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Consumption of a fructose-rich diet leads to insulin resistance and dyslipidemia in part due to elevated gluconeogenesis and lipogenesis. SIRT1, an NAD(+)-dependent protein deacetylase, can induce gluconeogenesis and lipogenesis. The aim of this study was to determine whether fructose increased hepatic SIRT1, leading to induction of gluconeogenesis and lipogenesis. Rat hepatocytes were incubated with fructose (1-5 mM). SIRT1 protein, SIRT1 activity, and NAD(+)/NADH ratio were measured. The effects of SIRT1 inhibitors (EX-527 and nicotinamide) and activators (SIRT1 activator 3 and SRT1720) and the mitochondrial complex I inhibitor rotenone were examined on fructose-induced increases in gluconeogenesis and lipogenesis. Fructose increased SIRT1 protein, SIRT1 activity, and NAD(+)/NADH ratio. Fructose also induced gluconeogenesis, with increases in peroxisome proliferator-activated receptor coactivator 1-alpha (PGC1α) and phosphoenolpyruvate carboxykinase (PEPCK; gene code Pck1) gene expression, PEPCK activity, and hepatocyte glucose production. In addition, levels of 3-hydroxy-3-methylglutaryl coenzyme A reductase (Hmgcr) and acetyl-coA carboxylase (Acc) mRNA, and intracellular cholesterol were increased. Increases in gluconeogenesis, Hmgcr, Acc, and cholesterol were abolished by SIRT1 inhibitors and rotenone, while SIRT1 activators increased gluconeogenesis, Hmgcr, Acc, Pgc1β, and sterol regulatory element-binding protein 1c (Srebp1c) gene expression. In conclusion, fructose induces gluconeogenesis and lipogenesis through a SIRT1-dependent mechanism, suggesting that induction of hepatic SIRT1 could play a pivotal role in the metabolic changes observed in humans and animals consuming a fructose-rich diet. These results highlight the need for a greater understanding of the role of SIRT1 in metabolic regulation and indicate the potential for adverse effects of SIRT1 activators if used therapeutically.

FRUCTOSE INDUCES GLUCONEOGENESIS AND LIPOGENESIS THROUGH A SIRT1-DEPENDENT MECHANISM