Background & Aims The paradox of selective hepatic insulin resistance, wherein the insulin-resistant liver fails to suppress glucose production but continues to produce lipids, has been central to the pathophysiology of hepatosteatosis and hyperglycemia. Our study was designed to investigate the mechanism(s) by which microRNA-206 alleviates the pathogenesis of hepatosteatosis and hyperglycemia. Methods Dietary obese mice induced by a high fat diet were used to study the role of microRNA-206 in the pathogenesis of hepatosteatosis and hyperglycemia. A mini-circle vector was used to deliver microRNA-206 into the livers of mice. Results Lipid accumulation impaired biogenesis of microRNA-206 in fatty livers of dietary obese mice and human hepatocytes (p <0.01). Delivery of microRNA-206 into the livers of dietary obese mice resulted in the strong therapeutic effects on hepatosteatosis and hyperglycemia. Mechanistically, miR-206 interacted with the 3′ untranslated region of PTPN1 (protein tyrosine phosphatase, non-receptor type 1) and induced its degradation. By inhibiting PTPN1 expression, microRNA-206 facilitated insulin signaling by promoting phosphorylation of INSR (insulin receptor) and impaired hepatic lipogenesis by inhibiting Srebp1c transcription. By simultaneously modulating lipogenesis and insulin signaling, microRNA-206 reduced lipid (p = 0.006) and glucose (p = 0.018) production in human hepatocytes and livers of dietary obese mice (p <0.001 and p <0.01 respectively). Re-introduction of Ptpn1 into livers offset the inhibitory effects of microRNA-206, indicating that PTPN1 mediates the inhibitory effects of microRNA-206 on both hepatosteatosis and hyperglycemia. Conclusions MicroRNA-206 is a potent inhibitor of lipid and glucose production by simultaneously facilitating insulin signaling and impairing hepatic lipogenesis. Our findings potentially provide a novel therapeutic agent for both hepatosteatosis and hyperglycemia. Lay summary The epidemic of obesity is causing a sharp rise in the incidence of insulin resistance and its major complications, type 2 diabetes and non-alcoholic fatty liver disease (NAFLD). However, there are no effective treatments because the mechanisms underlying both disorders are not well described. We identified microRNA-206 as a novel and effective inhibitor for both glucose and lipid production in liver and potentially provide a unique therapeutic drug for both hepatosteatosis and hyperglycemia.
Bibliographical noteFunding Information:
This work was in part supported by the National Institutes of Health (R01 DK102601, G.S. and R01 CA136606, XC), Research Scholar Grant (ISG-16-210-01-RMC) from the American Cancer Society, Gilead Sciences Liver Research Program (G.S), and the Minnesota Obesity Center (G.S).
- Diet, high-fat
- Insulin signaling