Endogenous fructose production: what do we know and how relevant is it?

PURPOSE OF REVIEW: Excessive sugar and particularly fructose consumption has been proposed to be a key player in the pathogenesis of metabolic syndrome and kidney disease in humans and animal models. However, besides its dietary source, fructose can be endogenously produced in the body from glucose via the activation of the polyol pathway. In this review, we aim to describe the most recent findings and current knowledge on the potential role of endogenous fructose production and metabolism in disease. RECENT FINDINGS: Over the recent years, the activation of the polyol pathway and endogenous fructose production has been observed in multiple tissues including the liver, renal cortex, and hypothalamic areas of the brain. The activation occurs during the development and progression of metabolic syndrome and kidney disease and results from different stimuli including osmotic effects, diabetes, and ischemia. Even though the potential toxicity of the activation of the polyol pathway can be attributed to several intermediate products, the blockade of endogenous fructose metabolism either by using fructokinase deficient mice or specific inhibitors resulted in marked amelioration of multiple metabolic diseases. SUMMARY: New findings suggest that fructose can be produced in the body and that the blockade of tis metabolism could be clinically relevant for the prevention and treatment of metabolic syndrome and kidney disease.

Fructose and uric acid in diabetic nephropathy.

Clinical studies have reported associations between serum uric acid levels and the development of diabetic nephropathy, but the underlying mechanisms remain elusive. There is evidence from animal studies that blocking uric acid production protects the kidney from tubulointerstitial injury, which may suggest a causal role for uric acid in the development of diabetic tubular injury. In turn, when fructose, which is endogenously produced in diabetes via the polyol pathway, is metabolised, uric acid is generated from a side-chain reaction driven by ATP depletion and purine nucleotide turnover. For this reason, uric acid derived from endogenous fructose could cause tubulointerstitial injury in diabetes. Accordingly, our research group recently demonstrated that blocking fructose metabolism in a diabetic mouse model mitigated the development of tubulointerstitial injury by lowering tubular uric acid production. In this review we discuss the relationship between uric acid and fructose as a novel mechanism for the development of diabetic tubular injury.

Postoral glucose sensing, not caloric content, determines sugar reward in C57BL/6J mice.

Recent studies suggest that because of their energy value, sugars are more rewarding than non-caloric sweeteners. However, intragastric infusion data indicate that sugars differ in their postoral appetite-stimulating effects. We therefore compared the preference for isocaloric 8% sucrose, glucose, and fructose solutions with that of a non-caloric sweetener solution (0.8% sucralose) in C57BL/6J mice. Brief 2-bottle tests indicated that sucralose was isopreferred to sucrose but more preferred than glucose or fructose. Yet, in long-term tests, the mice preferred sucrose and glucose, but not fructose to sucralose. Additional experiments were conducted with a non-caloric 0.1% sucralose + 0.1% saccharin mixture (S + S), which does not have the postoral inhibitory effects of 0.8% sucralose. The S + S was preferred to fructose in brief and long-term choice tests. S + S was also preferred to glucose and sucrose in brief tests, but the sugars were preferred in long-term tests. In progressive ratio tests, non-deprived and food-deprived mice licked more for glucose but not fructose than for S + S. These findings demonstrate that the nutrient-specific postoral actions, not calories per se, determine the avidity for sugar versus non-caloric sweeteners. Furthermore, sweet taste intensity and potential postoral inhibitory actions must be considered in comparing non-caloric and caloric sweeteners.

Functional roles of fructose.

