-fructose in adipose and tissue conversion

to oxidize fatty acids diets (68). Likewise, is impaired to glycogen with (62, respect 69).

by hormones

and

also

by allostenic

modifiers

often

acting

on the acis thus Unaccu-

of glucose oxidation,

key regulatory molecule-fructosc-2,6-bisphosphatc-which tivates phosphofructokinase and inhibits fructosc-1,6-bisphosphatase elevated activating (50). The concentration from fed rats ,6-bisphosphatase of fructose-2,6-bisphosphatc but falls during and the and starvation, gluconeogenic glycolysis. does not in liver fructose-i

Effects
Immediate

of fructose
effects

on lipid
on the initial

metabolism
pathways of lipid metabolism

pathway and inhibiting der these conditions,

phosphofructokinasc fructose1,6-bisphosphate from fructose Therefore,

and on lipogenesis Fructose metabolism. has both immediate or acute metabolism effects result high and effects long-term arc those effects that enzyme enzyme on occur lipid as a

mulate even when the flux phosphate level increases. gluconcogenesis some increase concentrations
cling at the

metabolites there is no

at the triose inhibition of is cy-

Short-term

by fructose. In isolated in fructose-2,6-bisphosphate of fructose,

locus of

hepatocytes there under physiological substrate

fructosc-i,6-bisand

result of fructose whereas long-term to diets containing

by existing mainly from

capacity, adaptation or fructose. uptake from arc found in acid oxidangers must be is a more

which there

leads

to increased that

concentrations

of sucrose

phosphofructokinasc

phosphatase gluconeogenesis

(51).

However, from fructose.

is no evidence

this

inhibits

Because of the importance of the liver in fructose the blood, many of its effects on lipid metabolism this organ. They involve the major pathways

of fatty

Long-term Experimental consuming quirement diets leads

effects

of a high data have

fructose been obtained

intake from humans or animals re-

dation and estcnification, and lipogenesis. In this respect, of applying results in experimental animals to humans appreciated. For example, it is likely that lipogenesis important pathway in rats than in humans, be confined to the liver and where even of lipogenesis In the liver, dihydroxyacetone acetone phosphate may be low in activity (70).

between as fructose. to adaptive

7.5% and Long-term increases

70% of their energy-intake feeding of fructose-containing in the activity of many enzymes

where lipogenesis may there the key enzymes

in the pathways of fructose grouped into those involved metabolism

synthesis (13).

metabolism. initially
effects of

These enzymes can be with fructose uptake and and

high-fructose

lipid metabolism is affected by fructose at the phosphate and pyruvate locations. Dihydroxyis in equilibrium with glycerol-3-phosphatc, in the synis the major lipoprotcins the bulk of also the de-

and

those
Long-term

involved

in lipogenesis
feeding

triglyceride
diets

may differ from moiety of sucrose turn would

those may

of feeding sucrose, because the cause increased insulin secretion. to cause adaptive effects. The

glucose This in majority

cosubstrate for esterification of long-chain acyl-CoA thesis of triglyceride and phospholipids. Triglyceride precursor and determinant of very-low-density (VLDLs) secreted by the liver and which constitute endogenously derived plasma triglyceride generates pyruvate, which, besides forming mitochondnion to form acetyl-CoA

be expected

of opinion, however, sucrose diet as being

would regard the long-term effects of a due mainly to its fructose content (52).

(71). Fructose lactate, enters of pyruvate

as a result

758S hydrogenase for acid three cycle; (PDH) products: long-chain activity. carbon fatty Here dioxide, acids, it can after after act entering as a carbon in the the source citric

MAYES It is amount particularly tration. likely that if this if fructose there was were might administered well be increased by a rise with in insulin an equal

oxidation (72, 73). However,

must be

of glucose,

lipogenesis, concen-

lipogenesis Acetyl-CoA as lipogentransported

accompanied

sequence of reactions; and, ketone bodies is the major carbon source for lipogenesis.
esis occurs in the cytosol, acetyl-CoA

through

the mitochondnial

membrane is converted intermediate carbon acylglycerol

as citrate,

reforming

acetyl-

Immediate effects on fatty acid oxidation on lipoprotein formation and utilization Although diate increase immediate as a result fructose effects of lipid does not seem by itself,

and esterification

and

CoA
citrate

in the cytosol
lyase. important fructose acyl portions

by the action
cytosolic provides of the

of the lipogenic
to long-chain malonyl-CoA. atoms

enzyme,
fatty

AlTacid to cause it does These tissue by that inverse any marked marked acids fatty immeand arise hydroBy these in lipogenesis on the fate mobilization have

