Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice
Targeted deletion of the ileal bile acid transporter eliminates enterohepatic cycling of bile acids in mice
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DOI：
10.1074/jbc.m306370200
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发表时间：
2003-09-05
影响因子：
4.8
通讯作者：
Parks, JS
中科院分区：
文献类型：
--
作者：
Dawson, PA;Haywood, J;Parks, JS
回肠顶端胆汁酸钠协同转运蛋白参与胆汁酸的肠肝循环。在原发性胆汁酸吸收不良的患者中，回肠胆汁酸转运蛋白基因（Slc 10a 2）突变导致先天性腹泻、脂肪肝和血浆胆固醇水平降低。为了阐明Slc 10a 2在肠道胆汁酸吸收中的定量作用，通过小鼠中的同源重组破坏Slc 10a 2基因。该突变的杂合（Slc 10a 2（+/-））和纯合（Slc 10a 2（-/-））动物在物理上与野生型小鼠无法区分。在Slc 10a 2（-/-）小鼠中，粪便胆汁酸排泄量增加了10- 20倍，并且通过饲喂胆汁酸结合树脂没有进一步增加。尽管胆汁酸合成增加，但Slc 10a 2（-/-）小鼠的胆汁酸池大小减少了80%，并选择性富集胆酸。在低脂肪饮食中，Slc 10a 2（-/-）小鼠没有脂肪酸。粪便中性固醇排泄仅增加3倍，肠胆固醇吸收仅减少20%，表明较小的富含胆酸的胆汁酸池足以促进肠脂质吸收。在Slc 10a 2（-/-）小鼠中，肝脏胆固醇酯含量降低了50%，并且意外地血浆高密度脂蛋白胆固醇水平略微升高。这些数据表明，Slc 10a 2是必不可少的胆汁酸的有效肠吸收和替代的吸收机制是无法弥补Slc 10a 2功能的损失。
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.