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

Publication date: Available online 30 June 2016
Source:Cell Reports
Author(s): Jingling Jin, Leila Valanejad, Thuy Phuong Nguyen, Kyle Lewis, Mary Wright, Ashley Cast, Lauren Stock, Lubov Timchenko, Nikolai A. Timchenko
The 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.

Graphical abstract

Teaser

Jin et al. show that cdk4 activation triggers non-alcoholic fatty liver disease (NAFLD) development. They find that an increased level of cdk4 protein in mice and humans leads to C/EBPα-p300 complex formation and hepatic steatosis. Disruption of this pathway or inhibition of cdk4 prevents NAFLD development and reverses steatosis.


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