Acctyl-CoA

via the pathways, and the

for both molecule.

the glycerol the fate of to [ADP] 76,

of NEFAs. in adipose

or from

The activity of PDH pyruvate. It is activated and by an increase concentrations fructose pletion the ratio of NEFA

is a key factor by a decreased (74); 75). (74,

in determining ratio of [AlT] it is inhibited

lysis of triglyceride-rich established in the perfused up by the dized onstrated dioxide in liver this liver or esterified between and kctonc acylglyccrols controlled (88,

lipoprotcins rat liver 89). An

lipoprotcin lipase. We NEFAs, which are taken per pass, relationship oxidized and those VLDL are either was oxidem-

in pyruvate

by increased in reference causes detherefore, Oral produces of Al? and in he-

to the extent

of 30-40%

As discussed

administration, not only of AlT of [ATP] of large which nucleotides

particularly at high amounts, but of all adenine nucleotides; may not change amounts is known (77, of fructose to follow 78). However, to humans depletion

the quantity of fatty acids bodies on the one hand, and both in VLDLS ketogenesis and

to carbon esterified of in secretion

to [ADP]

appreciably.

on the other.

Regulation

administration hypcruriccmia, other patic otide adcninc [ATP] was concentrations

balance

Downloaded from ajcn.nutrition.org by guest on April 6, 2013

no decrease

a reciprocal the liver, esterified

manner. For a given livers from fed animals more than did livers from

load of fatty acids taken up by oxidized less fatty acids but starved animals, demonstratby the nutritional between these two from fasted animals

found in fructose-fed and PDH activity

rats (79). Adenine nudedid not change when frucconcenAlP and

tose was added to the perfused rat liver at physiological trations of 1 .3 mmol/L. However, at 1 1 .0 mmol/L both total (80). adenine nucleotides were At a fructose concentration increase change of fructose, in PDH in adenine was the

ing that a mechanism state, for regulating major pathways. We

exists, which is affected the partition of fatty acids showed (89) that livers

decreased and PDH was activated of 1 .5 mmol/L there was a peraccompanied (13). concenoleate (a Of

ceptible by any more tration

activity, which was not nucleotide concentrations that at this effect physiological of increased

maintained a constant of the NEFA load, availability could not ification. site for cation

fractional rate of cstcrification irrespective demonstrating that glycerol-3-phosphate have been rate limiting in fatty acid esterestablished that between oxidation where The fatty but the regulatory and esterifiacyl in by

significance

the fact inhibitory

It has now been firmly controlling the balance lies in the oxidative

pathway,

long-chain

NEFA)
support the ratio

on PDH
the view of [Al?]

activity
that

was

reversed.
causes (81).

Generally,
increases rather than

these
in PDH it would

results
activity appear

fructose

groups enter mitochondnial palmitoyltransferasc dna ately. whose active

the mitochondrion (90). oxidation of long-chain I. Fatty do not acids accumulate

rate-limiting step acids is catalyzed to enter are the mitochonimmediesterified

by increasing

pyruvate

concentrations,

by decreasing

failing

to [ADP]

In summary,

for oxidation

that some activation of PDH occurs with high centrations of fructose, especially in antagonism effect of increased concentrations of NEFAs. When fructose was injected intravenously an immediate and pyruvate ministration administered

physiological conto the depressant into rats there was adwas

Palmitoyltransfcrasc concentration lipogcnesis.

I is inhibited by malonyl-CoA increases in the fed condition when This can explain the of fatty change acids between

(90), there is belivers

in balance

though transient increase in glycerol-3-phosphate concentrations (82). In contrast, after glucose there was no immediate increase. When fructose intrapenitoneally phosphate, Similar results 84, 85). Acetyl-CoA there was an increase glycerol-3-phosphate, have been obtained concentrations

twecn esterification of fed and starved

and oxidation animals.

To test whether

fructose

and insulin

had direct

and immediate

in hepatic pyruvate, in the peralso increase

effects on VLDL secretion fed rats with whole blood fused to maintain a constant

by the liver, we perfused livers from into which [4C]oleate NEFA was inphysiological concentration (46, 91). of a physioand increased triglyceride with fructose,

dihydroxyacetone and lactate (83). fused liver (27,

Increased concentrations of insulin or an infusion logical quantity of fructose decreased oxidation estenification from the liver. the separate idation and of fatty When acids insulin and was secretion added of VLDL together

(72). It is also likely that malonyl-CoA concentrations rise when fructose is administered because an increase has been recorded in hepatocytes in the presence of lactate and pyruvate (86), both of which increase in the presence of fructose. Thus, fructose causes increased concentrations and glycolytic of its metabolites and acetyl-CoA in both branches the of glycerol-3-phosphatc

effects were enhancement

additive with of estenification

a further decrease in oxand VLDL secretion.

