Cholic acid mediates negative feedback regulation of bile acid synthesis in mice
Cholic acid mediates negative feedback regulation of bile acid synthesis in mice
复制标题
DOI：
10.1172/jci200216309
复制
发表时间：
2002-10-01
影响因子：
15.9
通讯作者：
Eggertsen, G
中科院分区：
文献类型：
--
作者：
Li-Hawkins, J;Gåfvels, M;Eggertsen, G
胆固醇通过受核受体法尼醇X受体（FXR）和其他效应物介导的负反馈调节的途径转化为数十种初级和次级胆汁酸。在小鼠中破坏甾醇12 α-羟化酶基因（Cyp 8b 1）可阻止胆酸盐（一种初级胆汁酸）及其代谢产物的合成。Cyp 8b 1（-/-）小鼠中限速生物合成酶胆固醇7 α-羟化酶（CYP 7A 1）的反馈调节丢失，导致胆汁酸池扩大和胆固醇代谢改变。其他FXR靶基因的表达在这些小鼠中未改变。胆酸盐在体内和体外恢复CYP 7A 1调节。结果表明胆酸盐是胆汁酸合成的重要负调节因子，并为核受体激活配体特异性基因提供了初步证据。
Cholesterol is converted into dozens of primary and secondary bile acids through pathways subject to negative feedback regulation mediated by the nuclear receptor farnesoid X receptor (FXR) and other effectors. Disruption of the sterol 12alpha-hydroxylase gene (Cyp8b1) in mice prevents the synthesis of cholate, a primary bile acid, and its metabolites. Feedback regulation of the rate-limiting biosynthetic enzyme cholesterol 7alpha-hydroxylase (CYP7A1) is lost in Cyp8b1(-/-) mice, causing expansion of the bile acid pool and alterations in cholesterol metabolism. Expression of other FXR target genes is unaltered in these mice. Cholate restores CYP7A1 regulation in vivo and in vitro. The results implicate cholate as an important negative regulator of bile acid synthesis and provide preliminary evidence for ligand-specific gene activation by a nuclear receptor.