Mol Nutr Food Res. 2020 Dec;64(23):e2000383.doi: 10.1002/mnfr.202000383. Epub 2020 Nov 9.

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Saturated Fatty Acids Promote Hepatocytic Senecence through Regulation of miR-34a/Cyclin-Dependent Kinase 6



  • 1 Department of Gynecology and Obstetrics, The People’s Hospital of China Three Gorges University/The First People’s Hospital of Yichang, Yichang, Hubei, 443000, China.
  • 2 Medical College, China Three Gorges University, Yichang, Hubei, 443002, China.
  • 3 Department of Clinical Laboratory, Shenzhen People’s Hospital, Shenzhen, Guangdong, 518020, China.


Scope: Obesity increases intracellular lipid accumulation in hepatocytes, which can induce non-alcoholic fatty liver disease (NAFLD). With progression of NAFLD, a sizable fraction of patients develop non-alcoholic steatohepatitis (NASH), eventually leading to cirrhosis and hepatocellular carcinoma (HCC). The mechanism involved in obesity-induced NAFLD remains unclear. Free fatty acids and high-fat diets, which induce hepatocyte senescence, are major risk factors for NAFLD. Therefore in this study, the mechanism of lipotoxicity-induced hepatocyte senescence is investigated.

Methods and results: The mice are fed a high-fat diet (HFD) and BNL CL.2 cells are treated with palmitate acid (PA) to establish in vivo and in vitro models of lipotoxicity, respectively. SA-β-gal staining is used to analyze the positively stained senescent hepatocytes. The results show that both PA and HFD induce cellular senescence. Real-time-PCR quantitative analysis reveals that miR-34a is significantly upregulated in the liver tissues of the HFD mice and in the PA-treated BNL CL.2 cells. Western blotting analysis shows that cyclin-dependent kinase inhibitor 1 (CDKN1, also known as p21) is upregulated, while cyclin-dependent kinase 6 (CDK6) is downregulated. Further investigation of the mechanism reveals that CDK6 is a target of miR-34a, which binds to the 3′ UTR of CDK6 and inhibits its expression.

Conclusion: The findings reveal that miR-34a is upregulated in a high-fat environment in the liver, and induces hepatocyte senescence by targeting CDK6. The miR-34a-CDK6 signaling axis may promote NAFLD development in a high-fat environment and therefore represents a potential target for NAFLD therapy.

Keywords: cyclin-dependent kinase 6 (CDK6); high-fat diet (HFD); miR-34a; palmitate acid (PA); senescence.