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

• Published in: Cell reports (Cambridge) Vol. 16; no. 3; pp. 744 - 756
• Main Authors: Jin, Jingling, Valanejad, Leila, Nguyen, Thuy Phuong, Lewis, Kyle, Wright, Mary, Cast, Ashley, Stock, Lauren, Timchenko, Lubov, Timchenko, Nikolai A.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 19.07.2016; Elsevier
• Subjects: Animals; C/EBP; Carcinoma, Hepatocellular - metabolism; Carcinoma, Hepatocellular - pathology; CCAAT-Enhancer-Binding Protein-alpha - metabolism; cdk4; cyclin D3; Cyclin-Dependent Kinase 4 - metabolism; Diet, High-Fat - adverse effects; Disease Models, Animal; E1A-Associated p300 Protein - metabolism; Fatty Liver - metabolism; Fatty Liver - pathology; hepatic steatosis; Humans; Liver - metabolism; Liver - pathology; Liver Cirrhosis - metabolism; Liver Cirrhosis - pathology; Liver Neoplasms - metabolism; Liver Neoplasms - pathology; Male; Mice; NAFLD; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; p300; Phosphorylation - physiology; p300; cyclin D3; C/EBP; NAFLD; cdk4; hepatic steatosis
• ISSN: 2211-1247; 2211-1247
• 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/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. [Display omitted] •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 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.