During the periimplantation period of pregnancy, pig blastocysts undergo morphological changes and differentiation requiring secretion and transport of nutrients (histotroph) into the uterine lumen. Of these nutrients, glucose is converted to fructose, an isomer of glucose, by conceptus trophectoderm. Although glucose is an energy source for proliferation and growth of mammalian cells, the role of fructose in uterine histotroph is unclear although it is the most abundant hexose sugar in fetal blood and fluids of ungulate mammals (e.g., cows, sheep, and pigs). In this study, we used porcine trophectoderm cells to determine that fructose increased cell proliferation, as did glucose. Western blot analyses of porcine trophectoderm cell extracts revealed that fructose increased the abundance of phosphorylated-RPS6K, -EIF4EBP1, and -RPS6 over basal levels within 30 min, and those levels remained elevated to 120 min. Phosphorylation of both RPS6K and EIF4EBP1 proteins in response to fructose was inhibited by inhibitors of both PI3K and MTOR. Further, when we investigated the inhibition of glutamine-fructose-6-phosphate transaminase 1 (GFPT1) by azaserine (an inhibitor of GFPT1) and GFPT1 siRNA, we found that MTOR-RPS6K and MTOR-EIF4EBP1 signaling in response to fructose is mediated via GFPT1 activation and the hexosamine pathway. We further demonstrated that fructose stimulates the production of hyaluronic acid via GFPT1 and the hexosamine biosynthesis pathway. Collectively, these results demonstrate critical roles for fructose that are mediated via the hexosamine biosynthesis pathway to stimulate MTOR cell signaling, proliferation of porcine trophectoderm cells, and synthesis of hyaluronic acid, a significant glycosaminoglycan in the pregnant uterus.

Inhibition of balloon injury-induced neointimal formation by olmesartan and pravastatin in rats with insulin resistance.

The combined effect of an angiotensin II type 1 receptor blocker and a 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitor on vascular lesion formation in the insulin-resistant state has not been examined. We tested whether or not combined treatment is superior to single-drug treatment for inhibiting vascular lesion formation in insulin-resistant rats. The rats were maintained on a fructose-rich diet for 4 weeks and then treated with olmesartan (1 mg/kg/day) and/or pravastatin (10 mg/kg/day) for 3 weeks. After 1 week of drug treatment, balloon injury of the carotid arteries was performed. Two weeks later, the injured arteries were harvested for morphometry and immunostaining. Olmesartan and pravastatin each modestly attenuated neointimal formation without significant changes in blood pressure or serum lipid levels. The combination of olmesartan and pravastatin significantly suppressed the neointimal formation compared with either monotherapy. The number of terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive cells was increased by olmesartan but not by pravastatin. Olmesartan and pravastatin each decreased the number of Ki-67-positive cells, which indicates cell proliferation, to the same extent. The combined treatment increased the number of TUNEL-positive cells but did not affect the number of Ki-67-positive cells. The combined treatment decreased the insulin level and increased the number of circulating endothelial progenitor cells. These results suggest that the combination of olmesartan and pravastatin is beneficial for the treatment of vascular diseases in the insulin-resistant state independently of blood pressure or cholesterol levels.

Crosstalk between auxin, cytokinins, and sugars in the plant cell cycle.

Plant meristems are utilization sinks, in which cell division activity governs sink strength. However, the molecular mechanisms by which cell division activity and sink strength are adjusted to a plant's developmental program in its environmental setting are not well understood. Mitogenic hormonal as well as metabolic signals drive and modulate the cell cycle, but a coherent idea of how this is accomplished, is still missing. Auxin and cytokinins are known as endogenous mitogens whose concentrations and timing, however, can be externally affected. Although the sites and mechanisms of signal interaction in cell cycle control have not yet been unravelled, crosstalk of sugar and phytohormone signals could be localized to several biochemical levels. At the expression level of cell cycle control genes, like cyclins, Cdks, and others, synergistic but also antagonistic interactions could be demonstrated. Another level of crosstalk is that of signal generation or modulation. Cytokinins affect the activity of extracellular invertases and hexose-uptake carriers and thus impinge on an intracellular sugar signal. With tobacco BY-2 cells, a coordinated control of cell cycle activity at both regulatory levels could be shown. Comparison of the results obtained with the root cell-representing BY-2 cells with literature data from shoot tissues or green cell cultures of Arabidopsis and Chenopodium suggests opposed and tissue-specific regulatory patterns of mitogenic signals and signal crosstalk in root and shoot meristems.

