title: Impact of Inhibiting Ileal Apical versus Basolateral Bile Acid Transport on Cholesterol Metabolism and Atherosclerosis in Mice.
abstract: BACKGROUND
  Bile acid sequestrants have been used for many years to treat hypercholesterolemia by increasing hepatic conversion of cholesterol to bile acids, thereby inducing hepatic LDL receptor expression and clearance of apoB-containing particles. In order to further understand the underlying molecular mechanisms linking gut-liver signaling and cholesterol homeostasis, mouse models defective in ileal apical membrane bile acid transport (Asbt-null) and ileal basolateral membrane bile acid transport (Ostα-null) were studied under basal and hypercholesterolemic conditions.
  
  
  CONCLUSIONS
  Hepatic conversion of cholesterol to bile acids is the major pathway for cholesterol catabolism and a major mechanism for cholesterol elimination. Blocking ileal apical membrane bile acid transport (Asbt-null mice) increases fecal bile acid excretion, hepatic Cyp7a1 expression, and the relative proportion of taurocholate in the bile acid pool, but decreases ileal FGF15 expression, bile acid pool size, and hepatic cholesterol content. In contrast, blocking ileal basolateral membrane bile acid transport (Ostα-null mice) increases ileal FGF15 expression, reduces hepatic Cyp7a1 expression, and increases the proportion of tauro-β-muricholic acid in the bile acid pool. In the hypercholesterolemic apoE-null background, plasma cholesterol levels and measurements of atherosclerosis were reduced in Asbt/apoE-null mice, but not in Ostα/apoE-null mice.
  
  
  CONCLUSIONS
  Blocking the intestinal absorption of bile acids at the apical versus basolateral membrane differentially affects bile acid and cholesterol metabolism, including the development of hypercholesterolemia-associated atherosclerosis. The molecular mechanism likely involves an altered regulation of ileal FGF15 expression.
authors.affiliation: Division of Gastroenterology, Hepatology and Nutrition, Department of Pediatrics, Emory University School of Medicine, Atlanta, Ga., USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Dawson
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism*; D001647:Bile Acids and Salts / Q000032:analysis / Q000378:metabolism*; D002784:Cholesterol / Q000032:analysis / Q000378:metabolism*; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D005243:Feces / Q000737:chemistry; D005346:Fibroblast Growth Factors / Q000378:metabolism; D015870:Gene Expression; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism*; D007082:Ileum / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D029363:Organic Anion Transporters, Sodium-Dependent / Q000235:genetics* / Q000378:metabolism; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D027981:Symporters / Q000235:genetics* / Q000378:metabolism; D013656:Taurocholic Acid / Q000378:metabolism
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; C108526:fibroblast growth factor 15, mouse; C476576:organic solute transporter alpha, mouse; C476578:organic solute transporter beta, mouse; C071908:sodium-bile acid cotransporter; D013656:Taurocholic Acid; D005346:Fibroblast Growth Factors; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse