Hepatic Diacylglycerol-Associated Protein Kinase C epsilon Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans

作者：ter Horst Kasper W; Gilijamse Pim W; Versteeg Ruth I; Ackermans Mariette T; Nederveen Aart J; la Fleur Susanne E; Romijn Johannes A; Nieuwdorp Max; Zhang Dongyan; Samuel Varman T; Vatner Daniel F; Petersen Kitt F; Shulman Gerald I; Serlie Mireille J

来源：Cell Reports, 2017, 19(10): 1997-2004.

DOI：10.1016/j.celrep.2017.05.035

Hepatic lipid accumulation has been implicated in the development of insulin resistance, but translational evidence in humans is limited. We investigated the relationship between liver fat and tissue-specific insulin sensitivity in 133 obese subjects. Although the presence of hepatic steatosis in obese subjects was associated with hepatic, adipose tissue, and peripheral insulin resistance, we found that intrahepatic triglycerides were not strictly sufficient or essential for hepatic insulin resistance. Thus, to examine the molecular mechanisms that link hepatic steatosis to hepatic insulin resistance, we comprehensively analyzed liver biopsies from a subset of 29 subjects. Here, hepatic cytosolic diacylglycerol content, but not hepatic ceramide content, was increased in subjects with hepatic insulin resistance. Moreover, cytosolic diacylglycerols were strongly associated with hepatic PKC epsilon activation, as reflected by PKCe translocation to the plasma membrane. These results demonstrate the relevance of hepatic diacylglycerol- induced PKCe activation in the pathogenesis of NAFLD-associated hepatic insulin resistance in humans.

• 出版日期2017-6-6