Calcium and fructose intake in relation to risk of prostate cancer.

Laboratory and clinical data indicate an antitumor effect of 1,25(OH)2 vitamin D (1,25(OH)2D) on prostate cancer. High calcium intake suppresses formation of 1,25(OH)2D from 25(OH)D, thereby decreasing the 1,25(OH)2D level. Ingestion of fructose reduces plasma phosphate transiently, and hypophosphatemia stimulates 1,25(OH)2D production. We thus conducted a prospective study among 47,781 men of the Health Professionals Follow-Up Study free of cancer in 1986 to examine whether calcium and fructose intake influenced risk of prostate cancer. Between 1986 and 1994, 1369 non-stage A1 and 423 advanced (extraprostatic) cases of prostate cancer were diagnosed. Higher consumption of calcium was related to advanced prostate cancer [multivariate relative risk (RR), 2.97; 95% confidence interval (CI), 1.61-5.50 for intakes > or = 2000 mg/day versus < 500 mg/day; P, trend, 0.002] and metastatic prostate cancer (RR, 4.57; CI, 1.88-11.1; P, trend, <0.001). Calcium from food sources and from supplements independently increased risk. High fructose intake was related to a lower risk of advanced prostate cancer (multivariate RR, 0.51; CI, 0.33-0.80, for intakes > 70 versus < or = 40 g/day; P, trend, 0.007). Fruit intake was inversely associated with risk of advanced prostate cancer (RR, 0.63; 95% CI, 0.43-0.93; for > 5 versus < or = 1 serving per day), and this association was accounted for by fructose intake. Non-fruit sources of fructose similarly predicted lower risk of advanced prostate cancer. A moderate positive association between energy-adjusted fat intake and advanced prostate cancer was attenuated and no longer statistically significant when controlled for calcium and fructose. Our findings provide indirect evidence for a protective influence of high 1,25(OH)2D levels on prostate cancer and support increased fruit consumption and avoidance of high calcium intake to reduce the risk of advanced prostate cancer.

Asynchronous ripening behavior of cactus pear (Opuntia ficus-indica) cultivars with respect to physicochemical and physiological attributes.

Physicochemical and physiological ripening events in cactus pear (Opuntia ficus-indica) fruit of cultivars 'Ntopia' and 'Hercules' were profiled against skin coloration from mature-green (S1) to over-mature (S5). Fructose and glucose accumulation were linear in 'Ntopia' but peaked near S3 in 'Hercules' synchronously to the appearance of sucrose. Betalains increased steadily in 'Ntopia' (103.2mg/l) but peaked before full skin coloration in 'Hercules' (49.7mg/l); whereas phenolic content remained invariable and ascorbate content peaked near S5 in both 'Ntopia' (108.6µg/g) and 'Hercules' (163.1µg/g). Cell wall material diminished with maturity though textural changes with ripening appeared not related to pectin solubilization but to weakening of glycan bonding and loss of neutral sugars. Fruit firmness rather was correlated to seed weight (r=0.89) and seed-to-pulp ratio (r=0.73). Cultivar differences highlighted in the chronology of ripening events are critical for defining optimum harvest maturity and postharvest handling protocols for premium quality cactus pear fruit.

Role of mitochondria in hepatic fructose metabolism.

