title: Potential biological functions of cytochrome P450 reductase-dependent enzymes in small intestine: novel link to expression of major histocompatibility complex class II genes.
abstract: NADPH-cytochrome P450 reductase (POR) is essential for the functioning of microsomal cytochrome P450 (P450) monooxygenases and heme oxygenases. The biological roles of the POR-dependent enzymes in the intestine have not been defined, despite the wealth of knowledge on the biochemical properties of the various oxygenases. In this study, cDNA microarray analysis revealed significant changes in gene expression in enterocytes isolated from the small intestine of intestinal epithelium-specific Por knock-out (named IE-Cpr-null) mice compared with that observed in wild-type (WT) littermates. Gene ontology analyses revealed significant changes in terms related to P450s, transporters, cholesterol biosynthesis, and, unexpectedly, antigen presentation/processing. The genomic changes were confirmed at either mRNA or protein level for selected genes, including those of the major histocompatibility complex class II (MHC II). Cholesterol biosynthetic activity was greatly reduced in the enterocytes of the IE-Cpr-null mice, as evidenced by the accumulation of the lanosterol metabolite, 24-dihydrolanosterol. However, no differences in either circulating or enterocyte cholesterol levels were observed between IE-Cpr-null and WT mice. Interestingly, the levels of the cholesterol precursor farnesyl pyrophosphate and its derivative geranylgeranyl pyrophosphate were also increased in the enterocytes of the IE-Cpr-null mice. Furthermore, the expression of STAT1 (signal transducer and activator of transcription 1), a downstream target of geranylgeranyl pyrophosphate signaling, was enhanced. STAT1 is an activator of CIITA, the class II transactivator for MHC II expression; CIITA expression was concomitantly increased in IE-Cpr-null mice. Overall, these findings provide a novel and mechanistic link between POR-dependent enzymes and the expression of MHC II genes in the small intestine.
authors.affiliation: Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, New York 12201-0509.
authors.forename: Jaime
authors.initials: J
authors.lastname: D'Agostino
authors.affiliation: Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, New York 12201-0509.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Ding
authors.affiliation: Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, New York 12201-0509.
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.affiliation: Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, New York 12201-0509.
authors.forename: Kunzhi
authors.initials: K
authors.lastname: Jia
authors.affiliation: Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, New York 12201-0509.
authors.forename: Cheng
authors.initials: C
authors.lastname: Fang
authors.affiliation: Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, New York 12201-0509.
authors.forename: Yi
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, New York 12201-0509.
authors.forename: David C
authors.initials: DC
authors.lastname: Spink
authors.affiliation: Wadsworth Center, New York State Department of Health, and School of Public Health, State University of New York, Albany, New York 12201-0509. Electronic address: zhangq@wadsworth.org.
authors.forename: Qing-Yu
authors.initials: QY
authors.lastname: Zhang
mesh_terms: D000818:Animals; D001483:Base Sequence; D005786:Gene Expression Regulation / Q000502:physiology*; D005802:Genes, MHC Class II / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000096:biosynthesis* / Q000235:genetics; D007421:Intestine, Small / Q000378:metabolism*; D007810:Lanosterol / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D008969:Molecular Sequence Data; D009251:NADPH-Ferrihemoprotein Reductase / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism
chemical_list: D000949:Histocompatibility Antigens Class II; C083728:MHC class II transactivator protein; D009687:Nuclear Proteins; D012333:RNA, Messenger; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D015534:Trans-Activators; D007810:Lanosterol; D009251:NADPH-Ferrihemoprotein Reductase