The organic solute transporter alpha-beta, Ostalpha-Ostbeta, is essential for intestinal bile acid transport and homeostasis.
The apical sodium-dependent bile acid transporter (Asbt) is responsible for transport across the intestinal brush border membrane; however, the carrier(s) responsible for basolateral bile acid export into the portal circulation remains to be determined. Although the heteromeric organic solute transporter Ostalpha-Ostbeta exhibits many properties predicted for a candidate intestinal basolateral bile acid transporter, the in vivo functions of Ostalpha-Ostbeta have not been investigated. To determine the role of Ostalpha-Ostbeta in intestinal bile acid absorption, the Ostalpha gene was disrupted by homologous recombination in mice. Ostalpha(-/-) mice were physically indistinguishable from wild-type mice. In everted gut sac experiments, transileal transport of taurocholate was reduced by >80% in Ostalpha(-/-) vs. wild-type mice; the residual taurocholate transport was further reduced to near-background levels in gut sacs prepared from Ostalpha(-/-)Mrp3(-/-) mice. The bile acid pool size was significantly reduced (>65%) in Ostalpha(-/-) mice, but fecal bile acid excretion was not elevated. The decreased pool size in Ostalpha(-/-) mice resulted from reduced hepatic Cyp7a1 expression that was inversely correlated with ileal expression of fibroblast growth factor 15 (FGF15). These data indicate that Ostalpha-Ostbeta is essential for intestinal bile acid transport in mice. Unlike a block in intestinal apical bile acid uptake, genetic ablation of basolateral bile acid export disrupts the classical homeostatic control of hepatic bile acid biosynthesis.
Rao
Anuradha
A
Department of Internal Medicine, Section on Gastroenterology, Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC 27157, USA.
Haywood
Jamie
J
Craddock
Ann L
AL
Belinsky
Martin G
MG
Kruh
Gary D
GD
Dawson
Paul A
PA
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism*; D001692:Biological Transport / Q000187:drug effects; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D019826:Cholic Acid / Q000008:administration & dosage / Q000494:pharmacology; D005243:Feces / Q000737:chemistry; D005786:Gene Expression Regulation / Q000187:drug effects; D018390:Gene Targeting; D006706:Homeostasis / Q000187:drug effects; D007408:Intestinal Absorption / Q000187:drug effects; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism; D007422:Intestines / Q000187:drug effects; D008055:Lipids / Q000302:isolation & purification; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D026901:Membrane Transport Proteins / Q000172:deficiency / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D010641:Phenotype; D012704:Serous Membrane / Q000187:drug effects / Q000378:metabolism
D001647:Bile Acids and Salts; D008055:Lipids; D026901:Membrane Transport Proteins; C476576:organic solute transporter alpha, mouse; C476578:organic solute transporter beta, mouse; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D019826:Cholic Acid