During metabolism of fructose at concentrations exceeding 5 mM, isolated liver cells accumulate fructose 1-phosphate and lose ATP. At added bicarbonate concentrations below 10 mM in the incubation medium, the addition of atractyloside (or carboxyatractyloside) causes a significant net accumulation of 2-phosphoglycerate, resulting in an increase in the ratio 2-phosphoglycerate: 3-phosphoglycerate from below 1 to greater than 5. Digitonin fractionation revealed that virtually all this 2-phosphoglycerate is associated with the mitochondrial fraction, where it achieves a concentration estimated to be about 40 mM. The amount of 2-phosphoglycerate that accumulates is directly related to the initial concentration of fructose. With DL-glyceraldehyde in place of fructose, an even greater accumulation of 2-phosphoglycerate occurs, and this is also dependent upon both the presence of atractyloside and low bicarbonate. Formation of 2-phosphoglycerate is also observed when isolated mitochondria from rat liver are incubated together with glyceraldehyde and an energy source. The obligatory role of atractyloside for the accumulation of 2-phosphoglycerate within intact cells indicates the involvement of the mitochondrial adenylate translocator in this process, possibly as a carrier directly responsible for 2-phosphoglycerate egress from the mitochondrial matrix. If this is so, competition between 2-phosphoglycerate and ATP for egress from the matrix would be predicted to further exaggerate the fructose-induced depletion of cytosolic ATP.

Glucose-induced activation of plasma membrane H(+)-ATPase in mutants of the yeast Saccharomyces cerevisiae affected in cAMP metabolism, cAMP-dependent protein phosphorylation and the initiation of glycolysis.

Addition of glucose-related fermentable sugars or protonophores to derepressed cells of the yeast Saccharomyces cerevisiae causes a 3- to 4-fold activation of the plasma membrane H(+)-ATPase within a few minutes. These conditions are known to cause rapid increases in the cAMP level. In yeast strains carrying temperature-sensitive mutations in genes required for cAMP synthesis, incubation at the restrictive temperature reduced the extent of H(+)-ATPase activation. Incubation of non-temperature-sensitive strains, however, at such temperatures also caused reduction of H(+)-ATPase activation. Yeast strains which are specifically deficient in the glucose-induced cAMP increase (and not in basal cAMP synthesis) still showed plasma membrane H(+)-ATPase activation. Yeast mutants with widely divergent activity levels of cAMP-dependent protein kinase displayed very similar levels of activation of the plasma membrane H(+)-ATPase. This was also true for a yeast mutant carrying a deletion in the CDC25 gene. These results show that the cAMP-protein kinase A signaling pathway is not required for glucose activation of the H(+)-ATPase. They also contradict the specific requirement of the CDC25 gene product. Experiments with yeast strains carrying point or deletion mutations in the genes coding for the sugar phosphorylating enzymes hexokinase PI and PII and glucokinase showed that activation of the H(+)-ATPase with glucose or fructose was completely dependent on the presence of a kinase able to phosphorylate the sugar. These and other data concerning the role of initial sugar metabolism in triggering activation are consistent with the idea that the glucose-induced activation pathways of cAMP-synthesis and H(+)-ATPase have a common initiation point.

Pysicochemical studies of taste reception. V. Suppressive effect of salts on sugar response of the frog.

The tast responses of frog to various kinds of sugars were measured quantitatively by use of the glossopharyngeal nerve activity under an appropriate condition where the water response was completely suppressed. The concentration dependences of response of frog tongue to D-fructose, D-glucose, and sucrose were almost the same, D-galactose, however, elicited a much larger response in comparison with the other sugars in the whole range of concentrations examined. The sugar response was suppressed extensively by the presence of small amount of salts in the stimulating sugar solution. The suppressive effects of NaCl, KCl, MgCl2, MgSO4, and K4Fe(CN)6 were examined with a fixed concentration of sugar. The results obtained with these salts, added in various concentrations, fell on a single curve when the data were plotted against the ionic strength in the stimulating solution. The present results were consistent with the notion that the taste receptor potential for salts or acids is attributable to a change in the phase boundary potential at the membrane-solution interface as proposed in the previous papers of this series.

Sugar import and phytopathogenicity of Spiroplasma citri: glucose and fructose play distinct roles.

