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Intermediary Peter metabolism of fructose3 A Mayes ABSTRACT due Most to its rapid phofructokinase reaching of regulatory and fatty acids, absorption increase nemia. ished loading inorganic ATP enzymes acid of the synthesis. formation metabolism. to esterification secretion effects liver with and of veryby fructose hyperinsuli- causes sequestra- fructose-l-phosphate the nucleotide and inhibition degradation with dimin- Al? is removed consequent of the and hyperuricemia. significance or hyperuricemic by eg, sylation tabolism. of proteins, lactacidemia, The paper concentrates uric hyperlipidemia, fructose, particularly and punine metabolism. of other Of reviews further hyperuricemia, concerning Other in this with an increase in plasma fructose insulin Thus whenever intake added effect of insulin is this alent to hydrolyzed 50% fructose athletes the case with contain sucrose itself but because fructose cause does (2). by glucose, into account. are HFSs 50% - apply and intake. directly feeding some they considerations both not is accompanied must be taken sucrose sucrose secretion of fructose does whereas of fructose secretion insulin effects feeding (1) (3). Similar that augmented of the metabolic glucose, only meof its impact on carbohydrate, lipid aspects referred to are the subjects is whether for some Compared fructo- in copper metabolism volume. consideration is responsible nonenzymic and disturbances on the general the Not are equiv- glucose and to supplements for glucose. These to potentially hypertrigly- Am individuals. terious, of are augmented tolerance, Consequently, of particular ceridemic These in accelerates are lipid far hepatic increases in pyof pyruvate dehydro- in increased glucose phosphate of adenine effects and to of fructose, which causes enzyme adaptalipogenesis and VLDL secretion, leading to decreased Acute of arc the phos- leading oxidation resulting (VLDL). triglyceridemia, glycolysis, from fructose J Clin Nutr General metabolism 1993;58(suppl):754S-765S. Utilization KEY WORDS Fructose, immediate olism, effects, lipid long-term metabolism, low-density intermediary pertriglyceridemia, effects, enzyme lipoproteins, metabolism, liver, sucrose, carbohydrate adaptation, insulin, metab- lipogenesis, nonesterified The fatty very- acids, hy- of blood foods absorption and into the tube Virtually all to two ulatory step. substrate its science or pressant, as the not, syrup fructose feeding, are and at the phosphofructokinase is the its tnreg- provision pathways metabolism a sweetener corn as a food by the liver, gluconeogenesis consequence in fructose use of fructose leading of infrom tn- because of 1). (Fig interest increased bypassing metabolic uptake or in all the metabolic of high-fructose enteral after properties its rapid of glycolysis The phosphate metabolic factors: level creased Current unique pathway phosphate ose the primary to the ose ognized in the (HFS). has been has food Also, industry promoted in the based as for non-insulin-dependent and as a food arisen whether an supplement for endurance form on sound appetite diabetics, half for many of the sucrose years as being molecule, largely fructose responsible abolic effects of high-sucrose diets. Concern of the realization that fructose, at elevated promote metabolic changes that are actually 754S of portal enzyme vein. system de- Am J C/in tissues by Therefore, of the intestinal fructose the for metabolizing fructose, a fractional presented rats (4). fructose- vegetables, is epithelium absorbed presence accounting for of the fructose fed or starved other some all Because and and of flows an active fructose readily uptake of 55% to the liver after In humans it was shown that the fractional high rate extraction of of fructose extraction low concentrations vessels after meals of (6). fructose of fructose containing by As a consequence the liver, of the correspondingly are found in the fructose or sucrose systemic blood are consumed (4, 7, 8). Some 20% of fructose administered intravenously up by the kidney (9). Thus, somewhat less than this amount be expected the liver smaller to be taken up takes up some fraction would by 50% be this organ after of the initial available for oral influx. is taken would feeding where A considerably adipose tissue (10) and for parathletes. has been red- for the met- has arisen because concentrations, can or potentially deleNutr feeding fruits, fructose initially. into of sucrose the liver metabolized at least half of the fructose injected intravenously (5). In the perfused rat liver we found a value of 40% for I Representing transport liver and uptake digestion as honey, passes into the liver, and 71%, respectively, Introduction entry such hepatic the hepatic due of the containing through hyperuricemia fructose consequence 1993;58(suppl):754S-65S. From the Division of Biochemistry, Sciences, Royal Veterinary 2 Supported by the British 3 Address Department University reprint of Printed requests Veterinary of London, in USA. College, Heart Department University Foundation. to PA Mayes, Basic Sciences, London NW1 © 1993 American 0Th, of Veterinary Basic of London. Division Royal of Biochemistry, Veterinary College, UK. Society for Clinical Nutrition Downloaded from ajcn.nutrition.org by guest on July 14, 2014 long-term tions that in of it by-passing immediate activation in balance low-density-lipoprotein tion step include production, a shift nonesterified effects and to carbohydrate consequences and lactate genase, metabolic by the liver consequences These ruvate the utilization METABOLISM OF 755S FRUCTOSE FRUCTSE I ciucose 6.pase_jcr3I G1uc::::L,.4 GLUCOSE6-P’.....#{216}. Glycogen () FRUCTOSE [ FRUCTOSE FRUCTOSE 1.6- bis.Pe 1-P FRUCTOSE 6-P I 4O6PHOFRUCTOKIP4ASE 1 ,6-bis-P Glyceraldehyde FIG 1. Fructose phosphatase; skeletal tose muscle is infused (11). above which oxidation is above and review Of particular centrations vein. 2.2 of (13) values rats were (4). In humans was recorded to resting in peripheral concentration fructose maximum concentrations recorded with glucose and fatty acid metabolism. Pase, that when fruc- this fruc- the metabolic many investiga- out using deductions after pathways involves (Fig uptake in adipose is the three particular the and blood, metabolism attained in (8) maximal after arc the the hepatic conportal concentrations a fructose or sucrose not of meal. when (14). of 1.0 mmol Because no fructose the fructoscfL normal is being blood absorbed, offructose utilization in individual tissues of most hexose fructose is present absorbed in the which do not essary for releasing by respect fructose aldolase and of fructose is rapidly ketohexose of to glucose model catalyzed of human This enzyme physiological much of the fructose aldolase droxyacetonc phosphate, intermediates. Aldolase significance underlies passing (aldolase through it. B) into a member B also in the the ability this rats necthere is In this metabolism. to form of the fructose specific