Increased fecal neutral sterol loss upon liver X receptor activation is independent of biliary sterol secretion in mice
Increased fecal neutral sterol loss upon liver X receptor activation is independent of biliary sterol secretion in mice
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DOI：
10.1053/j.gastro.2004.10.006
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发表时间：
2005-01-01
期刊：
影响因子：
29.4
通讯作者：
Kuipers, F
中科院分区：
文献类型：
--
作者：
Kruit, JK;Plösch, T;Kuipers, F
背景与目的：逆向胆固醇转运（RCT）被定义为高密度脂蛋白（HDL）介导的过量胆固醇从外周细胞到肝脏，然后分泌到胆汁并通过粪便排出。该途径的各个步骤由肝脏X受体（LXR）控制。我们讨论了肠道在lxr依赖性刺激粪便胆固醇排泄中的作用。方法：用LXR激动剂GW3965治疗不能将胆固醇分泌到胆汁中的野生型和Mdr2 p -糖蛋白缺陷小鼠（Mdr2(-/-)），分离胆汁和肠源性胆固醇。结果：GW3965使野生型小鼠胆道胆固醇分泌增加74%，但对Mdr2（-/-）小鼠无影响。LXR激活使野生型小鼠粪便中性固醇排泄量增加2.1倍。令人惊讶的是，在Mdr2（-/-）小鼠中观察到相同的增加。在两种菌株中，LXR激活降低了部分胆固醇吸收，但在Mdr2（-/-）小鼠中更为明显，与Npc111表达降低相一致。在LXR激活后，两株菌株的ATPbinding盒式转运体（Abc） Abca1、Abcg1、Abcg5和abc8的肠道基因表达均被强烈诱导，而控制胆固醇合成的HMGCoA还原酶的表达则未受影响。此外，LXR激活刺激Mdr2（-/-）小鼠将血浆来源的[H-3]胆固醇排泄到粪便中性固醇部分。结论：LXR激活后小鼠粪便胆固醇损失增加与胆道胆固醇分泌无关。过量胆固醇的一个重要部分是直接通过肠道排出的，这支持了胆固醇处理的另一个重要的定量途径的存在。
Background & Aims: Reverse cholesterol transport (RCT) is defined as high-density lipoprotein (HDL)-mediated flux of excess cholesterol from peripheral cells to liver, followed by secretion into bile and disposal via the feces. Various steps of this pathway are controlled by the liver X receptor (LXR). We addressed the role of the intestine in LXR-dependent stimulation of fecal cholesterol excretion. Methods: To segregate biliary from intestine-derived cholesterol, wild-type and Mdr2 P-glycoprotein-deficient mice (Mdr2(-/-)), which are unable to secrete cholesterol into bile, were treated with the LXR agonist GW3965. Results: Treatment with GW3965 increased biliary cholesterol secretion by 74% in wild-type mice but had no effect in Mdr2(-/-) mice. LXR activation increased fecal neutral sterol excretion 2.1-fold in wild-type mice. Surprisingly, an identical increase was observed in Mdr2(-/-) mice. Fractional cholesterol absorption was reduced on LXR activation in both strains but was more pronounced in Mdr2(-/-) mice, coinciding with reduced Npc111 expression. Intestinal gene expression of ATPbinding cassette transporters (Abc) Abca1, Abcg1, Abcg5, and Abcg8 was strongly induced upon LXR activation in both strains, whereas expression of HMGCoA reductase, controlling cholesterol synthesis, remained unaffected. Additionally, LXR activation stimulated the excretion of plasma-derived [H-3]cholesterol into the fecal neutral sterol fraction in Mdr2(-/-) mice. Conclusions: Increased fecal cholesterol loss upon LXR activation is independent of biliary cholesterol secretion in mice. An important part of excess cholesterol is excreted directly via the intestine, supporting the existence of an alternative, quantitatively important route for cholesterol disposal.