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

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, we investigated the mechanism of lipotoxicity-induced hepatocyte senescence. METHODS AND RESULTS We fed mice a high-fat diet (HFD) and treated BNL CL.2 cells with palmitate acid (PA) to establish in vivo and in vitro models of lipotoxicity, respectively. SA-β-gal staining was used to analyze the positively stained senescent hepatocytes. The results showed that both PA and HFD induced cellular senescence. Real-time-PCR quantitative analysis revealed that miR-34a was significantly upregulated in the liver tissues of the HFD mice and in the PA-treated BNL CL.2 cells. Western blotting analysis showed that cyclin-dependent kinase inhibitor 1 (CDKN1, also known as p21) was upregulated, while cyclin-dependent kinase 6 (CDK6) was downregulated. Further investigation of the mechanism revealed that CDK6 was a target of miR-34a, which bound to the 3' UTR of CDK6 and inhibited its expression. CONCLUSION Our findings revealed that miR-34a was upregulated in a high-fat environment in the liver, and induced 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. This article is protected by copyright. All rights reserved.