title: The mechanism of increased biliary lipid secretion in mice with genetic inactivation of bile salt export pump.
abstract: Human bile salt export pump (BSEP) mutations underlie progressive familial intrahepatic cholestasis type 2 (PFIC2). In the PFIC2 animal model, Bsep(-/-) mice, biliary secretion of bile salts (BS) is decreased, but that of phospholipids (PL) and cholesterol (CH) is increased. Under physiological conditions, the biliary secretion of PL and CH is positively related ("coupled") to that of BS. We aimed to elucidate the mechanism of increased biliary lipid secretion in Bsep(-/-) mice. The secretion of the BS tauro-β-muricholic acid (TβMCA) is relatively preserved in Bsep(-/-) mice. We infused Bsep(-/-) and Bsep(+/+) (control) mice with TβMCA in stepwise increasing dosages (150-600 nmol/min) and determined biliary bile flow, BS, PL, and CH secretion. mRNA and protein expression of relevant canalicular transporters was analyzed in livers from noninfused Bsep(-/-) and control mice. TβMCA infusion increased BS secretion in both Bsep(-/-) and control mice. The secreted PL or CH amount per BS, i.e., the "coupling," was continuously two- to threefold higher in Bsep(-/-) mice (P < 0.05). Hepatic mRNA expression of canalicular lipid transporters Mdr2, Abcg5, and Abcg8 was 45-55% higher in Bsep(-/-) mice (Abcg5; P < 0.05), as was canalicular Mdr2 and Abcg5 protein expression. Potential other explanations for the increased coupling of the biliary secretion of PL and CH to that of BS in Bsep(-/-) mice could be excluded. We conclude that the mechanism of increased biliary lipid secretion in Bsep(-/-) mice is based on increased expression of the responsible canalicular transporter proteins.
authors.affiliation: Research Laboratory Pediatrics, Beatrix Children's Hospital-University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;
authors.forename: K E R
authors.initials: KE
authors.lastname: Gooijert
authors.affiliation: Research Laboratory Pediatrics, Beatrix Children's Hospital-University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;
authors.forename: R
authors.initials: R
authors.lastname: Havinga
authors.affiliation: Research Laboratory Pediatrics, Beatrix Children's Hospital-University Medical Center Groningen, University of Groningen, Groningen, The Netherlands;
authors.forename: H
authors.initials: H
authors.lastname: Wolters
authors.affiliation: British Columbia Cancer Research Center, Vancouver, British Columbia, Canada; and.
authors.forename: R
authors.initials: R
authors.lastname: Wang
authors.affiliation: British Columbia Cancer Research Center, Vancouver, British Columbia, Canada; and.
authors.forename: V
authors.initials: V
authors.lastname: Ling
authors.affiliation: Department of General Medicine and Clinical Pharmacotherapy, Hiroshima University, Hiroshima, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Tazuma
authors.affiliation: Research Laboratory Pediatrics, Beatrix Children's Hospital-University Medical Center Groningen, University of Groningen, Groningen, The Netherlands; h.j.verkade@umcg.nl.
authors.forename: H J
authors.initials: HJ
authors.lastname: Verkade
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B / 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 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001648:Bile Canaliculi / Q000378:metabolism*; D002780:Cholestasis, Intrahepatic / Q000235:genetics / Q000378:metabolism; D005260:Female; D008074:Lipoproteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010743:Phospholipids / Q000378:metabolism*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013656:Taurocholic Acid / Q000031:analogs & derivatives* / Q000378:metabolism; D000097202:ATP-Binding Cassette Sub-Family B Member 4
chemical_list: 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; D008074:Lipoproteins; D010743:Phospholipids; D012333:RNA, Messenger; D013656:Taurocholic Acid; D000097202:ATP-Binding Cassette Sub-Family B Member 4; C462600:ABCG5 protein, mouse; C462601:ABCG8 protein, mouse; C490549:Abcb11 protein, mouse; C037351:tauromuricholic acid
keywords: bile salt export pump (Bsep); canalicular lipid transporters; cholesterol; phospholipid; tauro-β-muricholate