fructose diet. is (17), enzyme in the liver for is the only high ac- to extract so The of the liver Fructose-i-phosphate glyceraldehyde of the glycolysis functions or is virtually and and as the are able absorption. fructose by AlP metab- kidney species by the first enzyme (20). of fructokinase two during it is a kctohexokinase, tivity by liver the in these phosphorylated pathway-fructokinasc because (19) far (15), However, humans glucose-6-phosphatasc, 1-phosphate, fructose glucose. either Thus Hers for fructose in liver into of glucose. the rat is a good Fructose fructose Of (fructokinase, arc specific arc present intestine contain no conversion split the phosphorylation However, when some possible enters muscle. discovered enzymes enzymes it is probably from tissue pathway two of which 1). These its phosphorylation Nevertheless, to convert be in blood will vary from zero up to the above, according to the quantity in the diet. Hexokinase will catalyse sugars, including fructose. fructose, B, and triokinase), olism (10). to hepatic blood pathways that significance which unphymade concentrations by glucose probably in the small intestine of some species-such golden hamster (16), guinea pig (17), and dog (18)-that concentration is zero route greater that at physiological inhibited via muscles. out glucose and concentrations more with is largely a concentration be misleading, particularly when normal quantities of sucrose and baboons recorded a maximum metabolic its interrelationship within the range 1.1-2.2 mmolfL, when fed or given a large fructose meal by gastric intubation fructose Specific and been We found starved likely (14) showing is considerably we pointed relevance have showed in vitro had been carried of fructose and that fructose In humans mmol/L liver to maintain there exercising in vivo and concentrations (12) physiological from such observations could applied to humans consuming fructose. in the subjects concentration, by In a previous tions both siological study exercising the glucose tose A recent into of 5.5 mmol/L, utilization P, phosphate. in the liver is and dihy- sequence in glycolysis of Downloaded from ajcn.nutrition.org by guest on July 14, 2014 Co2 756S MAYES to split fructose-1,6-bisphosphate and dihydroxyacetone to glyceraldehyde-3-phosphate phosphate. The pathway is tniokinase (21), which glyceraldehyde by Al? to form other intermediate from this point tose has arrived through glycolysis, possibly tose (23). acid metabolism Smaller without in glycolysis estenification). in the quantities Thus, passing products sition of fructose carbon by changes in nutritional (13). The of 0.5 and of fructose fructose These will of fruc- lactate ketonc on glycolysis, As a result of the metabolism there loading lactate This initial resulting by increased concentrations enzyme allostenic metabolite (36, is normally under 37). Glycogen synthesis and breakdown series of reactions involving covalent (polyol) and The is responsible for fructose in activity as glucose concentrations tissues that are not undergoes reduction reductase, followed bitol (polyol) bitol and causing ogenesis aldose version Effects damage, of diabetic in the which of fructose with After venous there in those liver (28-31), cent investigations kidney in the path- dehydnogenase, of important the perfused administration loading 1-phosphate but not liven of fructose is a rapid tissues and 32), ‘ and (23, either marked orally or by increase small intestine pathway, (33, P magnetic-resonance though most by using logical concentrations were of fructose, obtained experiments 34). with Re- in the (35). Alunphysio- isolated enhanced passage phosphorylation ters around other phosphoenzymc, lated. Protein whereas hand control of pyruvate carbon kinase and is controlled modification out dephosphorylations is dephosphoryand protein from that of glycogen by Hers (39). of the literature metabolism reveals promoter osition cogen of glycogen appears to result synthase (40, 41) and inhibition of glycogenesis 6-phosphate fusions to be brought a is inhibited accumulates after increases and inhibits with acids into physiological the by liver of fed has been on whether with the balance that fructose (31). The about by several of is a net dep- mechanisms. fructosc-1-phosphate (42-44), of fructose. Also, and activates (45). rats, and from both activation of glyof glycogen phosphorylase in concentration phosphorylase enzymes. in results is glucose administration concentrations which than these allostenic modidiffers in some in muscle a disparity better thase of promotes liven glycogen deposition, in vivo in the fed condition indicating appears censynthase the inactive synthase b is phosphorylactive glycogen phosphorylase a is the detail which by a complex by protein ref 25 for a general review.) synthase (synthase a) is the de- are controlled by hormonal and of glycogen metabolism in liver This fa- (See carry 42). thus lactate. regulation whereas the inactive b form kinases carry out phosphorylations Phosphorylase of increases a similar (38), to pyruvate processes Control A study because are the large which extend Both fiers. fructose studies and lackinase. Although this fructose is added phosphatases reviewed to of glycolytic and dephosphorylation. Briefly, rate-controlling enzymes-glycogcn two phosphoenzyme, ated. On the We using whole of glucose, was infused glucose, rates (46). When either have amino glucose- glycogen carried blood acids, synout per- containing and free fatty fructose, or both sugars at sugar was infused alone. 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 he- of fructose glycogen phosphorylase. active form of glycogen physiological ie, spectroscopy 1-phosphate of fructose effects intra- in glucose the fructose more (40, 26, 27) and cath- that in the starved state, to glucose and up to 25% 8% may form glycogen containing (30, using intermediates have confirmed the accumulation of fructose human liver after intravenous administration of these son- metabolism etenized human subjects (9) indicate 66% of a fructose dose is converted is released as lactate. Up to a further (23). Both in diabetics, involved on carbohydrate both lens in liver and is responsible for the conderived sorbitol to fructose. on the concentrations Experiments of NAD. human Sorbitol in those as the lens. Glucose catalyzed by aldose to fructose by son- is probably cataract. reductase, is found of any exogenously Effects in diabetics in the presence accumulate osmotic rise insulin sensitive, such by NADPH to sorbitol, by oxidation of sorbitol dehydrogenase fructose forma- in the lens, seminal above. It increases span to pyruvate by pyruvate feed-forward olism 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 which In the activation by fructosc-1,6-bisphosphatc. may double in concentration when cilitating of fructose of glycolysis from glyceraldehyde-3-phosphate rate-controlling step is catalyzed activation (25), in5cc- in an increased flux through lactate formation and raised