title: Ablation of cytochrome P450 omega-hydroxylase 4A14 gene attenuates hepatic steatosis and fibrosis.
abstract: Nonalcoholic fatty liver disease (NAFLD) is characterized by simple hepatic steatosis (SS), nonalcoholic steatohepatitis (NASH), hepatic fibrosis, and cirrhosis. Dysregulated fatty acid metabolism in the liver plays a critical role in the pathogenesis of NAFLD. Cytochrome P450 omega-hydroxylase 4A14 (CYP4A14) is a homolog of human CYP4A hydroxylase that catalyzes omega-hydroxylation of medium-chain fatty acids and arachidonic acid in mice. The goal of this study was to determine the role of CYP4A14 in the development and the progression of NAFLD. Here, we showed that hepatic CYP4A expression was up-regulated in the livers of patients and three murine models of NAFLD. Adenovirus-mediated overexpression of CYP4A14 in the livers of C57BL/6 mice resulted in a fatty liver phenotype with a significant increase in hepatic fatty acid translocase (FAT/CD36) expression. In contrast, CYP4A14 gene-deficient mice fed a high-fat diet or a methionine and choline-deficient (MCD) diet exhibited attenuated liver lipid accumulation and reduced hepatic FAT/CD36 expression. In addition, hepatic inflammation and fibrosis was markedly ameliorated in MCD diet-fed CYP4A14-deficient mice. Collectively, CYP4A14 plays an important role in the pathogenesis of both SS and NASH and may represent a potential therapeutic target for the treatment of NAFLD.
authors.affiliation: Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China.|Center for Nephrology and Urology, Department of Physiology, Shenzhen University Health Science Center, Shenzhen 518060, China.
authors.forename: Xiaoyan
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Department of Pathophysiology, Medical College, Hebei University of Engineering, Handan 056002, Hebei Province, China.
authors.forename: Sha
authors.initials: S
authors.lastname: Li
authors.affiliation: Center for Nephrology and Urology, Department of Physiology, Shenzhen University Health Science Center, Shenzhen 518060, China.
authors.forename: Yunfeng
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Center for Nephrology and Urology, Department of Physiology, Shenzhen University Health Science Center, Shenzhen 518060, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Su
authors.affiliation: Center for Nephrology and Urology, Department of Physiology, Shenzhen University Health Science Center, Shenzhen 518060, China.
authors.forename: Xiongzhong
authors.initials: X
authors.lastname: Ruan
authors.affiliation: Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China.
authors.forename: Bing
authors.initials: B
authors.lastname: Wang
authors.affiliation: Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zheng
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204.|Center for Innovative Medicine, Department of Biosciences and Nutrition, Karolinska Institutet, Novum, 14186 Stockholm, Sweden.
authors.forename: Margaret
authors.initials: M
authors.lastname: Warner
authors.affiliation: Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX 77204; jgustafs@central.uh.edu guanyf@dmu.edu.cn.|Center for Innovative Medicine, Department of Biosciences and Nutrition, Karolinska Institutet, Novum, 14186 Stockholm, Sweden.
authors.forename: Jan-Åke
authors.initials: JÅ
authors.lastname: Gustafsson
authors.affiliation: Advanced Institute for Medical Sciences, Dalian Medical University, Dalian 116044, China; jgustafs@central.uh.edu guanyf@dmu.edu.cn.
authors.forename: Youfei
authors.initials: Y
authors.lastname: Guan
mesh_terms: D000818:Animals; D015415:Biomarkers; D001706:Biopsy; D000072470:Cytochrome P450 Family 4 / Q000235:genetics*; D059305:Diet, High-Fat; D004195:Disease Models, Animal; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D022781:Hepatocytes / Q000378:metabolism; D050356:Lipid Metabolism; D008103:Liver Cirrhosis / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D065626:Non-alcoholic Fatty Liver Disease / Q000209:etiology / Q000235:genetics* / Q000473:pathology*; D051381:Rats
chemical_list: D015415:Biomarkers; C436963:Cyp4a14 protein, mouse; D005227:Fatty Acids; D000072470:Cytochrome P450 Family 4
keywords: NAFLD; arachidonic acid; fatty acid; hepatic fibrosis; inflammation