Activation of CDK4 Triggers Development of Non-alcoholic Fatty Liver Disease

•HFD activates cdk2 and cdk4 and causes liver proliferation and NAFLD•Increase in Cdk4 protein level is a key event in NAFLD development•Inhibition of cdk2/cdk4 prevents development of hepatic steatosis•Inhibition of cdk4 in livers with existing steatosis reverses the steatosis

SummaryThe development of non-alcoholic fatty liver disease (NAFLD) is a multiple step process. Here, we show that activation of cdk4 triggers the development of NAFLD. We found that cdk4 protein levels are elevated in mouse models of NAFLD and in patients with fatty livers. This increase leads to C/EBPα phosphorylation on Ser193 and formation of C/EBPα-p300 complexes, resulting in hepatic steatosis, fibrosis, and hepatocellular carcinoma (HCC). The disruption of this pathway in cdk4-resistant C/EBPα-S193A mice dramatically reduces development of high-fat diet (HFD)-mediated NAFLD. In addition, inhibition of cdk4 by flavopiridol or PD-0332991 significantly reduces development of hepatic steatosis, the first step of NAFLD. Thus, this study reveals that activation of cdk4 triggers NAFLD and that inhibitors of cdk4 may be used for the prevention/treatment of NAFLD.

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