title: Inhibition of ileal apical but not basolateral bile acid transport reduces atherosclerosis in apoE⁻/⁻ mice.
abstract: OBJECTIVE
  Interruption of the enterohepatic circulation of bile acids induces hepatic bile acid synthesis, increases hepatic cholesterol demand, and increases clearance of apoB-containing lipoproteins in plasma. Based on these effects, bile acid sequestrants have been used for many years to treat hypercholesterolemia and the associated atherosclerosis. The objective of this study was to determine the effect of blocking ileal apical versus basolateral membrane bile acid transport on the development of hypercholesterolemia and atherosclerosis in mouse models.
  
  
  RESULTS
  ApoE(-/-) and Ldlr(-/-) mice deficient in the apical sodium-dependent bile acid transporter (Asbt) or apoE(-/-) mice deficient in the basolateral bile acid transporter (Ostα) were fed an atherogenic diet for 16 weeks. Bile acid metabolism, cholesterol metabolism, gene expression, and development of atherosclerosis were examined. Mice deficient in Asbt exhibited the classic response to interruption of the enterohepatic circulation of bile acids, including significant reductions in hepatic and plasma cholesterol levels, and reduced aortic cholesteryl ester content. Ileal Fibroblast Growth Factor-15 (FGF15) expression was significantly reduced in Asbt(-/-)apoE(-/-) mice and was inversely correlated with expression of hepatic cholesterol 7-hydroxylase (Cyp7a1). Ileal FGF15 expression was directly correlated with plasma cholesterol levels and aortic cholesterol content. In contrast, plasma and hepatic cholesterol levels and atherosclerosis development were not reduced in apoE(-/-) mice deficient in Ostα.
  
  
  CONCLUSIONS
  Decreases in ileal FGF15, with subsequent increases in hepatic Cyp7a1 expression and bile acid synthesis appear to be necessary for the plasma cholesterol-lowering and atheroprotective effects associated with blocking intestinal bile acid absorption.
authors.affiliation: Department of Internal Medicine, Wake Forest School of Medicine, Medical Center Blvd., Winston-Salem, NC 27157, USA.
authors.forename: Tian
authors.initials: T
authors.lastname: Lan
authors.forename: Jamie
authors.initials: J
authors.lastname: Haywood
authors.forename: Paul A
authors.initials: PA
authors.lastname: Dawson
mesh_terms: D000818:Animals; D001011:Aorta / Q000378:metabolism; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000378:metabolism*; D016764:Cell Polarity / Q000502:physiology; D002784:Cholesterol / Q000097:blood; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D005260:Female; D005346:Fibroblast Growth Factors / Q000235:genetics / Q000378:metabolism*; D007082:Ileum / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D027981:Symporters / Q000235:genetics / Q000378:metabolism*; D014280:Triglycerides / Q000097:blood
chemical_list: D001057:Apolipoproteins E; D001647:Bile Acids and Salts; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D011973:Receptors, LDL; D027981:Symporters; D014280:Triglycerides; C108526:fibroblast growth factor 15, mouse; C476576:organic solute transporter alpha, mouse; C071908:sodium-bile acid cotransporter; D005346:Fibroblast Growth Factors; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse
keywords: Atherosclerosis; Bile acids; Cholesterol; Fibroblast growth factor 15; Ileum; Transporters; apoE knockout mouse