title: Hepatic overexpression of Abcb11 in mice promotes the conservation of bile acids within the enterohepatic circulation.
abstract: The bile salt export pump, encoded by ABCB11, is the predominant canalicular transport protein for biliary bile acid secretion. The level of ABCB11 expression in humans is widely variable yet the impact of this variability on human disease is not well defined. We aim to determine the effect of hepatic Abcb11 overexpression on the enterohepatic circulation (EHC) in mice. We used a stable isotope dilution technique in transgenic mice overexpressing hepatic Abcb11 (TTR-Abcb11) to determine the pool size, fractional turnover rate (FTR), and synthesis rate of the primary bile acid, cholic acid (CA). The gallbladder was cannulated to determine bile flow, bile acid composition, and the biliary secretion rates of CA, total bile acids, phospholipid, and cholesterol. The combined data allowed for estimation of the CA cycling time and the fraction of CA lost per cycle. Hepatic and intestinal gene and protein expression were determined by qPCR and Western blot. Abcb11 overexpression strongly decreased FTR and synthesis rate of CA. Abcb11 overexpression decreased the fraction of CA that was lost per cycle of the EHC. Hepatic expression of Cyp7a1 was suppressed by nearly 50% and ileal expression of FGF15 was increased more than eightfold in TTR-Abcb11 mice. Despite the increased intestinal reabsorption of bile acids, ileal Asbt expression was suppressed. Hepatic Abcb11 overexpression in mice increases the conservation of bile acids within the enterohepatic circulation. These data provide strong evidence for the existence of feed-forward communication between hepatic expression of a bile acid transport protein and the intestine.
authors.affiliation: Division of Hepatology, Department of Medicine, Northwestern University, Chicago, Illinois, USA. a-henkel2@md.northwestern.edu
authors.forename: Anne S
authors.initials: AS
authors.lastname: Henkel
authors.forename: Karin E R
authors.initials: KE
authors.lastname: Gooijert
authors.forename: Rick
authors.initials: R
authors.lastname: Havinga
authors.forename: Renze
authors.initials: R
authors.lastname: Boverhof
authors.forename: Richard M
authors.initials: RM
authors.lastname: Green
authors.forename: Henkjan J
authors.initials: HJ
authors.lastname: Verkade
mesh_terms: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001646:Bile / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism*; D015153:Blotting, Western; D002784:Cholesterol / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D019826:Cholic Acid / Q000378:metabolism; D004764:Enterohepatic Circulation; D025461:Feedback, Physiological; D005346:Fibroblast Growth Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D007082:Ileum / Q000378:metabolism; D007201:Indicator Dilution Techniques; D008099:Liver / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D029363:Organic Anion Transporters, Sodium-Dependent / Q000378:metabolism; D010743:Phospholipids / Q000378:metabolism; D011228:Prealbumin / Q000235:genetics; D011401:Promoter Regions, Genetic; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027981:Symporters / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D000074020:ATP Binding Cassette Transporter, Subfamily B, Member 11; D018528:ATP-Binding Cassette Transporters; C490549:Abcb11 protein, mouse; D001647:Bile Acids and Salts; D029363:Organic Anion Transporters, Sodium-Dependent; D010743:Phospholipids; D011228:Prealbumin; D027981:Symporters; C108526:fibroblast growth factor 15, mouse; C071908:sodium-bile acid cotransporter; D005346:Fibroblast Growth Factors; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D019826:Cholic Acid