Activation of CDK4 Triggers Development of Non-alcoholic Fatty Liver Disease
Jingling Jin,
Leila Valanejad,
Thuy Phuong Nguyen,
Kyle Lewis,
Mary Wright,
Ashley Cast,
Lauren Stock,
Lubov Timchenko,
Nikolai A. Timchenko
Affiliations
Jingling Jin
Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA
Leila Valanejad
Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center (CCHMC), 3333 Burnet Avenue ML 7015, Cincinnati, OH 45229, USA
Thuy Phuong Nguyen
Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center (CCHMC), 3333 Burnet Avenue ML 7015, Cincinnati, OH 45229, USA
Kyle Lewis
Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center (CCHMC), 3333 Burnet Avenue ML 7015, Cincinnati, OH 45229, USA
Mary Wright
Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center (CCHMC), 3333 Burnet Avenue ML 7015, Cincinnati, OH 45229, USA
Ashley Cast
Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center (CCHMC), 3333 Burnet Avenue ML 7015, Cincinnati, OH 45229, USA
Lauren Stock
Department of Neurology, Cincinnati Children’s Hospital Medical Center (CCHMC), 3333 Burnet Avenue ML 7015, Cincinnati, OH 45229, USA
Lubov Timchenko
Department of Neurology, Cincinnati Children’s Hospital Medical Center (CCHMC), 3333 Burnet Avenue ML 7015, Cincinnati, OH 45229, USA
Nikolai A. Timchenko
Division of Pediatric General and Thoracic Surgery, Cincinnati Children’s Hospital Medical Center (CCHMC), 3333 Burnet Avenue ML 7015, Cincinnati, OH 45229, USA
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.