but pathway pathways for intermediates Although the primary purpose of this paper is to review the effects of exogenously derived fructose, discussion of the metab- tissues tion from glucose. This pathway is present vesicles, and placenta of the groups mentioned and in following and gluconeogenesis of the is a tendency increase in concentration, the pathway, evidenced reactions tate, the or ad- glycogenesis, of more significance concentrations, in mammalian 3-phos- ATP, without in glycogen. a concomitant Fructose glucose uptake infusion. was the same with or Downloaded from ajcn.nutrition.org by guest on July 14, 2014 diabetes, Effects blood dispo- between its major end products is altered and endocrine status, eg, gluconeogen- offructose which meal. may alter glycerol lactate, be discussed to hepatocytes (31), in fructose-1-phosphate Biosynthesis fructosc/L, include pyruvate, demon- 1-phosphate after a fructose concentrations administration (Pi). (31) fructose 1 .0 mmol in vivo whose 2,6-bisphosphate, phosphate of tions. and general fructose is increased during starvation, of ethanol or glucagon (24). phate, of fructose elevations by liver are glucose, glycogen, and arc oxidized to carbon dioxide, to tniacylglyccrol concentrations at concentrations organic catalyzed graded significant are available in the portal vein Other important intermediates Fruc- lipogenesis, major occurred as a result on presentation increased subtriose phosphate gluconeogenesis, that in the and similar. (22). In this way fructose, phosphorylated, providing pathways leading from or converted esis from ministration step using strated of an- metabolism of metabolism in metabolism, glycogenesis, fatty bodies stage fructose stage is qualitatively rate-controlling phosphofructokinase to the liver, is rapidly strate to the metabolic (ie, metabolism at this the main patocytes in the fructose pathway. of glucose and triose phosphate on, their enzyme catalyzes the phosphorylation glyceraldehyde-3-phosphate, of the glycolytic Thus, the pathways liver converge at the third METABOLISM Thus, fructose in the sucrose take on its own synthesis activation of glycogen. of glycogen but fructose an increase creased which (22). It was the fed state, fructose lyzed to lactate rather oral load increases from would appear than converted lactate The glycolysis and nonequilibrium and also unique 1). Their producthe many in vitro, make to each use of arc both often phatase (50). The in liver activating concentration from fed fructose-i of fructose, the locus phosphatase of (51). gluconeogenesis the from fructose Therefore, effects which leads However, Unaccu- at the triose inhibition of hepatocytes there under physiological and there gluconeogenic to increased substrate is cy- fructosc-i,6-bis- is no evidence that this inhibits fructose. of a high most ganism when exhibited data have been consuming quirement between as fructose. 7.5% and Long-term diets to adaptive increases leads in the pathways of fructose grouped into those involved metabolism synthesis and (13). may differ from moiety of sucrose turn would those Long-term those may be expected of opinion, however, sucrose diet as being involved effects from humans or animals 70% of their energy-intake feeding of fructose-containing in the activity metabolism. initially of many feeding and adaptive does (54). not 63). creased This glycogen to increased appear insulin of individual plasma feeding resistance, brought fatty (NEFA) acid in the whole or -fructose tissues. high-fructose effects. for to be an insuf- (60, 61). of glucose, as found on a high-sucrose is no doubt a starchreason by the hypoglycemic (59). Thus decreased nonestenified by an increased there is decreased activity The rather the reverse. Increased been reported after sucrose increased and utilization utilization in studies accompanied in the liver diet, However, this or- is also is usually ability to metabolize fructose. Thus, utilization and oxidation of glucose due to depressed glucokinase of glucose-6-phosphatasc in the and liver after infruc- diets are consumed (64). As opposed to the of fructose in facilitating conversion of glucose in the liver (46), long-term feeding imto of fructosc-containing 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 Muscle of a sucrose lactate tissue compared also shows of glucose in adipose oxidation, and tissue conversion load did with a starch decreased and increased ability been fed high-fructose Effects of fructose Immediate not elicit diet ability any extra in- (67). to metabolize to oxidize fatty acids diets (68). Likewise, glu- after animals the utilization is impaired with respect to glycogen (62, 69). to its uptake, effects on lipid metabolism on the initial pathways of lipid metabolism and on lipogenesis Fructose has metabolism. both result of fructose whereas long-term to diets immediate Short-term and or acute metabolism effects result containing high long-term effects effects on that occur arc those by existing mainly from concentrations enzyme enzyme of sucrose Because of the importance of the liver in fructose the blood, many of its effects on lipid metabolism organ. They involve the major pathways The For diets glucose This in majority would regard the long-term effects of a due mainly to its fructose content (52). example, it is likely that important pathway in rats than in humans, be confined to the liver and where even of lipogenesis enzymes triglyceride of feeding sucrose, because the cause increased insulin secretion. to cause re- These enzymes can be with fructose uptake and in lipogenesis of humans has been with may In the liver, dihydroxyacetone acetone phosphate be low in activity secreted or fructose. of fatty acid lipogenesis oxi- dangers must be is a more where lipogenesis may there the key enzymes (70). lipid metabolism is affected by fructose at the phosphate and pyruvate locations. Dihydroxyis in equilibrium with by the liver and which endogenously derived plasma triglyceride generates pyruvate, which, besides forming mitochondnion as a uptake from arc found in glycerol-3-phosphatc, cosubstrate for esterification of long-chain acyl-CoA thesis of triglyceride and phospholipids. Triglyceride precursor and determinant of very-low-density (VLDLs) lipid capacity, adaptation dation and estcnification, and lipogenesis. In this respect, of applying results in experimental animals to humans intake obtained by placed appreciated. Experimental tolerance is due likely concentrations The decreased this fructose and tolerance compared is thus glycolysis. does not metabolites there is no tolerance about cose have ac- (53) glucose and insulin sensitivity, as measured to administered insulin, is less glucose by starvation, and phosphofructokinasc from Long-term and by fructose. In isolated in fructose-2,6-bisphosphate concentrations at during phosphofructokinasc fructose1,6-bisphosphate mulate even when the flux phosphate level increases. cling falls ,6-bisphosphatase pathway and inhibiting der these