We have shown previously that the glucose PTS (phosphotransferase system) permease enzyme II of Spiroplasma citri is split into two distinct polypeptides, which are encoded by two separate genes, crr and ptsG. A S. citri mutant was obtained by disruption of ptsG through homologous recombination and was proved unable to import glucose. The ptsG mutant (GII3-glc1) was transmitted to periwinkle (Catharanthus roseus) plants through injection to the leaf-hopper vector. In contrast to the previously characterized fructose operon mutant GMT 553, which was found virtually nonpathogenic, the ptsG mutant GII3-glc1 induced severe symptoms similar to those induced by the wild-type strain GII-3. These results, indicating that fructose and glucose utilization were not equally involved in pathogenicity, were consistent with biochemical data showing that, in the presence of both sugars, S. citri used fructose preferentially. Proton nuclear magnetic resonance analyses of carbohydrates in plant extracts revealed the accumulation of soluble sugars, particularly glucose, in plants infected by S. citri GII-3 or GII3-glc1 but not in those infected by GMT 553. From these data, a hypothetical model was proposed to establish the relationship between fructose utilization by the spiroplasmas present in the phloem sieve tubes and glucose accumulation in the leaves of S. citri infected plants.

Fructose-responsive genes in the small intestine of neonatal rats.

The intestinal brush border fructose transporter GLUT5 (SLC2A5) typically appears in rats after weaning is completed. However, precocious consumption of dietary fructose or in vivo perfusion for 4 h of the small intestine with high fructose (HF) specifically stimulates de novo synthesis of GLUT5 mRNA and protein before weaning is completed. Intermediary signals linking the substrate, fructose, to GLUT5 transcription are not known but should also respond to fructose perfusion. Hence, we used microarray hybridization and RT-PCR to identify genes whose expression levels change during HF relative to high-glucose (HG) perfusion. Expression of GLUT5 and NaPi2b, the intestinal Na+-dependent phosphate transporter, dramatically increased and decreased, respectively, with HF perfusion for 4 h. Expression of >20 genes, including two key gluconeogenic enzymes, glucose-6-phosphatase (G6P) and fructose-1,6-bisphosphatase, also increased markedly, along with fructose-2,6-bisphosphatase, an enzyme unique to fructose metabolism and regulating fructose-1,6-bisphosphatase activity. GLUT5 and G6P mRNA abundance, which increased dramatically with HF relative to HG, alpha-methylglucose, and normal Ringer perfusion, may be tightly and specifically linked to changes in intestinal luminal fructose but not glucose concentrations. G6P but not GLUT5 mRNA abundance increased after just 20 min of HF perfusion. This cluster of gluconeogenic enzymes and their common metabolic intermediate fructose-6-phosphate may regulate fructose metabolism and GLUT5 expression in the small intestine.

Why do sugars taste good?

The preference humans and animals show for sweet solutions has been the subject of hundreds of publications. Nevertheless, the evolutionary origin of sweet preference remains enigmatic because of the relatively low nutritional value of sugars and the absence of specific tastes for other, more essential, nutrients. Moderate concentrations of sugars are found in most plant foods because sugars play an important role in plant physiology. Widespread occurrence of sugars in plants is paralleled by widespread preference for sugar solutions in mammals. These observations suggest that preference for sugars evolved because they are common in plants and easy to detect rather than because of any special nutritional merits they offer. Perception of sweetness cannot be used to accurately meter the metabolizable energy or nutritive value of a food.

The age-related changes in lipogenic enzymes: the role of dietary factors and thyroid hormone responsiveness.

