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.
Highlights
The ileal apical sodium bile acid cotransporter participates in the enterohepatic circulation of bile acids
ASBT is thought to be the only sodium bile acid cotransporter expressed in the ileal apical brush border membrane [30]
Intestinal uptake of bile acids was thought to be the result of a combination of passive absorption in the jejunum, active transport in the distal ileum, and passive absorption in the colon [2]
Summary
Generation of Slc10a2Ϫ/Ϫ Mice—The targeting vector was constructed as shown (see Fig. 1A). Preparation of Intestinal BBMV and Measurement of Ileal Bile Acid Transporter Protein and Activity—Small intestines from wild type and Slc10a2 null mice (mixed C57BL/6:129S6/SvEv background) were divided into five sections of equal length and used to isolate brush border membranes by the calcium precipitation method [15]. The stools were extracted as described by Turley et al [18] and used to determine the total bile acid content by an enzymatic method [19]. Bile Acid Pool Size and Composition—Pool size was determined as the bile acid content of the small intestine, liver, and gallbladder These tissues were removed and extracted in ethanol as described [23]. Individual bile acid species were detected by measuring refractive index; the total bile acid content of the tissue extracts was measured using an enzymatic assay [19]. Differences were considered statistically significant at p Ͻ 0.05
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