Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice
Intestinal Farnesoid X Receptor Controls Transintestinal Cholesterol Excretion in Mice
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DOI：
10.1053/j.gastro.2016.12.037
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发表时间：
2017-04-01
期刊：
影响因子：
29.4
通讯作者：
Groen, Albert K.
中科院分区：
文献类型：
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作者：
de Boer, Jan Freark;Schonewille, Marleen;Groen, Albert K.
背景与目的：肠道在维持胆固醇稳态中的作用越来越被人们所认识。胆固醇的粪便排泄是动脉粥样硬化保护性胆固醇反向转运途径的最后一步，胆汁和经肠胆固醇排泄（TICE）对此有贡献。然而，控制胆固醇通过TICE途径的机制知之甚少。我们的目标是确定调节和刺激TICE的机制。方法：我们对C57 Bl/6 J小鼠、法尼醇X受体（FXR）的精氨酸特异性敲除小鼠、在肠道中特异性表达FXR转基因的小鼠和ABCG 8敲除小鼠进行了研究。给小鼠喂食对照饮食或补充有FXR激动剂PX 20606的饮食，有或没有胆固醇吸收抑制剂依折麦布。一些FXR基因敲除的小鼠每天注射成纤维细胞生长因子（FGF）19。为了测定胆固醇吸收分数，给小鼠静脉注射胆固醇D5和口服胆固醇D 7。给小鼠饮用水中的13 C-乙酸盐，以测量胆固醇合成。进行胆汁插管，并评估胆汁胆固醇分泌率。在另一组实验中，将雄性Wistar大鼠的胆管外置，允许用模型胆汁替代内源性胆汁。结果：在小鼠中，我们发现TICE通过其靶基因Fgf 15（大鼠和人中为FGF 19）的诱导而受到肠道FXR的调节。刺激这一途径导致小鼠每天排泄高达60%的总胆固醇含量。PX 20606和FGF 19各自增加胆汁中的鼠胆酸盐：胆酸盐的比率，诱导更亲水的胆汁盐池。改变的胆盐池刺激胆固醇通过固醇输出异二聚体三磷酸腺苷结合盒亚家族G成员5/8（ABCG 5/G8）稳健分泌到肠腔中。值得注意的是，由PX 20606诱导的TICE增加与胆固醇吸收的变化无关。结论：由FXR和FGF 15/19控制的胆盐池的亲水性是通过TICE去除胆固醇的重要决定因素。改变胆盐池组成的策略可能会被开发用于预防心血管疾病。成绩单分析：http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? token=irsrayeohfcntqx&acc= GSE 74101。
BACKGROUND & AIMS: The role of the intestine in the maintenance of cholesterol homeostasis increasingly is recognized. Fecal excretion of cholesterol is the last step in the atheroprotective reverse cholesterol transport pathway, to which biliary and transintestinal cholesterol excretion (TICE) contribute. The mechanisms controlling the flux of cholesterol through the TICE pathway, however, are poorly understood. We aimed to identify mechanisms that regulate and stimulate TICE. METHODS: We performed studies with C57Bl/6J mice, as well as with mice with intestine-specific knockout of the farnesoid X receptor (FXR), mice that express an FXR transgene specifically in the intestine, and ABCG8-knockout mice. Mice were fed a control diet or a diet supplemented with the FXR agonist PX20606, with or without the cholesterol absorption inhibitor ezetimibe. Some mice with intestine-specific knockout of FXR were given daily injections of fibroblast growth factor (FGF) 19. To determine fractional cholesterol absorption, mice were given intravenous injections of cholesterol D5 and oral cholesterol D7. Mice were given 13C-acetate in drinking water for measurement of cholesterol synthesis. Bile cannulations were performed and biliary cholesterol secretion rates were assessed. In a separate set of experiments, bile ducts of male Wistar rats were exteriorized, allowing replacement of endogenous bile by a model bile. RESULTS: In mice, we found TICE to be regulated by intestinal FXR via induction of its target gene Fgf15 (FGF19 in rats and human beings). Stimulation of this pathway caused mice to excrete up to 60% of their total cholesterol content each day. PX20606 and FGF19 each increased the ratio of muricholate: cholate in bile, inducing a more hydrophilic bile salt pool. The altered bile salt pool stimulated robust secretion of cholesterol into the intestinal lumen via the sterol-exporting heterodimer adenosine triphosphate binding cassette subfamily G member 5/8 (ABCG5/G8). Of note, the increase in TICE induced by PX20606 was independent of changes in cholesterol absorption. CONCLUSIONS: Hydrophilicity of the bile salt pool, controlled by FXR and FGF15/19, is an important determinant of cholesterol removal via TICE. Strategies that alter bile salt pool composition might be developed for the prevention of cardiovascular disease. Transcript profiling: http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?token=irsrayeohfcntqx&acc=GSE74101.