期刊
JOURNAL OF HEPATOLOGY
卷 57, 期 2, 页码 359-365出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.jhep.2012.03.025
关键词
Bile acids; Enterohepatic circulation; Transporters; Cholesterol; Cyp7a1; FXR
资金
- NIH Institutes of Health
- NIH [DK047987, F32 DK079576]
- American Heart Association
Background & Aims: Blocking intestinal bile acid (BA) absorption by inhibiting or inactivating the apical sodium-dependent BA transporter (Asbt) classically induces hepatic BA synthesis. In contrast, blocking intestinal BA absorption by inactivating the basolateral BA transporter, organic solute transporter alpha-beta (Ost alpha-Ost beta) is associated with an altered homeostatic response and decreased hepatic BA synthesis. The aim of this study was to determine the mechanisms underlying this phenotype, including the role of the farnesoid X receptor (FXR) and fibroblast growth factor 15 (FGF15). Methods: BA and cholesterol metabolism, intestinal phenotype, expression of genes important for BA metabolism, and intestinal FGF15 expression were examined in wild type, Ost alpha(-/-), Fxr(-/-), and Ost alpha(-/-) Fxr(-/-) mice. Results: Inactivation of Ost alpha was associated with decreases in hepatic cholesterol 7 alpha-hydroxylase (Cyp7a1) expression, BA pool size, and intestinal cholesterol absorption. Ost alpha(-/-) mice exhibited significant small intestinal changes, including altered ileal villus morphology, and increases in intestinal length and mass. Total ileal FGF15 expression was elevated almost 20-fold in Ost alpha(-/-) mice as a result of increased villus epithelial cell number and ileocyte FGF15 protein expression. Ost alpha(-/-) Fxr(-/-) mice exhibited decreased ileal FGF15 expression, restoration of intestinal cholesterol absorption, and increases in hepatic Cyp7a1 expression, fecal BA excretion, and BA pool size. FXR deficiency did not reverse the intestinal morphological changes or compensatory decrease for ileal Asbt expression in Ost alpha(-/-) mice. Conclusions: These results indicate that signaling via FXR is required for the paradoxical repression of hepatic BA synthesis but not the complex intestinal adaptive changes in Ost alpha(-/-) mice. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据