title: Comparative effects of fructose and glucose on lipogenic gene expression and intermediary metabolism in HepG2 liver cells.
abstract: Consumption of large amounts of fructose or sucrose increases lipogenesis and circulating triglycerides in humans. Although the underlying molecular mechanisms responsible for this effect are not completely understood, it is possible that as reported for rodents, high fructose exposure increases expression of the lipogenic enzymes fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC-1) in human liver. Since activation of the hexosamine biosynthesis pathway (HBP) is associated with increases in the expression of FAS and ACC-1, it raises the possibility that HBP-related metabolites would contribute to any increase in hepatic expression of these enzymes following fructose exposure. Thus, we compared lipogenic gene expression in human-derived HepG2 cells after incubation in culture medium containing glucose alone or glucose plus 5 mM fructose, using the HBP precursor 10 mM glucosamine (GlcN) as a positive control. Cellular metabolite profiling was conducted to analyze differences between glucose and fructose metabolism. Despite evidence for the active uptake and metabolism of fructose by HepG2 cells, expression of FAS or ACC-1 did not increase in these cells compared with those incubated with glucose alone. Levels of UDP-N-acetylglucosamine (UDP-GlcNAc), the end-product of the HBP, did not differ significantly between the glucose and fructose conditions. Exposure to 10 mM GlcN for 10 minutes to 24 hours resulted in 8-fold elevated levels of intracellular UDP-GlcNAc (P<0.001), as well as a 74-126% increase in FAS (P<0.05) and 49-95% increase in ACC-1 (P<0.01) expression above controls. It is concluded that in HepG2 liver cells cultured under standard conditions, sustained exposure to fructose does not result in an activation of the HBP or increased lipogenic gene expression. Should this scenario manifest in human liver in vivo, it would suggest that high fructose consumption promotes triglyceride synthesis primarily through its action to provide lipid precursor carbon and not by activating lipogenic gene expression.
authors.affiliation: Department of Nutrition, University of California Davis, Davis, California, United States of America.
authors.forename: Kristin M
authors.initials: KM
authors.lastname: Hirahatake
authors.forename: John K
authors.initials: JK
authors.lastname: Meissen
authors.forename: Oliver
authors.initials: O
authors.lastname: Fiehn
authors.forename: Sean H
authors.initials: SH
authors.lastname: Adams
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000378:metabolism; D064429:Fatty Acid Synthases / Q000378:metabolism; D005632:Fructose / Q000378:metabolism / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects*; D005944:Glucosamine / Q000494:pharmacology; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology*; D056945:Hep G2 Cells; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D014537:Uridine Diphosphate N-Acetylglucosamine / Q000378:metabolism
chemical_list: D005632:Fructose; D014537:Uridine Diphosphate N-Acetylglucosamine; D064429:Fatty Acid Synthases; D000103:Acetyl-CoA Carboxylase; D005947:Glucose; D005944:Glucosamine
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