Malonyl-CoA

is the product

of acctyl-CoA
is activated by glucagon increase

carboxylase

activity

its metabolism. Although many lipogenic intermediates increase in concentration after administration of fructose, there is little evidence that fructose on its own has an immediate effect on lipogenesis. Thus, fructose stimulated lipogenesis from acetate in chick liver slices, Using the tnitiated strate any increase in the presence but not when water technique in lipogenesis of physiological fructose was added we were unable in perfused concentrations livers alone (87). to demonfrom fed rats (13).

and it is known that this enzyme fication by insulin and inhibited insulin raising though fructose mediate phosphate and fructose can independently

by covalent modi(92). Therefore, the concentration

of malonyl-CoA.

Fructose

may

also

enhance

estenification
(93, 94) concentrations of this by insulin glycerol

by
alof

the concentration of glyccrol-3-phosphate this seems unlikely if physiological do not (82). in fact we influence have activity the shown concentration that Also,

inter(95),

mitochondnial

of fructose

acyltransferase

is enhanced

METABOLISM
and this These this sugar. infusion perfusate infusion could effects providing of also account and of fructose physiological liver Only for VLDL a direct secretion. metabolism glucose, with are unique the effect of fructose infusion to with were the of an in the boosted (46). When simultanethere were as VLDL. of a frucmmollL) (1.5 mmol/ (8.9 effect of insulin in pro-

OF
that

FRUCTOSE
ketogenesis was increase progressively raised (13). compared Some (72) At increased 1.5 with mmol control studies also as the fructose/L, perfusions used concentration there

759S of was a

moting

esterification In a direct

fructose significant sence came fructose

on NEFA

in the ab[4C]fructosc.

comparison

of fructose. from and fructose

of these whereas

concentrations compared fructose

At 20 mmol/L,

all of the carbon

at the physiological of the carbon atoms fructose has also

atoms

found

in ketone
half came of i .5 mmol

bodies
from fruc-

of the perfused glucose.

a comparable

at 8.9 mmol/L, concentration originated been used

[4C]NEFA estenification and [4C]VLDL similar amounts of the two sugars were ously to simulate no further increases Perfusions tose against one-third tration.
quining

secretion then infused absorption, or secretion the effect range range physiological is a complex

tose/L, 15% Radiolabeled taken there enous

from fructose (73). to follow the course pathways. Initially, there is no endogis converted acid metabolism, into

sucrose digestion and in NEFA esterification also carried above the within out (73) physiological

by the sugar is no dilution pool of free common

in the various metabolic of fructose label because fructose, with but glucose as fructose and fatty

were

to test

concentration a concentration of the Because

process,

intermediates

the physiological

L). At the higher

concentration,
amount lipoprotein
the lower

VLDL
under
ATP

production

was

cut to
concen-

the label is extensively diluted. Therefore, although it is not possible to quantify the fate of fructose in a whole animal or tissue without pools, fructose. pared, knowledge some Thus, it was idea when of the may specific radioactivity of the fate of starved of intermediary of administered rats given either be obtained the metabolism

found

the
availability

production

energy-rewith

associated

high-fructose concentrations reduced VLDL output under When a 20% fructose triglycerides decreased whereas a comparable both
likely the fall

(76) was probably these conditions. was given baboons of glucose increase
on the

the reason intravenously,

for the serum

[ U-4C]glucosc
synthesized administered formed istered glucose

or [U-4C]fructose shown that although triglyceride fructose, (102).

by gastric intubation was com2.5 times as much newly

Downloaded from ajcn.nutrition.org by guest on April 6, 2013

solution in female solution the

effect

but increased in males, caused a decrease in in triglycerides is most

above, to a decrease as described due

came from twice as much compared These with data

total body glucose of the administered a similar quantity fact that the

as from fructose of adminfructose is

triglyceride

sexes
the

(96).
result

Although
of a direct

reflect

liver,

in triglyceride

concentration

is probably

taken up predominantly mainly by the extrahepatic fructose triglyceride have guinea been pigs

by the liver whereas tissues. In liver

glucose is utilized slices, radiolabeled carbon dioxide, and (103). Similar results

in NEFA strate mans,

concentration,

which

in turn

provides

less

NEFA

sub-

for the fructose

liver and therefore causes a decrease

less VLDL production. In huin NEFAs with little change in that any reduced secretion availability and any into the direct hepatic action by the liver is therefore a effects ketogenic state, is nearly from adipose of fructose. depending always tissue due (97), on the intake to its inwhich a physiological

is converted to lactate, pyruvate, more rapidly than is glucose reported (104) and for incorporation (105). baboons

into After

plasma administration

lipids

in of

insulin concentrations of VLDL is due creased secretion of fructose. The balance Fructose circumstances. of fructose hibition results liver. between is both

