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Saturated Fatty Acids Promote Hepatocytic Senecence through Regulation of miR‐34a/Cyclin‐Dependent Kinase 6
Author(s) -
Qin Yue,
Duan Li,
He Yumin,
Yuan Chengfu,
Wang Ting,
Yuan Ding,
Zhang Changcheng,
Liu Chaoqi
Publication year - 2020
Publication title -
molecular nutrition and food research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.495
H-Index - 131
eISSN - 1613-4133
pISSN - 1613-4125
DOI - 10.1002/mnfr.202000383
Subject(s) - lipotoxicity , cyclin dependent kinase 6 , fatty liver , downregulation and upregulation , endocrinology , steatohepatitis , hepatocyte , medicine , senescence , chemistry , nonalcoholic fatty liver disease , cancer research , cyclin d1 , biology , kinase , cyclin dependent kinase 2 , microbiology and biotechnology , cell cycle , protein kinase a , biochemistry , cancer , in vitro , insulin resistance , disease , gene , insulin
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.