Abstract 601: MicroRNAs and Hedgehog Signaling in the Pathogenesis of Progressive Liver Injury from NAFLD to Fibrosis

Abstract

Non-alcoholic fatty liver disease (NAFLD) is very common (~70%) in subjects with diabetes and is associated, independently of several confounding factors, with an increased risk of cardiovascular disease (CVD). Diabetes is an independent risk factor for progression of liver fibrosis. Recent studies in human subjects with NAFLD and animal models have demonstrated that microRNAs, a group of noncoding small RNAs, are intimately involved in the development and progression of liver injury, and act to alter expression of genes involved in lipid metabolism and apoptosis. MiR-34a and miR-29 family were among the most frequently dysregulated miRNAs in NAFLD. Thus, the objective of this study was to determine the role of miR-34a and miR-29 in the onset and progression of hepatic steatosis to liver fibrosis in a diabetic mouse model. We showed that streptozotocin (STZ)-induced diabetes predisposed mice to a high-fat-diet (HFD) induced severe liver injury in a much short time course compared to non-diabetic mice. The livers exhibited the development of a spectrum pathological change, with hepatic steatosis at week 6, NASH at week 8 and liver fibrosis at week 12 upon high fat feeding. More importantly, the progressive live injury was closely associated with significantly increased or reduced expression of miR-34a and miR-29 family, respectively, resulting in the activation of hedgehog signaling and the markers of fibrogenesis, Col1A1 and alpha-SMA. Treatment with nanoparticles carrying miR-29b1 mimics improved insulin sensitivity and prevented HFD induced liver fibrosis. In vitro, treatment of McA-RH7777 cells, a rat hepatoma cell line, with a hedgehog signaling inhibitor MDB5 prevented overexpression of miR-34a induced by a free fatty acid, palmitic acid but significantly enhanced expression of miR-29 family in both hepatocytes and hepatic stellate cells. This action hindered the activation of fibrogenesis by lipotoxicity and inflammatory cytokine TNFα. Our study, for the first time, delineates the interaction between miR-34a and miR-29 family and hedgehog signaling in the development of NAFLD and liver fibrosis. This novel finding may provide rationale for developing miRNAs as pharmaceutical targets for the prevention and treatment of liver injury.