title: PXR induces CYP27A1 and regulates cholesterol metabolism in the intestine.
abstract: Mitochondrial sterol 27-hydroxylase (CYP27A1) catalyzes oxidative cleavage of the sterol side chain in the bile acid biosynthetic pathway in the liver and 27-hydroxylation of cholesterol in most tissues. Recent studies suggest that 27-hydroxycholesterol (27-HOC) activates liver orphan receptor alpha (LXRalpha) and induces the cholesterol efflux transporters ABCA1 and ABCG1 in macrophages. The steroid- and bile acid-activated pregnane X receptor (PXR) plays critical roles in the detoxification of bile acids, cholesterol metabolites, and xenobiotics. The role of CYP27A1 in the intestine is not known. This study investigated PXR and CYP27A1 regulation of cholesterol metabolism in the human intestinal cell lines Caco2 and Ls174T. A human PXR ligand, rifampicin, induced CYP27A1 mRNA expression in intestine cells but not in liver cells. Rifampicin induced CYP27A1 gene transcription, increased intracellular 27-HOC levels, and induced ABCA1 and ABCG1 mRNA expression only in intestine cells. A functional PXR binding site was identified in the human CYP27A1 gene. Chromatin immunoprecipitation assays revealed that rifampicin induced the PXR recruitment of steroid receptor coactivator 1 to CYP27A1 chromatin. Cholesterol loading markedly increased intracellular 27-HOC levels in intestine cells. Rifampicin, 27-HOC, and a potent LXRalpha agonist, T0901317, induced ABCA1 and ABCG1 protein expression and stimulated cholesterol efflux from intestine cells to apolipoprotein A-I and HDL. This study suggests an intestine-specific PXR/CYP27A1/LXRalpha pathway that regulates intestine cholesterol efflux and HDL assembly.
authors.affiliation: Department of Microbiology, Immunology, and Biochemistry, Northeastern Ohio Universities College of Medicine, Rootstown, OH 44272, USA.
authors.forename: Tiangang
authors.initials: T
authors.lastname: Li
authors.forename: Wenling
authors.initials: W
authors.lastname: Chen
authors.forename: John Y L
authors.initials: JY
authors.lastname: Chiang
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters / Q000235:genetics; D001483:Base Sequence; D002460:Cell Line; D053493:Cholestanetriol 26-Monooxygenase / Q000378:metabolism*; D002784:Cholesterol / Q000378:metabolism*; D008076:Cholesterol, HDL / Q000378:metabolism; D017930:Genes, Reporter; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D006845:Hydrocarbons, Fluorinated; D006888:Hydroxycholesterols / Q000378:metabolism / Q000494:pharmacology; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology / Q000187:drug effects / Q000201:enzymology; D050356:Lipid Metabolism; D008969:Molecular Sequence Data; D000077297:Pregnane X Receptor; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D011987:Receptors, Steroid / Q000378:metabolism*; D020218:Response Elements / Q000235:genetics; D012293:Rifampin / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
chemical_list: D064286:ATP Binding Cassette Transporter 1; D000070998:ATP Binding Cassette Transporter, Subfamily G, Member 1; D018528:ATP-Binding Cassette Transporters; D053493:Cholestanetriol 26-Monooxygenase; D002784:Cholesterol; D008076:Cholesterol, HDL; D006845:Hydrocarbons, Fluorinated; D006888:Hydroxycholesterols; D000077297:Pregnane X Receptor; D012333:RNA, Messenger; D011987:Receptors, Steroid; D012293:Rifampin; D013449:Sulfonamides; C577836:ABCA1 protein, human; C419353:ABCG1 protein, human; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C076996:27-hydroxycholesterol; C506831:CYP27A1 protein, human