conditions, gluconcogenesis some increase but (55-58) response consumption on the regime in insulin secretion, concentrations have in blood of fructose-2,6-bisphosphatc rats glucose crease key regulatory molecule-fructosc-2,6-bisphosphatc-which tivates phosphofructokinase and inhibits fructosc-1,6-bisphoselevated the decreased before induced acting that sucrose in animals and These arc catalyzed fructose-i,6-bisphosphaactivities both (25). arc reciprocal modifiers diet, the case a long-term tose-containing mediate effect by pathway based (62, rates but arc controlled the activities by allostenic to of fructose (ic present discus- pathways enzymes these pathways. in glycolysis and (Fig and glucose exceeding Unfortunately, particularly gluconeogenic for which in gluconeogenesis by hormones and even also leads (47, 48). high concentrations be considered in the enzymes reactions, the uptake of lactate pro- not glucose, in humans process. intermediates pivotal in- to be predominantly glycoto glycogen or glucose. An lactate (23, 49). from fructose, unphysiologically and will not common concentrations it has been under ficiency insulin of phosphorylase, gluconcogenesis is an active coordinated, dominate phosphofructokinase tase that Generally, worse to form acetyl-CoA constitute in the synis the major lipoprotcins the bulk (71). Fructose lactate, enters as a result of pyruvate of also the de- Downloaded from ajcn.nutrition.org by guest on July 14, 2014 used 5 mmol/L) by use of the facility because inhibits fructose-i,6-bis- of a fructose infusion, account for the increased condition fructose presumably, 757S FRUCTOSE but case after a glucose up- of a simultaneous glucose infusion, there increment in lactate production. Thus in of gluconeogenesis from studies on gluconcogenesis several inhibition of fructose or sucrose, but in blood lactate concentration In the starved Two and significant duction. In the presence was an additional small many is achieved, synthase only in the presence into the liver could sion. to be glycogenic This itself is not able to make in fructose-1,6-bisphosphate phosphatase have not seem presence of extra glucose, as would be the meal, fructose ‘ ‘opens the door’ ‘ for hepatic and tion does OF 758S MAYES hydrogenase for (PDH) three acid activity. products: cycle; carbon long-chain Here it can dioxide, after fatty acids, after act as a carbon oxidation entering the sequence of reactions; and, ketone bodies is the major carbon source for lipogenesis. (72, 73). However, esis must occurs through CoA in the cytosol, in the cytosol citrate lyase. via the important pathways, and acyl concentrations the carbon of the acylglycerol in pyruvate of NEFA of [ATP] to [ADP] may hypcruriccmia, which is known adcninc [ATP] was concentrations nucleotides not the fate of to [ADP] in reference change of fructose to follow (77, 78). depletion However, found in fructose-fed and PDH activity Oral produces of Al? adenine nucleotides were At a fructose concentration ceptible by any more increase change in PDH in adenine significance was of fructose, NEFA) on PDH activity support the view that by increasing the ratio the pyruvate of [Al?] that at this inhibitory was causes of fructose an immediate and pyruvate ministration in PDH rather than liver activity though transient increase in glycerol-3-phosphate concentrations (82). In contrast, after glucose there was no immediate increase. When fructose adwas intrapenitoneally (27, there phosphate, Similar results 84, 85). was an rats increase glycerol-3-phosphate, have been obtained Acetyl-CoA concentrations in hepatic pyruvate, in the peralso increase as a result of lipid mobilization lysis of triglyceride-rich established in the perfused dized liver between and kctonc in liver acylglyccrols balance a reciprocal the liver, more major ification. site for cation lies its metabolites in both the and branches of acetyl-CoA 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 but not when water technique fructose was added we were unable strate in lipogenesis in perfused any increase in the presence of physiological concentrations livers alone (87). to demonfrom of fructose than and the Palmitoyltransfcrasc concentration fed rats (13). was oxidized and those and starved that animals, acids from where The fatty failing fasted the can explain and oxidation animals. fructose of fatty are the raising though the and insulin do not in fact Also, we acyltransferase (90), there is in balance acids between belivers and immediate together additive with of estenification may influence have increase the shown activity triglyceride with fructose, carboxylase is activated by glucagon also 91). a further decrease in oxand VLDL secretion. of acctyl-CoA independently (46, of a physioand increased of VLDL added enhance the concentration of glyccrol-3-phosphate this seems unlikely if physiological (82). immedi- concentration secretion was Fructose mediate phosphate can in by mitochon- esterified had direct physiological is the product fructose acyl by the liver, we perfused livers from into which [‘4C]oleate NEFA was in- effects were enhancement and fructose regulatory and esterifi- long-chain change of fatty and insulin acids When of malonyl-CoA. animals rate-limiting step acids is catalyzed to enter but and it is known that this enzyme fication by insulin and inhibited insulin in demonstrat- I is inhibited by malonyl-CoA increases in the fed condition when a constant liver. of by the nutritional between these two Increased concentrations of insulin or an infusion logical quantity of fructose decreased oxidation the to carbon esterified secretion established that between oxidation pathway, effects on VLDL secretion fed rats with whole blood from oxidem- Regulation VLDL livers accumulate This to maintain either load of fatty acids taken up by oxidized less fatty acids but (89) I. Fatty To test whether are on the other. from oxidative lipogcnesis. hydro- fractional rate of cstcrification irrespective demonstrating that glycerol-3-phosphate have been rate limiting in fatty acid ester- do not twecn esterification of fed and starved arise relationship exists, which is affected the partition of fatty acids showed and acids or from per pass, inverse the mitochondrion (90). oxidation of long-chain for oxidation fused that imme- lipoprotcin lipase. We NEFAs, which are taken ketogenesis did livers We in Malonyl-CoA of concen- marked fatty tissue by in VLDLS It has now been firmly controlling the balance groups enter mitochondnial ately. whose An both maintained a constant of the NEFA load, availability could not causes glycolytic equal marked have These of 30-40% and pathways. any the quantity of fatty acids bodies on the one hand, ing that a mechanism state, for regulating the separate idation and and in insulin it does of NEFAs. manner. For a given livers from fed animals esterified to cause in adipose 89). controlled in hepatocytes in the presence of lactate and pyruvate (86), both of which increase in the presence of