MicroRNA-185 regulates expression of lipid metabolism genes and improves insulin sensitivity in mice with non-alcoholic fatty liver disease

Abstract

AIM: To assess the regulatory effect of microRNA-185 (miR-185) on lipid metabolism and the insulin signalling pathway in human HepG2 hepatocytes and a high-fat diet mouse model.

METHODS: Quantitative reverse transcription-polymerase chain reaction was used to assess the mRNA levels of lipogenic genes after loss or gain of miR-185. In addition, the amounts of insulin signalling intermediates were determined after transfection of HepG2 cells with pre-miR-185.

RESULTS: MiR-185 levels decreased in a time- and dose-dependent manner in response to palmitic acid in human HepG2 hepatocytes. Transfection of HepG2 cells with miR-185 significantly decreased the mRNA levels of fatty acid synthase, 3-hydroxy-3-methylglutaryl-CoA reductase, sterol-regulatory element binding protein-2, and sterol-regulatory element binding protein-1c, whereas inhibition of miR-185 using an anti-miR-185 oligonucleotide produced the opposite effect in HepG2 cells. In a high-fat diet mouse model, the accumulation of lipids was significantly improved after treatment with miR-185, compared with control animals. Induction of miR-185 enhanced the insulin signalling pathway by up-regulating the insulin-receptor substrate-2.

CONCLUSION: These findings suggest that miR-185 plays an important role in regulating fatty-acid metabolism and cholesterol homeostasis in hepatocytes, as well as in improving insulin sensitivity, both in vitro and in vivo.

Keywords: MiR-185, Insulin signalling pathway, Lipid metabolism, Non-alcoholic fatty liver disease

Core tip: Our study presents important information on the pathogenesis of non-alcoholic fatty liver disease (NAFLD) and insulin resistance. We used a bioinformatics method to identify microRNAs potentially involved in the regulation of lipid metabolism and insulin signalling. We chose microRNA-185 (miR-185) to validate in vitro and in vivo in regard to regulation of lipid metabolism gene expression and blockade of the insulin signalling pathway. We found that overexpression of miR-185 improved insulin sensitivity and reduced liver steatosis in an NAFLD animal model. No previous studies have reported the regulatory effect of miR-185 on the insulin signalling pathway. MiR-185 might be useful in the design of therapeutic strategies for treating NAFLD and insulin resistance.