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

Sunmi Seok, Hao Sun, Young-Chae Kim, Byron Kemper, Jongsook Kim Kemper

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)733-744
Number of pages12
JournalDiabetes
Volume70
Issue number3
Early online dateDec 16 2020
DOIs
StatePublished - Mar 1 2021

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism

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