fructose. Thus, fructose concentrations (88, onstrated dioxide estenification increased an lipogenesis, and esterification itself, lipoprotcins rat liver to the extent or esterified (72). It is also likely that malonyl-CoA concentrations rise when fructose is administered because an increase has been recorded glycerol-3-phosphatc by on the fate active into with increased by a rise not seem effects dna appear physiological conto the depressant intravenously does in lipogenesis palmitoyltransferasc by decreasing it would was dihydroxyacetone and lactate (83). fused injected (a results there administered was oleate these In summary, Of concen- increased increases concentrations, (81). accompanied (13). Generally, that some activation of PDH occurs with high centrations of fructose, especially in antagonism effect of increased concentrations of NEFAs. When concenAlP and physiological effect reversed. fructose to [ADP] in he- decreased and PDH was activated of 1 .5 mmol/L there was a per- the fact tration and no decrease activity, which was not nucleotide concentrations be accompanied immediate this rats (79). Adenine nudedid not change when fruc- 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). 76, appreciably. fructose increase up by the causes detherefore, to humans was well the concentration estenification by (93, 94) concentrations alof concentration that of this mitochondnial is enhanced activity by covalent modi(92). Therefore, by inter- glycerol insulin (95), Downloaded from ajcn.nutrition.org by guest on July 14, 2014 amounts diate by increased As discussed Although acid molecule. particularly at high amounts, but of all adenine nucleotides; of large patic otide 75). if this administered might AlT- the glycerol it is inhibited were there Immediate effects on fatty acid oxidation on lipoprotein formation and utilization By these for both if fructose tration. acetylfatty in determining ratio of [AlT] (74); (74, administration other atoms is a key factor by a decreased administration, not only of AlT ratio malonyl-CoA. provides by an increase fructose pletion intermediate that of glucose, particularly transported enzyme, to long-chain cytosolic portions of the lipogenic likely amount lipogenesis reforming is converted It is citric Acetyl-CoA as lipogen- be as citrate, by the action Acctyl-CoA fructose the membrane The activity of PDH pyruvate. It is activated and acetyl-CoA the mitochondnial source in the METABOLISM and this moting could These this also account esterification effects sugar. providing a direct VLDL of fructose In a direct infusion for and on NEFA comparison of the perfused infusion of glucose. Perfusions tose metabolism with were also glucose, liver were compared Only the fructose against carried above a concentration one-third Because quining process, amount lower ATP fructose triglycerides decreased whereas a comparable both sexes likely the the fall (96). result in female solution Although the of a direct effect in triglyceride in NEFA strate mans, mmol/ cut to associated with intravenously, serum but increased in males, caused a decrease in in triglycerides the liver, in turn is most as described due provides NEFA sub- less VLDL production. In huin NEFAs with little change in (97), indicating to decreased NEFA that any reduced secretion availability and any in- creased secretion of fructose. The is most likely due net output of VLDL to the direct hepatic action by the liver is therefore a balance these effects between Fructose is both circumstances. opposing antiketogenic In vivo, of fructose and in the starved is antiketogenic. hibition of NEFA results liver. two This ketogenic state, from depending on the a physiological is nearly mobilization always adipose intake due tissue to its in- (97), which in reduced uptake of the main ketogenic substrate by the It appears that there is also a direct antiketogenic effect of fructose on the liver, as demonstrated a constant plasma NEFA concentration have been cytes in the of these unclear carried out presence experiments whether immediate were or not carried out these in the inhibition these acctyl-CoA of liver and isolated hepato(72, 84, 91, 99, 100). Most NEFA malonyl-CoA of under in vivo in the presence (98). Similar experiments perfused I can explain activation reported phate cation in the of added mitoyltransferase been of fructose. results. starved of carnitine It would carboxylase, conditions. state. Although to ketonc fructose bodies can also livers from starved The phenomenon rats was metabolism was first shown triglyceride istered glucose fructose triglyceride have but as fructose glucose and from of i .5 mmol fruc- is converted fatty specific acid radioactivity be obtained of the into metabolism, the metabolism compared of starved reported pigs data a similar reflect the by the liver whereas tissues. In liver for (104) and as from fructose quantity of adminfructose that is glucose is utilized slices, radiolabeled plasma After lipids in administration of is found in glyceride glycerol of hepatic triglyceride (102, 103), due in part to greater dilution and exchange way from fructose to long-chain fatty acids erol-3-phosphatc (Fig maintain a concentration either fact into (105). [‘4C}fructosc, more radioactivity than in the fatty acid portions given carbon dioxide, and (103). Similar results incorporation baboons rats total body glucose of the administered with These of administered by gastric intubation was com2.5 times as much newly came from twice as much (102). of intermediary fate is converted to lactate, pyruvate, more rapidly than is glucose been guinea of label in the paththan in that to glyc- 1). When [U-’4Clfructose was of 1.5 mmol/L in the perfusate infused to of livers 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 cholesterol (13). into VLDLS, As the fructose and load only was 0.4% was increased, in total proportion- 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 Long-term pathways. liver with are present Hence, respect ketone bodies to carbohydrate fulfill a similar as they do when in excess. in perfused infused with the sugar at 20 mmollL (72). also demonstrated with livers from fed effects of a high fructose adaptation is also term effects of a high-fructose as for the long-term effects liver, less (98). be ketogenic when formed Enzyme concentration That bodies came the not the normal and of the may triglyceride fructose, acids has of NEFAs with or [U-’4C]fructose shown that although it was synthesized administered fatty cause oxidation Thus, pal- glyccrol-3-phos- of fructose half concentration fructose, idea [ U-’4C]glucosc in the could estenification fructose. metabolic above as a result at 8.9 mmol/L, pathways. Initially, there is no endog- knowledge role does not appear to be rate-limiting on esterifiit is possible that boosting its concentration fractional [‘4C]fructosc. in ketone in the various metabolic of fructose label because of free some the availability of NEFAS, a greater used a in the ab- from fructose (73). to follow the course common It is require which also was originated been used taken up predominantly mainly by the extrahepatic above, to a decrease less whereas perfusions found of there the label is extensively diluted. Therefore, although it is not possible to quantify the fate of fructose in a whole animal or tissue pared, given atoms of the carbon atoms fructose has also pool pools, for the control studies (72) concentration fructose/L, of these by the sugar is no dilution without concenenergy-re- the reason is probably which (1.5 was physiological increase liver and therefore causes a decrease insulin concentrations of VLDL is due range Some as the mmol with at the physiological intermediates mmollL) is a complex baboons of glucose concentration concentration, for the fructose enous production and 1.5 all of the carbon fructose tose/L, 15% Radiolabeled of a fruc- availability on fructose taken there (8.9 from At compared of fructose. came there were as VLDL. the was sence At 20 mmol/L, increased (13). increase of an absorption, or secretion (76) was probably these conditions. solution significant raised in the boosted the effect progressively was fructokinase (106). Fructose glycerol-3-phosphate conversion intermediate activity intake responsible for many diet on lipid on carbohydrate increased or sucrose feeding dehydrogenase, longas well In the in rats on a fructose-rich also (107, on a fructose diet, rats increased creased liver substantially PDH activity tamed genesis and triglyceride formation, ATP-citratc lyase (108, 111, 112), acetyl-CoA carboxylase (111-113), fatty acid synthase with fructose within in perfused physiological livers from concentrations fed animals we studand showed diet, via the glycolytic 108). After 50 d animals by using lower but still unphysiological concentrations of fructose (73, 101). To test whether this effect could be obied ketogenesis not on a sucrose diet increased the activity of which is necessary for the of fructose to glycerol-3-phosphate dihydroxyacetone phosphate but of the metabolism. metabolism. pyruvate (109). Similarly fructose in rats (1 10). In the pathway kinase in diets inof lipo- Downloaded from ajcn.nutrition.org by guest on July 14, 2014 a 20% ketogenesis (46). When simultane- range production to a comparable infusion to test under that secretion then infused VLDL found high-fructose concentrations reduced VLDL output under When (73) with the physiological lipoprotein the the effect of fructose physiological concentration, of the tration. out the within L). At the higher are unique concentrations sucrose digestion and in NEFA esterification concentration in pro- 759S FRUCTOSE fructose [‘4C]NEFA estenification and [‘4C]VLDL similar amounts of the two sugars were ously to simulate no further increases of insulin secretion. physiological perfusate effect OF 760S MAYES (1 1 i-i 14), and phosphatidate phosphohydrolase (1 15) are re- plasma triglyceride crose ing power (107-109, poprotcin trations lipase activity of triglyceride cluding humans, (107, for lipogencsis-glucose-6-phosphatc iii, 112, 116), 6-phosphogluconate 108, 1 1 1, 1 12), enzyme’) Many (107, of these unique their for adaptive fructose activities of soluble NADP changes (107), kinase, reduces this the activities lyase, malate dehydrogenase or starch enhances activity will general interest is that tissue, (52). whereas It would that lipogenesis tissue of sucrose- fed with conclusion animals. In keeping acctyl-CoA acyl-CoA (1 17, 1 18), acetoacetyl-CoA, (1 17). However, to increase (120) in liver or sucrose (121, 122), long-chain (lipogenesis) rats as measured fed has either directly by using la- than in rats on a glucose diet (125). In isolated livers perfused with whole blood, pogenesis in rats that had been fed the standard we studied laboratory or a sucrose-supplemented the diet (13, 126). Half with fructose to maintain a physiological of 1 .4 mmolfL. Incorporation of 3H2O acylglycerol fatty of perfusions acids Thus, lipogenesis fructose specifically to those found enhanced ids, not fructose in liver slices from and rats of the lipogenic clearly based tose (127). This view of the fact in the group into sucrose-fed diet, slices from on into fatty specific to different adaptations to fatty rats acids but not and selective sugars previously in the diet, discussed. increase in both humans and carbohydrate, especially sucrose has been, that raised ac- a fructose and still is, of considerable concentrations of plasma previously triglyceride described, from all lead the liver, to increased interest triglyceride increasing the amount tion. The resultant concentration of triglyceride the rate of hydrolysis by lipoprotein lipase and of this enzyme would also lead to increased output in of VLDL of secretion adipose 61), because under conditions precursors they of fruc- of VLDL will augment or -sucrose triglyc- VLDL diets. for- Mindful of [1-’4C]oleate in those oxidation derived animals more than and NEFA in both from were (126). the livers with Because estenification rats. When fructose, shifts of NEFAs tnwith sucrose-fed infused doubled. VLDL infused the in balance in the direction 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 perfusions infusion bination lowest when livers from or sucrose feeding and increased output of [‘4C]VLDL. in the combined group has been reviewed a review of a large number Similar average It was that cornthe and metabolism concluded normal quantities conclusions of fructose to plasma normal addition, the combination would appear to favor have this is only information of triglycerides, condition was exac- defects in carbohydrate metabolism even with low intakes of fruc- apply than from individuals concentrations. However, clearance and does not give and postprandial concentrations be raised on these diets. The if higher The on lipid 131). of studies in individuals having to hypertniglycenidemia, increase 126). of fructose (130, containing normal fasting triglyceride a measure of triglyceride tose. of [‘4C]VLDL. The marked extra increase in VLDL output was probably due to increased lipogenesis in humans erbated leading animals were used. the balance in favor plus sucrose feeding showed the highest rate of estenification from fructose in this group (13, The potential adverse effects diets normal shifted output of fructose infusion rate of oxidation and of fructose amounts cholesterol, which of VLDLS may arc present. In of saturated fat and fructose in the diet elevated cholesterol concentrations. of on The hyperuricemic It was and effect first reported intravenously uric acid. depends on impairment concentrations Effects fructose in the circulaalso any from (60, rats when and fruc- 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 major increased and on prandial which might which with sucrose-fed consuming rats. diets but only when This finding is similar of [‘4C]glucose where adaptations on the enzyme Plasma triglycerides diets are enriched with perfusate into liver on a glucose