Defective FXR-SHP Regulation in Obesity Aberrantly Increases miR-802 Expression, Promoting Insulin Resistance and Fatty Liver

Aberrantly elevated expression in obesity of microRNAs (miRs), including miR-802, contributes to obesity-associated metabolic complications but the mechanisms underlying the elevated expression are unclear. Farnesoid-X-Receptor (FXR), a key regulator of hepatic energy metabolism, has great potential for treatment of obesity-related diseases. We examined whether a nuclear receptor cascade involving FXR and FXR-induced Small Heterodimer Partner (SHP) regulates expression of miR-802 to maintain glucose and lipid homeostasis. Hepatic miR-802 levels are increased in FXR-knockout (KO) or SHP-KO mice and are decreased by activation of FXR in a SHP-dependent manner. Mechanistically, transactivation of miR-802 by Aromatic Hydrocarbon Receptor (AHR) is inhibited by SHP. In obese mice, activation of FXR by obeticholic acid treatment reduced miR-802 levels and improved insulin resistance and hepatosteatosis, but these beneficial effects were largely abolished by overexpression of miR-802. In non-alcoholic fatty liver disease patients and obese mice, occupancy of SHP is reduced and that of AHR is modestly increased at the miR-802 promoter, consistent with elevated hepatic miR-802 expression. These results demonstrate that normal inhibition of miR-802 by FXR-SHP is defective in obesity, resulting in increased miR-802 levels, insulin resistance and fatty liver. This FXR-SHP-miR-802 pathway may present novel targets for treating type 2 diabetes and NAFLD.