To determine whether resistance to insulin or to thyroid hormones rather than an inherent defect in enzyme activity expression account for the age-related changes in lipogenic enzymes, the activities of malic enzymes (ME), fatty acid synthase (FAS), glucose-6-phosphate dehydrogenase (G-6PD) and 6-phosphogluconate dehydrogenase (6-PGD) were assayed in hepatic, retroperitoneal fat and epididymal fat cytosol of male Fischer 344 rats at 3.5, 12 and 25 months of age. The rats were maintained on either regular rat chow with 62% of calories as complex carbohydrates or were given either high glucose or fructose diet with 65.7% of calories provided by glucose or fructose respectively. Additional groups of young and aged rats were treated with L-triiodothyronine (T3) (15 microg/100 g body weight) for 10 days. Treatment with T3 resulted in higher levels of hepatic ME activity regardless of the diet consumed or the age of the rats. T3 had no consistent effect on FAS, G-6PD or 6-PGD activities. ME response to T3 in young rats was significantly greater than that found in aged rats regardless of diet. The age-related decrease in basal hepatic ME activity was not apparent in rats maintained on the high glucose or the high fructose diets, yet the T3 responsiveness of ME in rats maintained on these diets was not normalized. In adipose tissue, with the exception of the age-related changes in basal activity of the lipogenic enzymes, neither T3 nor the feeding of the test diets had any consistent effects. Since insulin resistance induced by high fructose feeding did not reduce hepatic lipogenic enzymes, it is unlikely that the age-related increase in insulin resistance explains the reduced lipogenic enzyme activity in aged rats. However, resistance to thyroid hormone action found in aged rats may partly account for the reduced hepatic lipogenic enzyme activity.

Mechanisms of insulin resistance in rat models of hypertension and their relationships with salt sensitivity.

Several lines of evidence suggest that insulin resistance and the resultant hyperinsulinaemia are causally related to hypertension. Insulin actions are initiated by binding to a high-affinity transmembrane protein receptor which is present in all mammalian cells. These effects are predominant in skeletal muscle, liver, and fat and involve a number of tissue-specific and biochemically diverse events. Less well known are effects of insulin occurring in tissues not usually considered as insulin targets, which are hypothetical contributors to the pro-hypertensive action of the hormone. These effects include activation of renal sodium reabsorption, stimulation of the sympathetic nervous system, growth-promoting activity on vascular smooth muscle cells, and modulation of transmembrane cation transport. Epidemiological investigations have implicated sodium intake in the pathogenesis of hypertension. Because of the sodium-retaining effects of insulin, it has been postulated that insulin resistance with associated hyperinsulinaemia may be critical for the pathogenesis of salt-sensitivity in essential hypertensive subjects. Insulin resistance is present also in strains of rats with genetic hypertension that can be utilized as models to study the molecular mechanisms of this abnormality. In the present article, we summarize the current knowledge of the mechanisms of insulin resistance in rat models of arterial hypertension in which decreased sensitivity to insulin occurs and propose a rationale hypothesis that links insulin resistance with salt-sensitivity and hypertension.

[Regulation of pyruvate kinase gene expression and its clinical application].

Pyruvate kinase (PK), an important glycolytic enzyme, has two genes per haploid genome in mammals and each gene encodes two isozymes. The L gene produces the L- and R-types using alternative promoters. The M gene generates the M1- and M2-types by alternative RNA splicing. Expression of the PK isozymes is tissue-specific and regulated developmentally. Carcinogenesis apparently reverses the developmental process. Expression of the L-type is regulated by dietary and hormonal factors. These regulations occurred at post-transcriptional as well as transcriptional levels. The transcription of hepatic L-type PK is stimulated by insulin and inhibited by glucagon. The insulin action requires ongoing protein synthesis and metabolism of glucose, and is enhanced by glucocorticoid. Dietary fructose also stimulates expression of the L-type in liver, kidney, and small intestine, but its mechanism is dependent on tissues, and on plasma insulin levels in the case of the liver. In normal liver, the fructose induction is explained by stimulation of gene transcription. On the other hand, fructose acts mainly at the post-transcriptional level in diabetic liver and other tissues. These fructose effects are attributable to common metabolite(s) of fructose and glycerol. Studies on transgenic mice indicate that the 5'-flanking region up to -3 kb of the L-type PK gene contains cis-acting elements responsible for insulin regulation and tissue-specific expression of the L-type. Further analysis using a transient expression assay revealed the presence of multiple elements necessary for expression of the L-type in hepatocytes in the region up to -170b.(ABSTRACT TRUNCATED AT 250 WORDS)

Short-term dietary supplementation with fructose accelerates gastric emptying of a fructose but not a glucose solution.