incorporated [‘4Cjfructose They demonstrate the highly nature only infused the conversion ‘4Cjfructose, diet selectively [‘4C]glucose. significantly was is increased on sucrose acts as the substrate. selectively but increased in which lidiet perfusions were infused concentration alone of estenification diet by of NEFAs within adipose in adipose tissue depends on on high-fructose infused from control Fructose was incorporated more rapidly into fatty acids and glycerol in plasma and liver in rats on a fructose secretion catabolism. of NEFAs concentration Therefore, production between 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, F‘4C]fructosc acylglycerol livers livers been of li- 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 per- fructose fructose of VLDL of VLDL is depressed are the (71). in animals glyceride concentrations acids from rate the release which liver su- increases an enhancement rate its plasma NEFAs in the mation rate slices enhances utilization, fused pyruvate, and glycerol-3-phosphate apparently do not increase (119). Biosynthesis of long-chain fatty shown glucose from a is elevated in or fructose- are elevated: an increased an increased increasing feeding. eride the concentrations in the liver indicating or and (52). Therefore, raised plasma concenin fructoseor sucrose-fed animals, in- with feeding fructose (55-58) to both intolerance, The specific detectible because (132) there infusion metabolism of fructose that normal hyperunicemic the fructose to cause purine when children was appears to be > 0.5 hyperunicemia. comparable and an increase effect needs fructose infusions Also, was those administered with in serum to be dose gkg the of either hereditary and body effect glucose urinary dependent wt ‘ is fructose or galac- Downloaded from ajcn.nutrition.org by guest on July 14, 2014 malate, this intermediates tose NADP feeding appear activities in adipose glucose fatty and long-term of a decreased rate of re-esterification tissue (69). Esterification of NEFAs pyruvate carboxylase, review of these enzyme the livers but depressed of the following effect activity, reflects together (60), However, in hyperinsulinemia lipolytic Fructose tissue sucrose of hexokinase, dehydrogenase, in adipose their activities increase results hepanin the liver arc not also is a more acetyl-CoA glucose-6-phosphatc in activity. enzyme feeding that (‘malic increased Of considerable ATP-citrate synthase, in liver illustrating feeding PDH, dehydrogenase all glucose post dehydrogenase dehydrogcnase malate 1 16)-are because carbohydrates. or fructose acid and 1 1 1, 1 12, feeding (129). ported to be increased in activity in animals on fructose-containing diets. Also, the enzymes responsible for generation of reduc- METABOLISM tose do tients not raise the suffering istration plasma from than are uric gout arc normal acid more as are diabetics (130). effect The curred in all groups those subjects, suming 9% but or higher of feeding than as fructose) it was offspring of 18% showed hyperunicemia have tose lower serum diets; cemia marked energy increases healthy Adenosine con- as sucrose in serum Note that conccntrations individuals a diet when Adenylo- may high be at 9 steps Inossne of 5-Phosphoribosylamine p do ATP AMP. MJdIEOS1O#{128} lower-fruc- risk IMP4 acid patients fed 2ADP 1 (ic, uric gouty 3.f in Subjects intake 1P gout, oc- prolonged gout. AMP+ATP of 1 g! that the average intake of fructose is on the borderline for provoking acid consuming and with individuals. uric even when more parents, significant in normal at a dose subjects, in patients with gout (78). Hyperunicemia of their (130). These results suggest or sucrose in a mixed diet fructose FRUCTOSE e consumed studied in healthy of parents with FRUCTOSE These administered parenterally, but is it posuric acid concentrations when fructose is orally? ICT1 (133). Pato fructose admin- results apply to fructose sible to increase blood kg body wt was and in children 76lS FRUCTOSE concentration sensitive subjects, OF GMP I 4 hyperuni- PRPP GL.UTAMYI. M4IDOTR4jG:ER*.SE Hypoxanthine in fructose. A Pathways of adenine catabolism mechanism of the and biosynthesis PRPP (O)DASE) To understand the fructose regulation a knowledge is necessary. between the (ADP), and three adenine adenine However, pathway of reverse of action as with the pathway of AMP patocytes for AMP many of of other adenine deaminase. indicated as that intracellular of this enzyme. xanthine and its common is then Alternatively, but experiments appears adeninc Inosinc by 5’- 1-pyrophosphate; be he- a route reaction is an important down and to uric other step and inhibitor acid primates via hypo- this is the 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. 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 in the pathway This pathway in- steps (137). Of these, because they catalyze of which are held in check back regulation because of high concentrations otides. In addition, 5-phosphonibosyl-1-pyrophosphatc the product of the first reaction in the activator of the second reaction PRPP glutamyl amidotransferase Mechanism The fructose underlying essential finding administration the observation that that caused it was by a feed- of puninc pathway in the pathway (Fig 2). the hyperuricemic only the the rate- action nude(PRPP), by of fructose led to the explanation as to why increased uric acid formation was accompanied by a sharp fall Ribose GMP, in hepatic guanosine IMP, AlT (27). Thus, involves the rapid adenosine this sequence but also of events phosphorylation because in total became apparent accumulated and after not only Pi, organic 5-phosphonibosyl- of a shortage adeninc nucleotides when it was Pi concentrations fructose of the phate because of the high activity depletion of ATP due to inhibition of ADP triphosphate; PRPP, monophosphate. concentration (76). The reason for that fructosc-1-phosphatc fructose metabolism and uric acid AMP, adenosine monophosphate: monophosphate; inosine 5-P sugar shown fell administration to fructose-1-phos- of fructokinase. of oxidative This leads phosphorylation of Pi sequestered in fructose-i- to 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 of Pi and hibition deaminase on the and centration that pletion ATP leads depletion to the adenine removal degrade There to increased of the total The leads enzymes that 5’-nuclcotidase. formation nucleotide of adenine of the cleotides removes in the pathway amidotransferase. the of uric also tivator of PRPP thesis. If 5’-nucleotidase uric acid rather glutamyl than inhibition by PRPP production leads converted production of uric acid from mented by dc novo synthesis. active, to AMP. the adenine acid with de- to stimulation as a feedback of adenine of the synthetase of PRPP first renu- two steps and PRPP glutamyl acts as a further ac- amidotransferase, is still inAMP con- pool. nucleotides allostenic catalyzed The allostenic AMP, respectively, is a rise in inosinc of the pathway of punine nucleotide synthesis action (Fig 2). The