2015 Grant Award - Guisheng Song, Ph.D.

Translational Research of microRNA-206 for the Treatment of Obesity and Non-alcoholic Fatty Liver Disease (NAFLD)

Guisheng Song, Ph.D.
Department of Medicine, University of Minnesota

Obesity is a major risk factor for non-alcoholic fatty liver disease (NAFLD), type II diabetes with its associated insulin resistant state, and hyperlipidemia. Many individuals with NAFLD can ultimately progress to non-alcoholic steatohepatitis (NASH), and its potential sequels including fibrosis, cirrhosis and hepatocellular carcinoma (HCC). Although many aspects of obesity have been studied extensively, much of its pathogenesis remains unclear. We are considering a unique and novel approach to investigate the underlying mechanisms and develop a potential therapeutic agent for both obesity and NAFLD.
The discovery of a class of naturally-occurring small non-coding RNAs, termed microRNAs (miRNAs), has stimulated a new field of research relevant to obesity. It is now well-established that the introduction of specific miRNAs or anti-miRs into diseased cells and tissues can induce favorable therapeutic responses. Indeed, miR-122 inhibitor has entered phase III clinical trial as a therapeutic agent for hepatitis C (HCV) infection. Our interest in miR-206 initially arose from a miRNA profiling study of human hepatocytes treated with fatty acid, in which we showed that fatty acid treatment significantly inhibited expression of miR-206. Subsequently, we determined that a high fat diet (HFD) reduced expression of miR-206 in livers of dietary obese mice, whereas overexpressing miR-206 led to a dramatic decrease in body and liver weight, hepatic lipid content, and fasting glucose in dietary obese mice. Mechanistically, we observed that PTPN1 (Protein tyrosine phosphatase nonreceptor type 1) is a direct target of miR-206. It is also now established that PTPN1 is a therapeutic target for obesity via leptin and insulin signaling pathways. This prior research, combined with our findings, led us to hypothesize that miR-206 is a potential therapeutic agent for obesity and NAFLD, and by so doing can improve hepatic insulin signaling and reduce insulin resistance. The main objective of this project is to dissect the molecular mechanism(s) by which miR-206 prevents obesity and NAFLD; and the long-term goal is to develop miR-206 as a therapeutic agent for both obesity and NAFLD. Two specific aims are designed to test our hypothesis. Specifically, we will (1) determine whether PTPN1 mediates the inhibitory effects of miR- 206 on obesity by improving hepatic insulin signaling. To investigate the role of PTPN1 and miR-206 on the development of NAFLD and obesity, we will design a Target Protector (TP) that is complimentary to the miR-206 binding site in the 3’UTR of PTPN1 mRNA and prevents miR-206 binding. If PTPN1 mediates the inhibitory effects of miR-206 on obesity and NAFLD, the introduction of PTPN1 TP will offset the effects of miR-206. We will further show that miR-206 improves insulin signaling by targeting PTPN1. (2) We will also establish the mechanism(s) by which miR-206 prevents lipogenesis via the SP1-Srebp1c pathway. Our preliminary data showed that overexpression of miR-206 in livers of dietary obese mice improved insulin signaling but inhibited expression of Srebp1c, which is counterintuitive to the fact that insulin signaling facilitates expression of Srebp1c. We found that SP1, a transcriptional activator of Srebp1c, is a potential therapeutic target of miR-206, suggesting that miR-206 inhibits expression of Srebp1c by repressing SP1. We will investigate the detailed mechanism by which miR-206 promotes lipogenesis via the SP1-Srebp1c pathway. Our studies are designed to establish miR-206 as a new pathway for the regulation of hepatic lipid accumulation and obesity, and the associated insulin resistant state of type II diabetes. The combination of strong preliminary data and a logical and rationally based experimental design makes this project highly feasible. The results will provide novel insights into the physiological roles and mechanisms of miRNAs in obesity and NAFLD, in addition to their potential therapeutic application for both of these hepatic disorders.