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

Hao Sun, Sunmi Seok, Hyunkyung Jung, Byron Kemper, Jongsook Kim Kemper

Research output: Contribution to journalArticlepeer-review


Objective: Obesity-associated nonalcoholic fatty liver disease (NAFLD) is a leading cause of liver failure and death. However, the pathogenesis of NAFLD and its severe form, nonalcoholic steatohepatitis (NASH), is poorly understood. The energy sensor, AMP-activated protein kinase (AMPK), has decreased activity in obesity and NAFLD, but the mechanisms are unclear. Here, we examined whether obesity-induced miR-802 has a role in promoting NASH by targeting AMPK. We also investigated whether miR-802 and AMPK have roles in modulating beneficial therapeutic effects mediated by obeticholic acid (OCA), a promising clinical agent for NASH. Methods: Immunoblotting, luciferase assays, and RNA-protein interaction studies were performed to test whether miR-802 directly targets AMPK. The roles of miR-802 and AMPK in NASH were examined in mice fed a NASH-promoting diet. Results: Hepatic miR-802 and AMPK levels were inversely correlated in both NAFLD patients and obese mice. MicroRNA in silico analysis, together with biochemical studies in hepatic cells, suggested that miR-802 inhibits hepatic expression of AMPK by binding to the 3’ untranslated regions of both human AMPKα1 and mouse Ampkβ1. In diet-induced NASH mice, OCA treatment reduced hepatic miR-802 levels and improved AMPK activity, ameliorating steatosis, inflammation, and apoptosis, but these OCA-mediated beneficial effects on NASH pathologies, particularly reducing apoptosis, were reversed by overexpression of miR-802 or downregulation of AMPK. Conclusions: These results indicate that miR-802 inhibits AMPK by directly targeting Ampkβ1, promoting NAFLD/NASH in mice. The miR-802-AMPK axis that modulates OCA-mediated beneficial effects on NASH may represent a new therapeutic target.

Original languageEnglish (US)
Article number101603
JournalMolecular Metabolism
StatePublished - Dec 2022


  • FXR
  • Hepatocellular apoptosis
  • Inflammation
  • NASH
  • OCA

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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