Defective FXR-SHP Regulation in Obesity Aberrantly Increases miR-802 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 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 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 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.

Obesity-induced miR-802 directly targets AMPK and promotes nonalcoholic steatohepatitis in mice

“…MiR-802 levels are increased in obesity [ 10 , 11 , 15 ], where hepatic AMPK activity is low [ 23 , 26 ]. We, thus, examined whether the miR-802 has a role in decreased AMPK function in obesity.…”

“…Primary mouse hepatocytes (PMH) were isolated as described previously [ 15 , [32] , [33] , [34] ]. Isolated hepatocytes were transfected with 5–50 nM pre-miR-802, antisense-miR-802, or siRNA for Ampkβ1 (ON-TARGETplus SMART pool, Dharmacon), and 2 days later, cells were harvested.…”

“…The mechanisms for aberrant expression of miRs in obesity are generally understudied, but aberrant activation of the gene-regulatory proteins, CRTC2 and FOXO1, was shown to increase transcription of hepatic miR-34a and pancreatic miR-802, respectively [ [11] , [12] , [13] , [14] ]. Further, defective nuclear receptor FXR-SHP function increased hepatic expression of miR-34a and miR-802 in obesity [ 4 , 15 ]. Indeed, treatment with obeticholic acid (OCA), an FXR agonist currently in clinical trials for NASH [ 16 ], decreased hepatic miR-802 levels, ameliorating insulin resistance and fatty liver in mice [ 15 ], but the role of miR-802 in NASH has not been determined.…”

“…Further, defective nuclear receptor FXR-SHP function increased hepatic expression of miR-34a and miR-802 in obesity [ 4 , 15 ]. Indeed, treatment with obeticholic acid (OCA), an FXR agonist currently in clinical trials for NASH [ 16 ], decreased hepatic miR-802 levels, ameliorating insulin resistance and fatty liver in mice [ 15 ], but the role of miR-802 in NASH has not been determined.…”

The Role and Mechanism of Oxidative Stress and Nuclear Receptors in the Development of NAFLD

“…FXR-SHP axis is closely associated with bile acid and lipid metabolism and represents a promising target for treating NAFLD. New evidence has shown that miR-802-mediated defective FXR-SHP regulation promotes insulin resistance and the development of fatty liver [ 204 , 259 ]. However, the expression level of FXR, but not SHP, was decreased in the liver tissue of patients with NAFLD [ 260 ].…”