Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1
Increased hepatobiliary and fecal cholesterol excretion upon activation of the liver X receptor is independent of ABCA1
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DOI：
10.1074/jbc.m206522200
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发表时间：
2002-09-13
影响因子：
4.8
通讯作者：
Kuiper, F
中科院分区：
文献类型：
--
作者：
Plösch, T;Kok, T;Kuiper, F
ATP结合盒转运蛋白ABCA 1是高密度脂蛋白（HDL）形成所必需的，并被认为是胆固醇逆向转运的速率控制。Abca 1基因的表达受肝脏X受体（LXR）的控制。我们评估了合成激动剂T0901317激活LXR对C57 BL/6 J和DBA/1野生型小鼠以及ABCA 1缺陷型DBA/1小鼠肝脏和肠道胆固醇代谢的影响。在野生型小鼠中，T0901317增加了肝和肠中Abca 1的表达，这与HDL升高60%有关。治疗后胆汁胆固醇排泄量增加2.7倍，粪便中性固醇产量增加150- 300%。Abca 1（-/-）小鼠的血浆胆固醇水平也增加了（+120%），但仅在极低密度脂蛋白大小的部分。尽管不存在HDL，但在Abca 1（-/-）小鼠中，LXR激活后肝胆胆固醇输出被刺激，导致胆汁胆固醇/磷脂比增加250%。最重要的是，在DBA/1野生型和Abca 1（-/-）小鼠中，LXR激动剂诱导的粪便中性固醇损失程度相似（+300%）。在T0901317处理的小鼠中诱导了最近与胆固醇的胆汁排泄及其肠吸收有关的Abcg 5和Abcg 8的表达。因此，小鼠中LXR的激活导致肝胆胆固醇分泌增强和粪便中性固醇损失，而与HDL（ABCA 1介导的）升高和肝脏和肠中ABCA 1的存在无关。
The ATP-binding cassette transporter ABCA1 is essential for high density lipoprotein (HDL) formation and considered rate-controlling for reverse cholesterol transport. Expression of the Abca1 gene is under control of the liver X receptor (LXR). We have evaluated effects of LXR activation by the synthetic agonist T0901317 on hepatic and intestinal cholesterol metabolism in C57BL/6J and DBA/1 wild-type mice and in ABCA1-deficient DBA/1 mice. In wild-type mice, T0901317 increased expression of Abca1 in liver and intestine, which was associated with a similar to60% rise in HDL. Biliary cholesterol excretion rose 2.7-fold upon treatment, and fecal neutral sterol output was increased by 150-300%. Plasma cholesterol levels also increased in treated Abca1(-/-) mice (+120%), but exclusively in very low density lipoprotein-sized fractions. Despite the absence of HDL, hepatobiliary cholesterol output was stimulated upon LXR activation in Abca1(-/-) mice, leading to a 250% increase in the biliary cholesterol/phospholipid ratio. Most importantly, fecal neutral sterol loss was induced to a similar extent (+300%) by the LXR agonist in DBA/1 wild-type and Abca1(-/-) mice. Expression of Abcg5 and Abcg8, recently implicated in biliary excretion of cholesterol and its intestinal absorption, was induced in T0901317-treated mice. Thus, activation of LXR in mice leads to enhanced hepatobiliary cholesterol secretion and fecal neutral sterol loss independent of (ABCA1-mediated) elevation of HDL and the presence of ABCA1 in liver and intestine.