Increasing dietary cholesterol induces different regulation of classic and alternative bile acid synthesis.
Increasing dietary cholesterol induces different regulation of classic and alternative bile acid synthesis.
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DOI：
10.1172/jci4414
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发表时间：
1999
期刊：
影响因子：
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通讯作者：
Guorong Xu;G. Salen;S. Shefer;G. Tint;L. Nguyen;Thomas S. Chen;D. Greenblatt
中科院分区：
文献类型：
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作者：
Guorong Xu;G. Salen;S. Shefer;G. Tint;L. Nguyen;Thomas S. Chen;D. Greenblatt
我们在新西兰白色家兔中研究了增加膳食胆固醇对胆汁酸池大小的影响以及两种胆汁酸合成途径（经典途径，通过胆固醇7 α-羟化酶，替代途径，通过甾醇27-羟化酶）的调节，这些家兔每天喂食3 g胆固醇，持续长达15天。饲喂胆固醇一天使肝脏胆固醇增加75%，胆固醇7 α-羟化酶活性增加1.6倍，而胆汁酸池大小或甾醇27-羟化酶活性无显著变化。胆固醇喂养3天后，胆汁酸池的大小增加了83%（P < 0.01），进一步喂养产生10%-20%的增量，而胆固醇7 α-羟化酶活性逐渐下降至基线以下60%。相比之下，胆固醇27-羟化酶活性上升58%后，三天的胆固醇喂养，并保持升高，继续摄入。胆汁引流耗尽胆汁酸池，刺激下调胆固醇7 α-羟化酶活性，但不影响甾醇27-羟化酶活性。因此，增加肝脏胆固醇不会直接抑制胆固醇7 α-羟化酶，并且最初有利于酶诱导，而增加胆汁酸库是胆固醇7 α-羟化酶的最强有力的抑制剂。甾醇27-羟化酶对胆汁酸流量不敏感，但通过增加肝胆固醇而上调。
We investigated the effect of increasing dietary cholesterol on bile acid pool sizes and the regulation of the two bile acid synthetic pathways (classic, via cholesterol 7alpha-hydroxylase, and alternative, via sterol 27-hydroxylase) in New Zealand white rabbits fed 3 g cholesterol/per day for up to 15 days. Feeding cholesterol for one day increased hepatic cholesterol 75% and cholesterol 7alpha-hydroxylase activity 1.6 times without significant change of bile acid pool size or sterol 27-hydroxylase activity. After three days of cholesterol feeding, the bile acid pool size increased 83% (P < 0.01), and further feeding produced 10%-20% increments, whereas cholesterol 7alpha-hydroxylase activity declined progressively to 60% below baseline. In contrast, sterol 27-hydroxylase activity rose 58% after three days of cholesterol feeding and remained elevated with continued intake. Bile drainage depleted the bile acid pool and stimulated downregulated cholesterol 7alpha-hydroxylase activity but did not affect sterol 27-hydroxylase activity. Thus, increasing hepatic cholesterol does not directly inhibit cholesterol 7alpha-hydroxylase and initially favors enzyme induction, whereas increased bile acid pool is the most powerful inhibitor of cholesterol 7alpha-hydroxylase. Sterol 27-hydroxylase is insensitive to the bile acid flux but is upregulated by increasing hepatic cholesterol.