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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Overexpression of cholesterol 7alpha-hydroxylase promotes hepatic bile acid synthesis and secretion and maintains cholesterol homeostasis.
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Overexpression of cholesterol 7alpha-hydroxylase promotes hepatic bile acid synthesis and secretion and maintains cholesterol homeostasis.

机译：胆固醇7α-羟化酶的过表达促进肝胆汁酸的合成和分泌，并维持胆固醇的体内稳态。

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We reported previously that mice overexpressing cytochrome P450 7a1 (Cyp7a1; Cyp7a1-tg mice) are protected against high fat diet-induced hypercholesterolemia, obesity, and insulin resistance. Here, we investigated the underlying mechanism of bile acid signaling in maintaining cholesterol homeostasis in Cyp7a1-tg mice. Cyp7a1-tg mice had two-fold higher Cyp7a1 activity and bile acid pool than did wild-type mice. Gallbladder bile acid composition changed from predominantly cholic acid (57%) in wild-type to chenodeoxycholic acid (54%) in Cyp7a1-tg mice. Cyp7a1-tg mice had higher biliary and fecal cholesterol and bile acid secretion rates than did wild-type mice. Surprisingly, hepatic de novo cholesterol synthesis was markedly induced in Cyp7a1-tg mice but intestine fractional cholesterol absorption in Cyp7a1-tg mice remained the same as wild-type mice despite the presence of increased intestine bile acids. Interestingly, hepatic but not intestinal expression of several cholesterol (adenosine triphosphate-binding cassette G5/G8 [ABCG5/G8], scavenger receptor class B, member 1) and bile acid (ABCB11) transporters were significantly induced in Cyp7a1-tg mice. Treatment of mouse or human hepatocytes with a farnesoid X receptor (FXR) agonist GW4064 or bile acids induced hepatic Abcg5/g8 expression. A functional FXR binding site was identified in the Abcg5 gene promoter. Study of tissue-specific Fxr knockout mice demonstrated that loss of the Fxr gene in the liver attenuated bile acid induction of hepatic Abcg5/g8 and gallbladder cholesterol content, suggesting a role of FXR in the regulation of cholesterol transport. CONCLUSION: This study revealed a new mechanism by which increased Cyp7a1 activity expands the hydrophobic bile acid pool, stimulating hepatic cholesterol synthesis and biliary cholesterol secretion without increasing intestinal cholesterol absorption. This study demonstrated that Cyp7a1 plays a critical role in maintaining cholesterol homeostasis and underscores the importance of bile acid signaling in regulating overall cholesterol homeostasis.
机译：我们以前曾报道过，过度表达细胞色素P450 7a1的小鼠（Cyp7a1; Cyp7a1-tg小鼠）可以防止高脂饮食引起的高胆固醇血症，肥胖症和胰岛素抵抗。在这里，我们研究了胆酸信号在维持Cyp7a1-tg小鼠体内胆固醇稳态中的潜在机制。 Cyp7a1-tg小鼠的Cyp7a1活性和胆汁酸池比野生型小鼠高两倍。在Cyp7a1-tg小鼠中，胆囊胆汁酸的组成从野生型的胆酸（57％）变为鹅去氧胆酸（54％）。与野生型小鼠相比，Cyp7a1-tg小鼠的胆汁和粪便胆固醇和胆汁酸分泌率更高。出人意料的是，在Cyp7a1-tg小鼠中明显诱导了肝脏从头胆固醇的合成，尽管存在增加的胆汁胆汁酸，但Cyp7a1-tg小鼠的肠道胆固醇吸收率仍与野生型小鼠相同。有趣的是，在Cyp7a1-tg小鼠中显着诱导了几种胆固醇（三磷酸腺苷结合盒G5 / G8 [ABCG5 / G8]，B类清道夫受体，成员1）和胆汁酸（ABCB11）转运蛋白的肝但不是肠表达。用法呢素X受体（FXR）激动剂GW4064或胆汁酸治疗小鼠或人类肝细胞诱导肝Abcg5 / g8表达。在Abcg5基因启动子中鉴定了功能性FXR结合位点。对组织特异性Fxr基因敲除小鼠的研究表明，肝脏中Fxr基因的缺失减弱了胆汁酸诱导的肝Abcg5 / g8和胆囊胆固醇含量，提示FXR在调节胆固醇转运中的作用。结论：这项研究揭示了一种新的机制，通过该机制增加的Cyp7a1活性可扩展疏水性胆汁酸池，在不增加肠道胆固醇吸收的情况下刺激肝脏胆固醇的合成和胆汁胆固醇的分泌。这项研究表明，Cyp7a1在维持胆固醇稳态中起着至关重要的作用，并强调了胆汁酸信号在调节总体胆固醇稳态中的重要性。

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