Stress-activated <i>miR-21/miR-21*</i> in hepatocytes promotes lipid and glucose metabolic disorders associated with high-fat diet consumption.

Abstract

<i>miR-21</i> is an oncomir highly upregulated in hepatocellular carcinoma and in early stages of liver diseases characterised by the presence of steatosis. Whether upregulation of <i>miR-21</i> contributes to hepatic metabolic disorders and their progression towards cancer is unknown. This study aims at investigating the role of <i>miR-21/miR-21*</i> in early stages of metabolic liver disorders associated with diet-induced obesity (DIO). Constitutive <i>miR-21/miR-21*</i> knockout (miR21KO) and liver-specific <i>miR-21/miR-21*</i> knockout (LImiR21KO) mice were generated. Mice were then fed with high-fat diet (HFD) and alterations of the lipid and glucose metabolism were investigated. Serum and <i>ex vivo</i> explanted liver tissue were analysed. Under normal breeding conditions and standard diet, <i>miR-21/miR-21*</i> deletion in mice was not associated with any detectable phenotypic alterations. However, when mice were challenged with an obesogenic diet, glucose intolerance, steatosis and adiposity were improved in mice lacking <i>miR-21/miR-21*</i>. Deletion of <i>miR-21/miR-21*</i> specifically in hepatocytes led to similar improvements in mice fed an HFD, indicating a crucial role for hepatic <i>miR-21/miR-21*</i> in metabolic disorders associated with DIO. Further molecular analyses demonstrated that <i>miR-21/miR-21*</i> deletion in hepatocytes increases insulin sensitivity and modulates the expression of multiple key metabolic transcription factors involved in fatty acid uptake, <i>de novo</i> lipogenesis, gluconeogenesis and glucose output. Hepatic <i>miR-21/miR-21*</i> deficiency prevents glucose intolerance and steatosis in mice fed an obesogenic diet by altering the expression of several master metabolic regulators. This study points out <i>miR-21/miR-21</i>* as a potential therapeutic target for non-alcoholic fatty liver disease and the metabolic syndrome.