Liver receptor homolog-1 regulates bile acid homeostasis but is not essential for feedback regulation of bile acid synthesis
Liver receptor homolog-1 regulates bile acid homeostasis but is not essential for feedback regulation of bile acid synthesis
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DOI：
10.1210/me.2007-0565
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发表时间：
2008-06-01
影响因子：
--
通讯作者：
Kliewer, Steven A.
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文献类型：
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作者：
Lee, Youn-Kyoung;Schmidt, Daniel R.;Kliewer, Steven A.
肝受体同源物 1 (LRH-1) 是一种孤儿核受体，在肝脏和肠道中高度表达，参与胆固醇、胆汁酸和类固醇激素稳态的调节。肝脏中拟议的 LRH-1 靶基因包括编码胆固醇 7 α-羟化酶 (CYP7A1) 和甾醇 12 α-羟化酶 (CYP8B1) 的基因，它们催化胆汁酸合成的关键步骤。体外研究表明，LRH-1 可能参与刺激基础 CYP7A1 和 CYP8B1 转录，并作为核胆汁酸受体 [法尼醇 X 受体 (FXR)]-小异二聚体伙伴信号级联的一部分参与抑制它们的表达，最终导致小异二聚体伙伴与 LRH-1 结合以抑制基因转录。然而，LRH-1 作用的体内分析因 Lrh-1 敲除小鼠的胚胎致死性而受到阻碍。为了克服这一障碍，我们培育了小鼠，其中肝细胞或肠上皮中的 Lrh-1 被选择性破坏。任一组织中 LRH-1 的缺乏都会改变涉及胆固醇和胆汁酸稳态的基因的 mRNA 水平。令人惊讶的是，肝细胞中 LRH-1 缺陷对 Cyp7a1 的基础表达或 FXR 对其的抑制没有显着影响。尽管在肝细胞中 LRH-1 缺陷的小鼠中，FXR 对 Cyp8b1 的抑制也完好无损，但基础 CYP8B1 mRNA 水平显着降低，并且胆汁酸池的组成也发生相应的变化。总而言之，这些数据揭示了 LRH-1 在调节胆汁酸稳态中的广泛作用，但表明 LRH-1 要么不参与胆汁酸合成的反馈调节，要么被其他因素补偿。
Liver receptor homolog 1 (LRH-1), an orphan nuclear receptor, is highly expressed in liver and intestine, where it is implicated in the regulation of cholesterol, bile acid, and steroid hormone homeostasis. Among the proposed LRH-1 target genes in liver are those encoding cholesterol 7 alpha-hydroxylase (CYP7A1) and sterol 12 alpha-hydroxylase (CYP8B1), which catalyze key steps in bile acid synthesis. In vitro studies suggest that LRH-1 may be involved both in stimulating basal CYP7A1 and CYP8B1 transcription and in repressing their expression as part of the nuclear bile acid receptor [farnesoid X receptor (FXR)]-small heterodimer partner signaling cascade, which culminates in small heterodimer partner binding to LRH-1 to repress gene transcription. However, in vivo analysis of LRH-1 actions has been hampered by the embryonic lethality of Lrh-1 knockout mice. To overcome this obstacle, mice were generated in which Lrh-1 was selectively disrupted in either hepatocytes or intestinal epithelium. LRH-1 deficiency in either tissue changed mRNA levels of genes involved in cholesterol and bile acid homeostasis. Surprisingly, LRH-1 deficiency in hepatocytes had no significant effect on basal Cyp7a1 expression or its repression by FXR. Whereas Cyp8b1 repression by FXR was also intact in mice deficient for LRH-1 in hepatocytes, basal CYP8B1 mRNA levels were significantly decreased, and there were corresponding changes in the composition of the bile acid pool. Taken together, these data reveal a broad role for LRH-1 in regulating bile acid homeostasis but demonstrate that LRH-1 is either not involved in the feedback regulation of bile acid synthesis or is compensated for by other factors.