Defective FXR-SHP Regulation in Obesity Aberrantly Increases <i>miR-802</i> Expression, Promoting Insulin Resistance and Fatty Liver.

Abstract

Aberrantly elevated expression in obesity of microRNAs (miRNAs), including the miRNA 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 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 <i>miR-802</i> 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 <i>miR-802</i> 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 patients with nonalcoholic fatty liver disease (NAFLD) and in obese mice, occupancy of SHP is reduced and that of AHR is modestly increased at the <i>miR-802</i> promoter, consistent with elevated hepatic miR-802 expression. These results demonstrate that normal inhibition of <i>miR-802</i> by FXR-SHP is defective in obesity, resulting in increased <i>miR-802</i> levels, insulin resistance, and fatty liver. This FXR-SHP-miR-802 pathway may present novel targets for treating type 2 diabetes and NAFLD.