title: Activation of CDK4 Triggers Development of Non-alcoholic Fatty Liver Disease.
abstract: 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.
authors.affiliation: Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Jingling
authors.initials: J
authors.lastname: Jin
authors.affiliation: Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center (CCHMC), 3333 Burnet Avenue ML 7015, Cincinnati, OH 45229, USA.
authors.forename: Leila
authors.initials: L
authors.lastname: Valanejad
authors.affiliation: Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center (CCHMC), 3333 Burnet Avenue ML 7015, Cincinnati, OH 45229, USA.
authors.forename: Thuy Phuong
authors.initials: TP
authors.lastname: Nguyen
authors.affiliation: Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center (CCHMC), 3333 Burnet Avenue ML 7015, Cincinnati, OH 45229, USA; Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA.
authors.forename: Kyle
authors.initials: K
authors.lastname: Lewis
authors.affiliation: Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center (CCHMC), 3333 Burnet Avenue ML 7015, Cincinnati, OH 45229, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Wright
authors.affiliation: Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center (CCHMC), 3333 Burnet Avenue ML 7015, Cincinnati, OH 45229, USA.
authors.forename: Ashley
authors.initials: A
authors.lastname: Cast
authors.affiliation: Department of Neurology, Cincinnati Children's Hospital Medical Center (CCHMC), 3333 Burnet Avenue ML 7015, Cincinnati, OH 45229, USA.
authors.forename: Lauren
authors.initials: L
authors.lastname: Stock
authors.affiliation: Department of Neurology, Cincinnati Children's Hospital Medical Center (CCHMC), 3333 Burnet Avenue ML 7015, Cincinnati, OH 45229, USA.
authors.forename: Lubov
authors.initials: L
authors.lastname: Timchenko
authors.affiliation: Division of Pediatric General and Thoracic Surgery, Cincinnati Children's Hospital Medical Center (CCHMC), 3333 Burnet Avenue ML 7015, Cincinnati, OH 45229, USA; Huffington Center on Aging, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030, USA. Electronic address: nikolai.timchenko@cchmc.org.
authors.forename: Nikolai A
authors.initials: NA
authors.lastname: Timchenko
mesh_terms: D000818:Animals; D022763:CCAAT-Enhancer-Binding Protein-alpha / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000378:metabolism / Q000473:pathology; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism*; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D005234:Fatty Liver / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease / Q000378:metabolism* / Q000473:pathology*; D010766:Phosphorylation / Q000502:physiology
chemical_list: D022763:CCAAT-Enhancer-Binding Protein-alpha; D050881:E1A-Associated p300 Protein; C495900:CDK4 protein, human; C495902:Cdk4 protein, mouse; D051358:Cyclin-Dependent Kinase 4
keywords: C/EBP; NAFLD; cdk4; cyclin D3; hepatic steatosis; p300