(97), indicating to decreased NEFA is most likely due net output of VLDL these two opposing and This antiketogenic

[4C}fructosc, more radioactivity than in the fatty acid portions

is found in glyceride glycerol of hepatic triglyceride (102, 103), of label in the paththan in that to glycinfused to of livers

due in part to greater dilution and exchange way from fructose to long-chain fatty acids erol-3-phosphatc (Fig maintain a concentration

In vivo, is antiketogenic.

in the starved

1). When [U-4Clfructose was of 1.5 mmol/L in the perfusate

of NEFA

mobilization

prepared from fed rats, 12% was oxidized to carbon dioxide and 2.4% was converted to ketone bodies; 4.1% was in liver lipids, 1.6% was incorporated (13). into VLDLS, load and was only 0.4% was in total cholesterol As the fructose increased, proportion-

in reduced uptake of the main ketogenic substrate by the It appears that there is also a direct antiketogenic effect of in vivo in the presence (98). Similar experiments of

fructose on the liver, as demonstrated a constant plasma NEFA concentration have

cytes

been
in the

carried
presence

out

in the
of added

perfused
NEFA

liver and isolated hepato(72, 84, 91, 99, 100). Most out in the inhibition results.
carboxylase,

ally less of the labeled fructose entered lipid products except for ketone bodies, which remained the same. Thus, ketonc bodies and lactate act as overflows of excess carbon as fructose saturates the role fatty metabolic in the acids liver pathways. with are present effects adaptation Hence, respect in excess. intake for many of the longas well In the diet ketone bodies fulfill as they a similar do when to carbohydrate

of these unclear
immediate

experiments whether
activation

were or not
of

carried these

starved It would
which

state. require
has

It is palthe
not

malonyl-CoA
acctyl-CoA

of carnitine

mitoyltransferase been phate cation above could oxidation That reported under

I can explain these

Long-term Enzyme

of a high fructose is also

conditions.

Although

glyccrol-3-phos-

responsible diet on lipid on carbohydrate

availability of NEFAS, the normal cause to ketonc fructose

does not appear to be rate-limiting on esterifiit is possible that boosting its concentration concentration fractional bodies rats was (98). be ketogenic was first shown in perfused as a result estenification of fructose metabolism and less of NEFAs

term effects of a high-fructose as for the long-term effects liver, fructokinase activity (106). Fructose glycerol-3-phosphate conversion intermediate on a fructose rats increased creased liver

metabolism. metabolism.

increased

in rats on a fructose-rich also

a greater

or sucrose feeding dehydrogenase,

increased the activity of which is necessary for the (107, diet, via the glycolytic 108). After 50 d pyruvate kinase in diets inof lipo-

can also

livers from starved The phenomenon

infused with the sugar at 20 mmollL (72). also demonstrated with livers from fed

of fructose to glycerol-3-phosphate dihydroxyacetone phosphate diet, but not on a sucrose substantially PDH activity

animals by using lower but still unphysiological concentrations of fructose (73, 101). To test whether this effect could be obtamed with fructose within physiological livers from concentrations fed animals and we studshowed ied ketogenesis in perfused

(109). Similarly fructose in rats (1 10). In the pathway

genesis and triglyceride formation, ATP-citratc lyase (108, 111, 112), acetyl-CoA carboxylase (111-113), fatty acid synthase

760S (1 1 i-i 14), and phosphatidate phosphohydrolase (1 15) are

MAYES

re-

plasma crose post poprotcin trations cluding the liver Fructose

tissue

triglyceride feeding hepanin results lipolytic

(129). activity,

However, indicating

long-term
(55-58)

fructose and

or increases

su-

ported to be increased in activity in animals on fructose-containing diets. Also, the enzymes responsible for generation of reducing power (107-109, (107, enzyme) Many unique their of soluble or fructose kinase, acid synthase, for activities 108, for lipogencsis-glucose-6-phosphatc iii, 112, 116), 6-phosphogluconate 1 1 1, 1 12), (107, of these fructose (107), feeding PDH, carbohydrates. reduces ATP-citrate adaptive and NADP 1 16)-are in liver glucose that Of considerable the activities lyase, acetyl-CoA dehydrogenase, tissue, (52). whereas It would this malate all feeding 1 1 1, 1 12, because illustrating increased enzyme will is a more interest of hexokinase, carboxylase, and feeding appear dehydrogenase dehydrogcnase dehydrogenase activity also general is that (malic in activity. arc not increase effect sucrose pyruvate fatty NADP glucose from a

