title: Regulation of Cytochrome P450 2B10 (CYP2B10) Expression in Liver by Peroxisome Proliferator-activated Receptor-β/δ Modulation of SP1 Promoter Occupancy.
abstract: Alcoholic liver disease is a pathological condition caused by overconsumption of alcohol. Because of the high morbidity and mortality associated with this disease, there remains a need to elucidate the molecular mechanisms underlying its etiology and to develop new treatments. Because peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) modulates ethanol-induced hepatic effects, the present study examined alterations in gene expression that may contribute to this disease. Chronic ethanol treatment causes increased hepatic CYP2B10 expression inPparβ/δ+/+mice but not in Pparβ/δ-/-mice. Nuclear and cytosolic localization of the constitutive androstane receptor (CAR), a transcription factor known to regulate Cyp2b10 expression, was not different between genotypes. PPARγ co-activator 1α, a co-activator of both CAR and PPARβ/δ, was up-regulated in Pparβ/δ+/+liver following ethanol exposure, but not in Pparβ/δ-/-liver. Functional mapping of the Cyp2b10 promoter and ChIP assays revealed that PPARβ/δ-dependent modulation of SP1 promoter occupancy up-regulated Cyp2b10 expression in response to ethanol. These results suggest that PPARβ/δ regulates Cyp2b10 expression indirectly by modulating SP1 and PPARγ co-activator 1α expression and/or activity independent of CAR activity. Ligand activation of PPARβ/δ attenuates ethanol-induced Cyp2b10 expression in Pparβ/δ+/+liver but not in Pparβ/δ-/-liver. Strikingly, Cyp2b10 suppression by ligand activation of PPARβ/δ following ethanol treatment occurred in hepatocytes and was mediated by paracrine signaling from Kupffer cells. Combined, results from the present study demonstrate a novel regulatory role of PPARβ/δ in modulating CYP2B10 that may contribute to the etiology of alcoholic liver disease.
authors.affiliation: From the Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis, Pennsylvania State University, University Park, Pennsylvania 16802.
authors.forename: Takayuki
authors.initials: T
authors.lastname: Koga
authors.affiliation: From the Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis, Pennsylvania State University, University Park, Pennsylvania 16802.
authors.forename: Pei-Li
authors.initials: PL
authors.lastname: Yao
authors.affiliation: the Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, D. C., 20057, and.
authors.forename: Maryam
authors.initials: M
authors.lastname: Goudarzi
authors.affiliation: From the Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis, Pennsylvania State University, University Park, Pennsylvania 16802.
authors.forename: Iain A
authors.initials: IA
authors.lastname: Murray
authors.affiliation: From the Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis, Pennsylvania State University, University Park, Pennsylvania 16802.
authors.forename: Gayathri
authors.initials: G
authors.lastname: Balandaram
authors.affiliation: the Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland 20892.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: From the Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis, Pennsylvania State University, University Park, Pennsylvania 16802.
authors.forename: Gary H
authors.initials: GH
authors.lastname: Perdew
authors.affiliation: the Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, D. C., 20057, and.
authors.forename: Albert J
authors.initials: AJ
authors.lastname: Fornace
authors.affiliation: From the Department of Veterinary and Biomedical Sciences and the Center of Molecular Toxicology and Carcinogenesis, Pennsylvania State University, University Park, Pennsylvania 16802, jmp21@psu.edu.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peters
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000096:biosynthesis* / Q000235:genetics; D000072467:Cytochrome P450 Family 2 / Q000096:biosynthesis* / Q000235:genetics; D000431:Ethanol / Q000633:toxicity; D015971:Gene Expression Regulation, Enzymologic; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D007728:Kupffer Cells / Q000378:metabolism / Q000473:pathology; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008108:Liver Diseases, Alcoholic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D047494:PPAR delta / Q000235:genetics / Q000378:metabolism*; D048068:PPAR-beta / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D016329:Sp1 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D013250:Steroid Hydroxylases / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D047494:PPAR delta; D048068:PPAR-beta; D016329:Sp1 Transcription Factor; D000431:Ethanol; D013250:Steroid Hydroxylases; D001189:Aryl Hydrocarbon Hydroxylases; C101679:Cyp2b10 protein, mouse; D000072467:Cytochrome P450 Family 2
keywords: Kupffer cells; alcoholic liver disease; cytochrome P450; cytochrome P450 2B10; gene regulation; liver; liver injury; peroxisome proliferator-activated receptor (PPAR); peroxisome proliferator-activated receptor-β/δ