Mir214-3pandhnf4a/Hnf4 Alpha Reciprocally Regulateulk1expression And Autophagy In Nonalcoholic Hepatic Steatosis

Macroautophagy/autophagy, a self-degradative process, regulates metabolic homeostasis in response to various stress conditions and is a therapeutic target for nonalcoholic fatty liver disease. We found that autophagic activity was inhibited as a result of a significant reduction in the expression of autophagy-related genes such asUlk1in a mouse model and patients with fatty liver. This downregulation was caused by increasedMir214-3plevels and decreasedHnf4a/Hnf4 alpha mRNA levels in hepatocytes.Mir214-3psuppressedUlk1expression through direct binding at a 3 ' untranslated region sequence.Hnf4adirectly activated transcription ofUlk1. We investigated lipid accumulation and the expression of autophagy-related genes in the livers of mice treated with anti-Mir214-3p. Hepatic steatosis was alleviated, andUlk1mRNA levels were significantly increased by locked nucleic acid-mediatedMir214-3psilencing. Additionally, autophagosome formation and MAP1LC3/LC3-II protein levels were increased, indicating an increase in autophagic activity. Interestingly, suppression ofMir214-3pdid not ameliorate fatty liver underUlk1suppression, suggesting that reducedMir214-3plevels mitigate hepatic steatosis through upregulation ofUlk1. These results demonstrate that inhibition ofMir214-3pexpression ameliorated fatty liver disease through increased autophagic activity by increasing the expression ofUlk1. Thus,Mir214-3pis a potential therapeutic target for nonalcoholic fatty disease.