Hepatic gene expression changes in mouse models with liver-specific deletion or global suppression of the NADPH-cytochrome P450 reductase gene: Mechanistic implications for the regulation of microsomal cytochrome P450 and the fatty liver phenotype

Yan Weng, Concetta C. DiRusso, Andrew A. Reilly, Paul N. Black, Xinxin Ding

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

NADPH-cytochrome P450 reductase (CPR) is an essential component for the function of many enzymes, including microsomal cytochrome P450 (P450) monooxygenases and heme oxygenases. In liver-Cpr-null (with liver-specific Cpr deletion) and Cpr-low (with reduced CPR expression in all organs examined) mouse models, a reduced serum cholesterol level and an induction of hepatic P450s were observed, whereas hepatomegaly and fatty liver were only observed in the liver-Cpr-null model. Our goal was to identify hepatic gene expression changes related to these phenotypes. Cpr-lox mice (with a floxed Cpr gene and normal CPR expression) were used as the control. Through microarray analysis, we identified many genes that were differentially expressed among the three groups of mice. We also recognized the 12 gene ontology terms that contained the most significantly changed gene expression in at least one of the two mouse models. We further uncovered potential mechanisms, such as an increased activation of constitutive androstane receptor and a decreased activation of peroxisomal proliferator-activated receptor-α by precursors of cholesterol biosynthesis, that underlie common changes (e.g. induction of multiple P450s and suppression of genes for fatty acid metabolism) in response to CPR loss in the two mouse models. Additionally, we observed model-specific gene expression changes, such as the induction of a fatty-acid translocase (Cd36 antigen) and the suppression of carnitine O-palmitoyltransferase 1 (Cpt1a) and acyl-CoA synthetase long chain family member 1 (Acsl1), that are potentially responsible for the severe hepatic lipidosis and an altered fatty acid profile observed in liver-Cpr-null mice.

Original languageEnglish (US)
Pages (from-to)31686-31698
Number of pages13
JournalJournal of Biological Chemistry
Volume280
Issue number36
DOIs
StatePublished - Sep 9 2005

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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