in hyperinsulinemia

an enhancement

of li-

lipase activity of triglyceride humans, together feeding

increasing

(52). Therefore, raised plasma concenin fructoseor sucrose-fed animals, inan increased an increased
its plasma

reflects with

rate rate

of VLDL of VLDL of NEFAs

(60,

secretion catabolism. from

61),

by

changes

enhances

the release
concentration

adipose
because

(60),

of a decreased rate of re-esterification tissue (69). Esterification of NEFAs glucose tose eride mation utilization, feeding. in the NEFAs liver (71). which is depressed major are the

of NEFAs within adipose in adipose tissue depends on under precursors they will or -sucrose conditions of VLDL augment diets. of fructriglycforof VLDL Mindful

glucose-6-phosphatc in adipose their activities activities in adipose with this

Therefore,

malate dehydrogenase or starch enhances

in animals

on high-fructose

review of these enzyme the livers but depressed fed animals. In keeping of the following malate, acyl-CoA acctyl-CoA (1 17).

that lipogenesis tissue of sucroseconclusion

is elevated in or fructosepyruvate, long-chain

the fact that NEFAs arc always present in plasma, we studied the effects on VLDL secretion of a physiological infusion of fructose, and of sucrose supplementation of the diet, in isolated perfused glyceride fructose livers rate from livers alone infused production and sucrose-fed more and with in those than [1-4C]oleate in both from were derived doubled. NEFA the infused Because of NEFAs (126). livers with shifts in the VLDL infused rats. fructose, direction tnwith increased animals estenification

the concentrations are elevated: and

intermediates However,

in the liver glycerol-3-phosphate acids from

Downloaded from ajcn.nutrition.org by guest on April 6, 2013

(1 17, 1 18), acetoacetyl-CoA,

sucrose-fed

When the

concentrations (lipogenesis) has by using been la-

apparently do not increase (119). Biosynthesis of long-chain fatty shown (120) to increase or sucrose in liver (121, 122), slices

of secretion oxidation

in balance

between

rats

fed directly

either

fructose

as measured

beled acetate or tritiated water. Increased incorporation of labeled fructose has also been shown (118, i23). In the whole animal, incorporation of tritiated water into liver fatty acids was elevated in rats fed fructose compared with those fed glucose (124). Also,

of estenification have been shown to increase secretion of VLDL triglyceride (89), we also measured these indexes. Oxidation of [ 4C]oleatc to 4C0 was highest and estenification was lowest in control Fructose bination lowest perfusions infusion when livers from or sucrose feeding and increased output normal shifted animals were used. the balance in favor The cornthe and

of estenification

of [4C]VLDL.

F4C]fructosc acylglycerol
diet

was incorporated more rapidly into fatty acids and glycerol in plasma and liver in rats on a fructose we studied laboratory the perfusions perfusate into liver rats. lidiet

of fructose infusion rate of oxidation and

plus sucrose feeding showed the highest rate of estenification

than in rats on a glucose diet (125). In isolated livers perfused with whole blood, pogenesis in rats that had been fed the standard or a sucrose-supplemented were infused concentration acylglycerol of perfusions diet (13, 126). Half

output of [4C]VLDL. in the combined group

The marked extra increase in VLDL output was probably due to increased lipogenesis 126). of fructose 131). that quantities on lipid It was normal metabolism from have individuals this is only information

from fructose in this group (13, The potential adverse effects in humans a review consuming has been of a large diets reviewed number

with fructose to maintain a physiological of 1 .4 mmolfL. Incorporation of 3H2O fatty acids increased fructose was significantly infused only in which

(130, average

concluded of fructose

of studies

in the group

containing

into sucrose-fed

Thus, lipogenesis fructose specifically to those enhanced

ids, but not

is increased on sucrose acts as the substrate. slices

and

diets but only when This finding is similar diet,

on

normal fasting triglyceride a measure of triglyceride on prandial which might erbated leading tose. increase

concentrations. However, clearance and does not give

found

in liver

from
where

rats
slices

on a glucose
from rats

which ac-

and postprandial concentrations be raised on these diets. The

of triglycerides, condition was exac-

selectively
4Cjfructose,

the conversion

of [4C]glucose into fatty specific sugars previously

to fatty
a fructose

in individuals having to hypertniglycenidemia, Similar conclusions than apply normal if higher

defects in carbohydrate metabolism even with low intakes of fructo plasma amounts cholesterol, of VLDLS which arc present. may In

diet selectively [4C]glucose. nature clearly based

incorporated [4Cjfructose They demonstrate the highly adaptations on the enzyme adaptations

acids but not and selective in the diet, discussed. rats when and frucinterest triglyceride in

of the lipogenic

to different

addition, the combination would appear to favor

of saturated fat and fructose in the diet elevated cholesterol concentrations.

