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

作者：Jin Jingling; Valanejad Leila; Thuy Phuong Nguyen; Lewis Kyle; Wright Mary; Cast Ashley; Stock Lauren; Timchenko Lubov; Timchenko Nikolai A^*

来源：Cell Reports, 2016, 16(3): 744-756.

DOI：10.1016/j.celrep.2016.06.019

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/EBP alpha phosphorylation on Ser193 and formation of C/EBP alpha-p300 complexes, resulting in hepatic steatosis, fibrosis, and hepatocellular carcinoma (HCC). The disruption of this pathway in cdk4-resistant C/EBP alpha-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.

• 出版日期2016-7-19