title: Peroxisome proliferator-activated receptor alpha (PPARalpha)-mediated regulation of multidrug resistance 2 (Mdr2) expression and function in mice.
abstract: Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear receptor that controls expression of genes involved in lipid metabolism and is activated by fatty acids and hypolipidaemic fibrates. Fibrates induce the hepatic expression of murine multidrug resistance 2 ( Mdr2 ), encoding the canalicular phospholipid translocator. The physiological role of PPARalpha in regulation of Mdr2 and other genes involved in bile formation is unknown. We found no differences in hepatic expression of the ATP binding cassette transporter genes Mdr2, Bsep (bile salt export pump), Mdr1a / 1b, Abca1 and Abcg5 / Abcg8 (implicated in cholesterol transport), the bile salt-uptake systems Ntcp (Na(+)-taurocholate co-transporting polypeptide gene) and Oatp1 (organic anion-transporting polypeptide 1 gene) or in bile formation between wild-type and Ppar alpha((-/-)) mice. Upon treatment of wild-type mice with ciprofibrate (0.05%, w/w, in diet for 2 weeks), the expression of Mdr2 (+3-fold), Mdr1a (+6-fold) and Mdr1b (+11-fold) mRNAs was clearly induced, while that of Oatp1 (-5-fold) was reduced. Mdr2 protein levels were increased, whereas Bsep, Ntcp and Oatp1 were drastically decreased. Exposure of cultured wild-type mouse hepatocytes to PPARalpha agonists specifically induced Mdr2 mRNA levels and did not affect expression of Mdr1a / 1b. Altered transporter expression in fibrate-treated wild-type mice was associated with a approximately 400% increase in bile flow: secretion of phospholipids and cholesterol was increased only during high-bile-salt infusions. No fibrate effects were observed in Ppar alpha((-/-)) mice. In conclusion, our results show that basal bile formation is not affected by PPARalpha deficiency in mice. The induction of Mdr2 mRNA and Mdr2 protein levels by fibrates is mediated by PPARalpha, while the induction of Mdr1a / 1b in vivo probably reflects a secondary phenomenon related to chronic PPARalpha activation.
authors.affiliation: Groningen University Institute for Drug Exploration, Center for Liver, Digestive and Metabolic Diseases, Laboratory of Pediatrics, University Hospital Groningen, The Netherlands. T.Kok@med.rug.nl
authors.forename: Tineke
authors.initials: T
authors.lastname: Kok
authors.forename: Vincent W
authors.initials: VW
authors.lastname: Bloks
authors.forename: Henk
authors.initials: H
authors.lastname: Wolters
authors.forename: Rick
authors.initials: R
authors.lastname: Havinga
authors.forename: Peter L M
authors.initials: PL
authors.lastname: Jansen
authors.forename: Bart
authors.initials: B
authors.lastname: Staels
authors.forename: Folkert
authors.initials: F
authors.lastname: Kuipers
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018435:ATP Binding Cassette Transporter, Subfamily B / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters / Q000187:drug effects / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000737:chemistry / Q000378:metabolism; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D002995:Clofibric Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D058607:Fibric Acids; D022781:Hepatocytes / Q000502:physiology*; D050356:Lipid Metabolism; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D008817:Mice, Mutant Strains; D009929:Organ Size / Q000187:drug effects; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent / Q000235:genetics / Q000378:metabolism; D020025:Peroxisome Proliferators / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D027981:Symporters; D013655:Taurochenodeoxycholic Acid / Q000008:administration & dosage / Q000494:pharmacology; D014157:Transcription Factors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018435:ATP Binding Cassette Transporter, Subfamily B; D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D000071018:ATP Binding Cassette Transporter, Subfamily G, Member 5; D000071019:ATP Binding Cassette Transporter, Subfamily G, Member 8; D018528:ATP-Binding Cassette Transporters; D002352:Carrier Proteins; D002995:Clofibric Acid; D058607:Fibric Acids; D008074:Lipoproteins; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D029362:Organic Anion Transporters, Sodium-Independent; D020025:Peroxisome Proliferators; D011743:Pyrimidines; D018160:Receptors, Cytoplasmic and Nuclear; D027981:Symporters; D013655:Taurochenodeoxycholic Acid; D014157:Transcription Factors; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; C490549:Abcb11 protein, mouse; C490548:Abcb11 protein, rat; C421102:Slco1a1 protein, rat; C071908:sodium-bile acid cotransporter; C031655:ursodoxicoltaurine; C006253:pirinixic acid; C095122:multidrug resistance protein 3; C019304:ciprofibrate