Plasma triglycerides diets are enriched with tose (127). This view of the fact

increase in both humans and carbohydrate, especially sucrose and still is, of considerable concentrations of plasma

has been, that raised

Effects

of fructose

on effect

purine of fructose that was needs

metabolism

may be an independent factor associated with coronary heart discase (128). The adaptive changes in enzyme activity, evidence of increase in lipogenic potential, plus the direct actions of fructose previously from described, the liver, all lead increasing to increased the amount output also any of VLDL depends on impairment of triglyceride in the circula-

The hyperuricemic It was intravenously fructose uric acid. and to cause specific The first reported

(132) normal there

when

fructose and those

was

administered hereditary and

body wt

to both intolerance,

children effect

with

an increase appears Also, to be > 0.5

in serum to be dose
gkg

urinary

hyperunicemic infusion comparable

dependent is fructose or galac-

tion. The resultant concentration of triglyceride the rate of hydrolysis by lipoprotein lipase and of this enzyme would also lead to increased

the fructose detectible because

hyperunicemia. infusions

the

effect glucose

concentrations

of either

METABOLISM
tose do not raise the plasma uric acid concentration

OF

FRUCTOSE

76lS

tients
istration

suffering
than are

from

gout

arc
subjects,

more
as

sensitive
are

(133). Pato fructose admin(130). These

ICT1
FRUCTOSE
FRUCTOSE 1P

normal

diabetics

3.f

results apply to fructose sible to increase blood consumed orally? The kg body wt was and in children curred
those subjects,

administered parenterally, but is it posuric acid concentrations when fructose is effect of feeding fructose at a dose of 1 g! gout, ocin
conAMP+ATP
1

2ADP

studied in healthy of parents with but

offspring

subjects, in patients with gout (78). Hyperunicemia more marked

with

in all groups
or

it was
of

and
gout.

prolonged
Subjects

parents,

Adenosine

Adenylo-

IMP4
9 steps

suming 9%

higher

than showed

18%

of their

energy increases

intake

as sucrose uric

(ic, acid Inossne do

MJdIEOS1O#{128} p

as fructose)

significant

in serum

(130). These results suggest or sucrose in a mixed diet hyperunicemia have

tose cemia

that the average intake of fructose is on the borderline for provoking Note
may high

in normal serum
even

individuals. acid conccntrations

individuals a diet

that when
be at

gouty fed
risk of

patients lower-fruchyperuni-

ATP

5-Phosphoribosylamine
AMP.

lower
diets; when

uric
healthy

4
Hypoxanthine
PRPP GL.UTAMYI. M4IDOTR4jG:ER*.SE
A

GMP

consuming

in fructose.

Pathways To

of adenine the

nucleotide mechanism of puninc Adenylate nucleotides

catabolism of the nucleotide kinase ATP,

and biosynthesis hyperunicemic effect of its

XANTHINE (O)DASE)

PRPP
AMP. ADP. AlP

Downloaded from ajcn.nutrition.org by guest on April 6, 2013

understand

fructose regulation between

a knowledge is necessary. the adenine adenosine nuclcotides

degradation the pathway

metabolism and maintains equilibrium adenosinc diphosphate

Xanthine

_____________
XANTHINE o&{DmGB (OXIDASE)

4
I
PRPP SYN1ETASE

(ADP), and three adenine AMP.

pathway reverse of of

monophosphate (AMP) (Fig 2). Thus, are able to be degraded and formed many
of of adenine biosynthesis.

all via the

Uric

acid

Ribose

5-P

However,

as with

other

common
In the

metabolites,
is not degradative the simple

nucleotides

path-

FIG 2. The relationship between formation in the liver. P. phosphate; ADP, adenosine diphosphate; ATP,
phosphate; 1-pyrophosphate; GMP, guanosine IMP, inosine

fructose metabolism and uric acid AMP, adenosine monophosphate:

adenosine triphosphate; PRPP, Pi, organic 5-phosphonibosyl-

way, action

inosine

monophosphate deaminase. to form inosine. AMP via adenosinc indicated as that

(IMP) Phosphate

is formed is then

from

AMP

by the by 5be he-

monophosphate; monophosphate.

of AMP

removed

nucleotidase formed from patocytes for AMP

Alternatively, but experiments

inosine may in isolated

(31) have degradation

that this is not as important via IMP. In addition, the appears adeninc to be the rate-limiting nucleotides (134-136), is an important down and to uric other acid primates

a route reaction step and inhibitor via this hypois the

in hepatic

AlT

concentration this

but also

in total

adeninc

nucleotides shown fell

catalyzed by AMP deaminase in the breakdown of hepatic Pi at normal of this xanthine enzyme. and intracellular Inosinc xanthinc.

