Targeted Deletion of the Ileal Bile Acid Transporter Eliminates Enterohepatic Cycling of Bile Acids in Mice

Abstract

The ileal apical sodium bile acid cotransporter participates in the enterohepatic circulation of bile acids. In patients with primary bile acid malabsorption, mutations in the ileal bile acid transporter gene (Slc10a2) lead to congenital diarrhea, steatorrhea, and reduced plasma cholesterol levels. To elucidate the quantitative role of Slc10a2 in intestinal bile acid absorption, the Slc10a2 gene was disrupted by homologous recombination in mice. Animals heterozygous (Slc10a2+/-) and homozygous (Slc10a2-/-) for this mutation were physically indistinguishable from wild type mice. In the Slc10a2-/- mice, fecal bile acid excretion was elevated 10- to 20-fold and was not further increased by feeding a bile acid binding resin. Despite increased bile acid synthesis, the bile acid pool size was decreased by 80% and selectively enriched in cholic acid in the Slc10a2-/- mice. On a low fat diet, the Slc10a2-/- mice did not have steatorrhea. Fecal neutral sterol excretion was increased only 3-fold, and intestinal cholesterol absorption was reduced only 20%, indicating that the smaller cholic acid-enriched bile acid pool was sufficient to facilitate intestinal lipid absorption. Liver cholesteryl ester content was reduced by 50% in Slc10a2-/- mice, and unexpectedly plasma high density lipoprotein cholesterol levels were slightly elevated. These data indicate that Slc10a2 is essential for efficient intestinal absorption of bile acids and that alternative absorptive mechanisms are unable to compensate for loss of Slc10a2 function.

Inflammatory Bowel Disease Alters Intestinal Bile Acid Transporter Expression

“…2A). This is in line with previous reports (Jung et al, 2004;Kwon and Carey, 2004;Wojtal et al, 2009); however, our data indicate that reductions in mRNA levels of ASBT mRNA persist during remission, consonant with increased fecal excretion of BA in patients with CD in clinical remission (Rutgeerts et al, 1979) and suggesting that alternative BA absorption mechanisms cannot compensate for reduced ASBT function (Dawson et al, 2003). The underlying mechanism for reduced ASBT levels in CD is not fully understood.…”

OSTα‐OSTβ

“…[ 3 H(G)]Taurocholic acid (2 Ci/mmol), [6, H(N) estrone 3-sulfate (46 Ci/mmol), and [1,2,6, Northern Blot Analysis. DNA probes were generated via polymerase chain reaction (PCR) from linearized polyA vectors (351-to 402-bp probes), and the resulting amplicons were sequenced.…”

“…4 Loss-of-function mutations in the human ASBT gene are associated with bile acid malabsorption, 5 and targeted deletion of the ASBT gene eliminates enterohepatic cycling of bile acids in mice. 2 In the bile duct-obstructed rat, downregulation of renal Asbt facilitates renal excretion of bile acids. 6 In contrast to the apical uptake step, the mechanism for sterol export across the basolateral membrane of these cells is not well defined.…”

“…[1][2][3][4] The initial step in bile acid reabsorption by these epithelial cells-namely, uptake across the apical membrane-is mediated in large part by the apical sodium bile acid transporter (ASBT; gene name SLC10A2). ASBT is most abundant on the apical (luminal) surface of ileal enterocytes, renal proximal tubular cells, and hepatic cholangiocytes.…”

The Heteromeric Organic Solute Transporter α-β, Ostα-Ostβ, Is an Ileal Basolateral Bile Acid Transporter

“…The majority of bile acids are reabsorbed from the intestine, returned to the liver via the portal venous circulation, and resecreted into bile (1). The major mechanism for intestinal absorption is active transport by the well characterized ileal apical sodium bile acid co-transporter (ASBT, 1 gene name Slc10a2) (3,4) in the distal ileum. Loss-of-function mutations in the human ASBT gene are associated with intestinal bile acid malabsorption (2), and targeted deletion of the ASBT gene eliminates enterohepatic cycling of bile acids in mice (3).…”