Stress-activated in hepatocytes promotes lipid and glucose metabolic disorders associated with high-fat diet consumption.

Objective: is an oncomir highly upregulated in hepatocellular carcinoma and in early stages of liver diseases characterised by the presence of steatosis. Whether upregulation of contributes to hepatic metabolic disorders and their progression towards cancer is unknown. This study aims at investigating the role of in early stages of metabolic liver disorders associated with diet-induced obesity (DIO).

Design: Constitutive knockout (miR21KO) and liver-specific 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 explanted liver tissue were analysed.

Results: Under normal breeding conditions and standard diet, 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 . Deletion of specifically in hepatocytes led to similar improvements in mice fed an HFD, indicating a crucial role for hepatic in metabolic disorders associated with DIO. Further molecular analyses demonstrated that deletion in hepatocytes increases insulin sensitivity and modulates the expression of multiple key metabolic transcription factors involved in fatty acid uptake, lipogenesis, gluconeogenesis and glucose output.

Conclusions: Hepatic 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 * as a potential therapeutic target for non-alcoholic fatty liver disease and the metabolic syndrome.