(76). The reason for that fructosc-1-phosphatc (27). involves Thus, the rapid sequence

became apparent accumulated and of events after of the sugar

when it was Pi concentrations

concentrations is broken In humans

fructose

administration This leads phosphorylation in fructose-ito

phosphorylation

to fructose-1-phos-

end product of purinc metabolism and is excreted as such, but other mammals possess the enzyme unicase, which allows further oxidation to the much more soluble allantoin. A consequence of the absence of unicase in humans is the occurrence of gout, which is associated with hypcruniccmia. in the pathway This pathway inonly the the rateby a feednude(PRPP), by IMP is also the first formed punine nucleotide of de novo synthesis from nibose 5-phosphate. volves no less than 1 1 separate first two need to be mentioned controlling reactions, both

phate because of the high activity depletion of ATP due to inhibition of ADP because of a shortage

of fructokinase. of oxidative of Pi sequestered

phosphate. The lowering of AlP concentration is also assisted by the activity of tniokinase in utilizing Al? in the phosphorylation of glyceraldehyde to glyccraldehyde-3-phosphatc. The depletion hibition deaminase centration pletion The of Pi and on the and that depletion ATP leads to the removal of the allostenic inAMP condeenzymes that 5-nuclcotidase. leads to increased adenine degrade There nucleotide nucleotides AMP, respectively, is a rise in inosinc of uric also leads acid with pool. to stimulation renusteps as a feedback of adenine first two

steps (137). Of these, because they catalyze are held in check of puninc

formation

of which

of the total

back regulation because of high concentrations otides. In addition, 5-phosphonibosyl-1-pyrophosphatc the product of the first reaction in the pathway activator of the second reaction PRPP glutamyl amidotransferase Mechanism The fructose underlying in the pathway (Fig 2). action

of adenine

is an allostenic catalyzed

of the pathway of punine nucleotide synthesis action (Fig 2). The lowering of the concentration cleotides removes the catalyzed The glutamyl than allostenic by PRPP production is still converted inhibition synthetase of PRPP active, to AMP. the adenine IMP in the pathway amidotransferase. tivator thesis. uric of PRPP acid rather

of the

and PRPP glutamyl acts as a further acleading will In this nuclcotidc way to IMP be degraded the pool initial is augsynto

the hyperuricemic that caused

of fructose

amidotransferase,

If 5-nucleotidase

essential finding administration that

led to the explanation as to why increased uric acid formation was by a sharp fall not only

the observation

it was

accompanied

production of uric acid from mented by dc novo synthesis.

762S The phosphates functions of free synthesis reduction has in concentration other profound of ATP effects and other high and energy

MAYES It will contributions be apparent that although metabolism there have been noteworthy most investi-

on metabolism of these (76) and

other

on fructose

in humans,

dependent energy, eg, (138).

on a continual supply inhibition of protein

vital sources nucleic acid

gations have been carried out in laboratory animals, particularly rats. This is inevitable when precise information about intracellular cedures. needed processes is required, that the involving systematic precise amounts, invasive investigations both and critical proare conddeoccur. as in It is clear to ascertain in humans of fructose

Summary Many

and

conclusions both in vivo and in vitro have been carried Deducparticuof in account

investigations

sumption and tenious effects Nuclear magnetic a noninvasive the concentration

of its concentration such as hyperlipidemia resonance technique of key in monitoring metabolites.

in the blood, at which and hyperunicemia is clearly intracellular

out by using unphysiological concentrations tions made from such observations can larly sucrose compiling when and applied fructose. this review. in the fructose liver-fructokinase, ready access to humans This aspect consuming has been

of fructose. be misleading, normal taken into

spectroscopy

of value changes

quantities

References
to the aldolase B, and tniose phosphate the phosfed state, with domiforload. and dioxide fructose 1. Bruckdorfer KR, Kang 55, Yudkin J. Plasma concentrations insulin, corticosterone, lipids and sugars in rats fed on meals
glucose and fructose. Proc Nutr Soc 1973;32: 12A-B.

