Metabolism and Bioenergetics
Mechanism of Hepatic Insulin Resistance in Non-alcoholic Fatty Liver Disease*

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Short term high fat feeding in rats results specifically in hepatic fat accumulation and provides a model of non-alcoholic fatty liver disease in which to study the mechanism of hepatic insulin resistance. Short term fat feeding (FF) caused a ∼3-fold increase in liver triglyceride and total fatty acyl-CoA content without any significant increase in visceral or skeletal muscle fat content. Suppression of endogenous glucose production (EGP) by insulin was diminished in the FF group, despite normal basal EGP and insulin-stimulated peripheral glucose disposal. Hepatic insulin resistance could be attributed to impaired insulin-stimulated IRS-1 and IRS-2 tyrosine phosphorylation. These changes were associated with activation of PKC-ϵ and JNK1. Ultimately, hepatic fat accumulation decreased insulin activation of glycogen synthase and increased gluconeogenesis. Treatment of the FF group with low dose 2,4-dinitrophenol to increase energy expenditure abrogated the development of fatty liver, hepatic insulin resistance, activation of PKC-ϵ and JNK1, and defects in insulin signaling. In conclusion, these data support the hypothesis hepatic steatosis leads to hepatic insulin resistance by stimulating gluconeogenesis and activating PKC-ϵ and JNK1, which may interfere with tyrosine phosphorylation of IRS-1 and IRS-2 and impair the ability of insulin to activate glycogen synthase.

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This work was supported by Grants K23 RR-17404, R01 DK-40936, P30 DK-45735 from the United States Public Health Service and a generous gift from the Eli Lilly Research Laboratories (to V. T. S.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.