lowering of the concentration is an allostenic catalyzed acid FIG 2. The relationship between formation in the liver. P. phosphate; ADP, adenosine diphosphate; ATP, inosine may in isolated to be the rate-limiting nucleotides (134-136), is broken In humans Uric phosphate; that this is not as important via IMP. In addition, the concentrations xanthinc. path- removed PRPP SYN1ETASE all via by the AMP I XANTHINE simple degradative from AlP S (OXIDASE) the the ADP. 4 o&{DmGB metabolites, In the AMP. Xanthine _____________ diphosphate is not is formed Phosphate catalyzed by AMP deaminase in the breakdown of hepatic Pi at normal metabolism and maintains equilibrium nucleotides (IMP) to form inosine. AMP via adenosinc (31) have degradation of adenosinc biosynthesis. monophosphate nucleotidase formed from ATP, effect monophosphate (AMP) (Fig 2). Thus, are able to be degraded and formed degradation inosine nucleotide kinase nucleotides adenosine nuclcotides AMP. way, of puninc Adenylate hyperunicemic leading IMP will In this nuclcotidc to IMP syn- be degraded way the pool to initial is aug- Downloaded from ajcn.nutrition.org by guest on July 14, 2014 nucleotide XANTHINE 762S MAYES The reduction in concentration phosphates has functions of free dependent energy, eg, synthesis other of ATP profound effects and other high on metabolism on a continual supply inhibition of protein energy and of these (76) and It will other be apparent contributions vital sources nucleic acid (138). lular and processes Many investigations both in vivo and in vitro out by using unphysiological concentrations tions made from such observations can larly when sucrose applied and compiling to humans fructose. this This been of fructose. be misleading, consuming aspect have normal has been Deducparticu- taken into account allows a greater liver-fructokinase, ready access saturation lactate of the production, aldolase B, and tniose phosphate to the and Glucose hanced production, glycogenesis, but there is an immediate and pathways body leading production estenification of fructose changed. and shift with and domi- dioxide under for- fructose load. lipogenesis are not enin the balance between of NEFAs of enzyme in favor of estenification. and enzymes liver, in the adaptation glucose-6-phosphatase and glucose. Enhanced but not leads long-term tissue, is gly- more fructose of lipogenic stimulates Fructose consequent raised VLDL production. plasma NEFA The increased centrations utilization glucose tolerance and quent hypeninsulinemia. metabolism concentrations triglyceride in adipose of glucose and with Acute loading little hyperunicemia. This rylation of fructose preventing the in LDL liver with Both can be adeninc demonstrated tentially hyperlipidemic quantities of fructose pool and of AlT in humans. and a cause from generation hyperuricemic ADP. of uric effects Although and critical pro- in humans both are of fructose con- in the blood, at which and hyperunicemia ddeoccur. spectroscopy is clearly in monitoring metabolites. these Be- acid. of fructose effects may be at increased who risk. take of value intracellular changes as in U Proc Nutr Soc 1973;32: of with 12A-B. DL, Mayes Crossley PA. Comparative and carbohydrate effects metabolism of fructose and glu- of perfused rat liver. 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 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 ministration 15. 16. 17. 18. seem in average fructose. on the lipid Br J Nutr 7. Macdonald constituent of individuals on normal diets, individuals on diets and individuals who are actually or p0or hyperunicemic cose 14. is also of Al? in the phosphoof Pi in fructose-1-phos- regeneration nucleotide the hyperlipidemic minimal in healthy very-high-fructose amounts, resonance technique of key and 1953;2:450-8. VLDLS conrise in plasma cholesterol. fructose is due to utilization and sequestration oxidative with consethe already cause the enzymes of adeninc nucleotide degradation are inhibited by AlT and Pi, removal of the inhibition leads to destruction of the total precise invasive investigations and fructose infusion. Acta Med Scand 1967;182:93-107. 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 ad- decreasing increasing insulin resistance This, in turn, will stimulate change of eswith and increased NEFA con- in muscle, increased VLDL production by the liver. Because tam 20% cholesterol, there is a corresponding cholesterol, investi- 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 8. long- causes impaired glucose utilization and impaired of fatty acids, which promotes release of NEFAs impair noteworthy most 1. Bruckdorfer KR, Kang 55, Yudkin J. Plasma concentrations insulin, corticosterone, lipids and sugars in rats fed on meals of augments the immediate hepatic VLDL triglyceride output. This to hypertniglycenidemia. phate, feeding allow activity in adipose chain fatty acid synthesis, which actions of fructose in promoting tissue also tenification to the diets, the pattern of fructose metabolism activity of fructose-1,6-bisphosphatase, cogen synthase, to form glycogen the magnetic 6. Topping or sucrose Enhanced involving systematic of its concentration such as hyperlipidemia a noninvasive the concentration glucose pathway PDH, to carbon when the phosfed state, 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 been 19. in man. 20. on liver lipid metabolism. In: Macdonald I, Vrana A, eds. Metabolic effects of dietary carbohydrates. Prog Biochem Pharmacol 1986;21 :33-58. Holdsworth CD, Dawson AM. Absorption of fructose in man. Proc Soc Exp Biol Med 1965;118:142-5. Hers HG. Fructose metabolism. (La m#{233}tabolisme du fructose.) Brussels: Arscia, 1957 (in French). Wilson TH, Vincent TN. Absorption of sugars in vitro by the intestine of the golden hamster. J Biol Chem 1955:216:851-66. Ginsburg V, Hers HG. On the conversion of fructose to glucose by guinea pig intestine. Biochim Biophys Acta 1960:38:427-34. Shoemaker WC, Yanof HM, Turk LN, Wilson TH. Glucose and fructose absorption in the unanesthetized dog. Gastroenterology l963;44:654-63. Cook GC, Jacobson J. Individual variation in fructose metabolism Br J Nutr 1971;26:187-95. Hers HG. Fructokinase Biochim Biophys Acta of the liver. 1952;8:416-23. (La fructokinase du foie.) Downloaded from ajcn.nutrition.org by guest on July 14, 2014 of the mation oxidation oxidative glycolysis activation nance ketone have in humans, References in the fructose pool and all pathways leading from it, after bypassing phofructokinase regulatory step in glycolysis. In the this there in review. Specific enzymes tniokinase-allow consequent Nuclear of that to ascertain sumption and tenious effects carried quantities is required, It is clear needed conclusions although metabolism gations have been carried out in laboratory animals, particularly rats. This is inevitable when precise information about intracelcedures. Summary that on fructose METABOLISM 21. Hers HG. Tniokinase. in enzymology. 22. 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