Specific enzymes tniokinase-allow

pool and all pathways leading from it, after bypassing phofructokinase regulatory step in glycolysis. In the this nance mation Glucose hanced oxidation allows of the and a greater lactate oxidative ketone body saturation production, pathways production of the activation leading when and shift glycolysis of PDH, to carbon under consequent

of with

pathway

production, glycogenesis, but there is an immediate and estenification

lipogenesis are not enin the balance between in favor of estenification.

of NEFAs

This leads to augmented output of VLDLS from the liver. In the liver of starved animals, the enzymes of gluconeogenesis are active and fructose will form much more glucose under these conditions. As a result fructose changed. of enzyme adaptation to the long-term feeding of is gly-

2. Reiser 5, Michaelis 0, Putney J, Hallfrisch J. Effect of sucrose feeding on the intestinal transport of sugars in two strains of rats. J Nutr 1975;105:894-905. 3. Silliman K, Coulston AM. Sugars in the diet. In: Kretchmer N, Hollenbeck CB, eds. Sugars and sweetners. London: CRC Press, 1991: 17-35. 4. Topping DL, Mayes PA. The concentrations of fructose, glucose and lactate in the splanchnic blood vessels of rats absorbing fructose. Nutr Metab 1971;13:331-8. 5. Mendeloff Al, Weichselbaum TE. Role of the human liver in the assimilation of intravenously administered fructose. Metabolism
1953;2:450-8.

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6. Topping
cose

DL, Mayes
and

PA. Comparative
carbohydrate

effects

of fructose
of perfused

and glurat liver.

on the lipid

metabolism

or sucrose Enhanced and

diets, the pattern of fructose metabolism activity of fructose-1,6-bisphosphatase, glucose-6-phosphatase and glucose. Enhanced but not in adipose allow activity tissue,

cogen synthase, to form glycogen enzymes in the

more fructose of lipogenic long-

Br J Nutr 7. Macdonald constituent

8. Crossley

1976;36:113-26. I, Turner U. Serum fructose levels after sucrose monosaccharides. Lancet 1968; 1:841-3.
JN, Macdonald I. The influence in male baboons

or its

of a high

liver,

stimulates

chain fatty acid synthesis, which actions of fructose in promoting leads to hypertniglycenidemia. tissue also tenification

augments the immediate hepatic VLDL triglyceride output. This Fructose metabolism in adipose eswith

causes impaired glucose utilization and impaired of fatty acids, which promotes release of NEFAs plasma NEFA The increased utilization concentrations triglyceride and

consequent raised VLDL production. centrations impair

and increased NEFA condecreasing with consethe already

sucrose diet on the portal and arterial levels of glucose and fructose following a sucrose meal. Nutr Metab 1970;12:171-8. 9. BjOrkman 0, Felig P. Role of the kidney in the metabolism of fructose in 60-hour fasted humans. Diabetes 1982:31:516-20. 10. Froesch ER, Ginsberg JL. Fructose metabolism of adipose tissue. I. Comparison of fructose and glucose metabolism in epididymal adipose tissue of normal rats. J Biol Chem 1962;237:3317-24. 1 1 . Bergstrom J, Hultman E. Synthesis of muscle glycogen in man after
glucose and fructose infusion. Acta Med Scand 1967;182:93-107.

of glucose

in muscle,

glucose tolerance and quent hypeninsulinemia.

increasing insulin resistance This, in turn, will stimulate

12. Ahlborg G, BjOrkman 0. Splanchnic and muscle fructose metabolism during and after exercise. J Appl Physiol 1990;69:1244-51. 13. Mayes PA, Laker ME. Effects of acute and long-term fructose administration on liver lipid metabolism. In: Macdonald I, Vrana A,

increased VLDL production by the liver. Because tam 20% cholesterol, there is a corresponding cholesterol, Acute with loading little of change the liver in LDL with cholesterol. fructose

VLDLS conrise in plasma 14. a cause of

15.

is also

hyperunicemia. This rylation of fructose phate, preventing

is due to utilization and sequestration regeneration

of Al? in the phosphoof Pi in fructose-1-phosof AlT from ADP. Be-

oxidative

16. 17. 18.

cause the enzymes of adeninc nucleotide degradation are inhibited by AlT and Pi, removal of the inhibition leads to destruction of the total Both can be adeninc nucleotide and in humans. pool and generation effects these of uric effects acid. seem the hyperlipidemic demonstrated hyperuricemic Although of fructose

minimal in healthy very-high-fructose tentially quantities hyperlipidemic of fructose

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