脱氧胆酸
法尼甾体X受体
细胞生长
MAPK/ERK通路
磷酸化
细胞生物学
化学
信号转导
熊去氧胆酸
原癌基因酪氨酸蛋白激酶Src
癌症研究
胆汁酸
生物
生物化学
核受体
转录因子
基因
作者
Avafia Dossa,Oswaldo H. Escobar,Jamie Golden,Mark R. Frey,Henri R. Ford,Christopher P. Gayer
出处
期刊:American Journal of Physiology-gastrointestinal and Liver Physiology
[American Physiological Society]
日期:2016-01-15
卷期号:310 (2): G81-G92
被引量:75
标识
DOI:10.1152/ajpgi.00065.2015
摘要
Bile acids (BAs) are synthesized in the liver and secreted into the intestine. In the lumen, enteric bacteria metabolize BAs from conjugated, primary forms into more toxic unconjugated, secondary metabolites. Secondary BAs can be injurious to the intestine and may contribute to disease. The epidermal growth factor receptor (EGFR) and the nuclear farnesoid X receptor (FXR) are known to interact with BAs. In this study we examined the effects of BAs on intestinal epithelial cell proliferation and investigated the possible roles for EGFR and FXR in these effects. We report that taurine-conjugated cholic acid (TCA) induced proliferation, while its unconjugated secondary counterpart deoxycholic acid (DCA) inhibited proliferation. TCA stimulated phosphorylation of Src, EGFR, and ERK 1/2. Pharmacological blockade of any of these pathways or genetic ablation of EGFR abrogated TCA-stimulated proliferation. Interestingly, Src or EGFR inhibitors eliminated TCA-induced phosphorylation of both molecules, suggesting that their activation is interdependent. In contrast to TCA, DCA exposure diminished EGFR phosphorylation, and pharmacological or siRNA blockade of FXR abolished DCA-induced inhibition of proliferation. Taken together, these results suggest that TCA induces intestinal cell proliferation via Src, EGFR, and ERK activation. In contrast, DCA inhibits proliferation via an FXR-dependent mechanism that may include downstream inactivation of the EGFR/Src/ERK pathway. Since elevated secondary BA levels are the result of specific bacterial modification, this may provide a mechanism through which an altered microbiota contributes to normal or abnormal intestinal epithelial cell proliferation.
科研通智能强力驱动
Strongly Powered by AbleSci AI