Ablation of cytochrome P450 omega-hydroxylase 4A14 gene attenuates hepatic steatosis and fibrosis

Xiaoyan Zhang, Sha Li, Yunfeng Zhou, Wen Su, Xiongzhong Ruan, Bing Wang, Feng Zheng, Margaret Warner, Jan Åke Gustafsson, Youfei Guan

Research output: Contribution to journalArticle

32 Scopus citations

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 ofmediumchain 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 highfat 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.

Original languageEnglish (US)
Pages (from-to)3181-3185
Number of pages5
JournalProceedings of the National Academy of Sciences of the United States of America
Volume114
Issue number12
DOIs
StatePublished - Mar 21 2017

Keywords

  • Arachidonic acid
  • Fatty acid
  • Hepatic fibrosis
  • Inflammation
  • NAFLD

ASJC Scopus subject areas

  • General

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