OBJECTIVE: Short-term dietary glucose supplementation has been shown to accelerate the gastric emptying rate of both glucose and fructose solutions. The aim of this study was to examine gastric emptying rate responses to monosaccharide ingestion following short-term dietary fructose supplementation. METHODS: The gastric emptying rate of a fructose solution containing 36 g of fructose and an equicaloric glucose solution containing 39.6 g glucose monohydrate were measured in 10 healthy non-smoking men with and without prior fructose supplementation (water control) using a randomized crossover design. Gastric emptying rate was assessed for a period of 1 h using the [(13)C]breath test with sample collections at baseline and 10-min intervals following drink ingestion. Additionally, appetite ratings of hunger, fullness, and prospective food consumption were recorded at baseline and every 10 min using visual analog scales. RESULTS: Increased dietary fructose ingestion resulted in significantly accelerated half-emptying time of a fructose solution (mean = 48, SD = 6 versus 58, SD = 14 min control; P = 0.037), whereas the emptying of a glucose solution remained unchanged (mean = 85, SD = 31 versus 78, SD = 27 min control; P = 0.273). Time of maximal emptying rate of fructose was also significantly accelerated following increased dietary fructose intake (mean = 33, SD = 6 versus 38, SD = 9 min control; P = 0.042), while it remained unchanged for glucose (mean = 45, SD = 14 versus 44, SD = 14 min control; P = 0.757). No effects of supplementation were observed for appetite measures. CONCLUSION: Three d of supplementation with 120 g/d of fructose resulted in an acceleration of gastric emptying rate of a fructose solution but not a glucose solution.

Review article: fructose in non-alcoholic fatty liver disease.

BACKGROUND: The role of excess fructose intake in the pathogenesis of non-alcoholic fatty liver disease (NAFLD) has recently received increasing attention, but the pathophysiology of this relationship has been only partly elucidated. AIM: To provide an overview of the potential role played by fructose in the pathogenesis of NAFLD by focusing on both indirect and direct harmful effects. METHODS: Experimental and clinical studies which investigated the relation of fructose with NAFLD are reviewed. RESULTS: Several factors may potentially contribute to fructose-induced NAFLD, including the induction of the metabolic syndrome, copper deficiency, bacterial translocation from the gut to the liver, the formation of advanced glycation endproducts and a direct dysmetabolic effect on liver enzymes. CONCLUSIONS: Experimentally-increased fructose intake recapitulates many of the pathophysiological characteristics of the metabolic syndrome in humans, which may in turn lead to NAFLD. However, the majority of experimental studies tend to involve feeding excessively high levels of fructose (60-70% of total energy intake) which is not reflective of average human intake. Hopefully, the combination of in vivo, in vitro and genetic research will provide substantial mechanistic evidence into the role of fructose in NAFLD development and its complications.

Regulation of adipose differentiation by fructose and GluT5.

Adipose tissue is an important metabolic organ that is crucial for whole-body insulin sensitivity and energy homeostasis. Highly refined fructose intake increases visceral adiposity although the mechanism(s) remain unclear. Differentiation of preadipocytes to mature adipocytes is a highly regulated process that is associated with characteristic sequential changes in adipocyte gene expression. We demonstrate that fructose treatment of murine 3T3-L1 cells incubated in standard differentiation medium increases adipogenesis and adipocyte-related gene expression. We further show that the key fructose transporter, GluT5, is expressed in early-stage adipocyte differentiation but is not expressed in mature adipocytes. GluT5 overexpression or knockdown increased and decreased adipocyte differentiation, respectively, and treatment of 3T3-L1 cells with a specific GluT5 inhibitor decreased adipocyte differentiation. Epidymal white adipose tissue was reduced in GluT5-/- mice compared with wild-type mice, and mouse embryonic fibroblasts derived from GluT5-/- mice exhibited impaired adipocyte differentiation. Taken together, these results demonstrate that fructose and GluT5 play an important role in regulating adipose differentiation.