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首页> 外文期刊>Journal of Lipid Research >FXR activation by obeticholic acid or nonsteroidal agonists induces a human-like lipoprotein cholesterol change in mice with humanized chimeric liver
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FXR activation by obeticholic acid or nonsteroidal agonists induces a human-like lipoprotein cholesterol change in mice with humanized chimeric liver

机译：奥贝胆酸或非甾体激动剂对FXR的激活在人源化嵌合肝小鼠中诱导人样脂蛋白胆固醇变化

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Obeticholic acid (OCA) is a selective farnesoid X receptor (FXR) agonist that regulates bile acid and lipid metabolism. FXR activation induces distinct changes in circulating cholesterol among animal models and humans. The mechanistic basis of these effects has been elusive because of difficulties in studying lipoprotein homeostasis in mice, which predominantly package circulating cholesterol in HDLs. Here, we tested the effects of OCA in chimeric mice whose livers are mostly composed ([≥]80%) of human hepatocytes. Chimeric mice exhibited a human-like ratio of serum LDL cholesterol (LDL-C) to HDL cholesterol (HDL-C) at baseline. OCA treatment in chimeric mice increased circulating LDL-C and decreased circulating HDL-C levels, demonstrating that these mice closely model the cholesterol effects of FXR activation in humans. Mechanistically, OCA treatment increased hepatic cholesterol in chimeric mice but not in control mice. This increase correlated with decreased SREBP-2 activity and target gene expression, including a significant reduction in LDL receptor protein. Cotreatment with atorvastatin reduced total cholesterol, rescued LDL receptor protein levels, and normalized serum LDL-C. Treatment with two clinically relevant nonsteroidal FXR agonists elicited similar lipoprotein and hepatic changes in chimeric mice, suggesting that the increase in circulating LDL-C is a class effect of FXR activation.
机译：奥贝胆酸（OCA）是一种选择性的法尼醇X受体（FXR）激动剂，可调节胆汁酸和脂质代谢。 FXR激活在动物模型和人类中引起循环胆固醇的明显变化。由于难以研究小鼠脂蛋白的动态平衡（主要将高密度脂蛋白封装循环胆固醇），因此这些作用的机理基础难以捉摸。在这里，我们测试了OCA在嵌合小鼠中的作用，这些嵌合小鼠的肝脏主要由人类肝细胞组成（≥80％）。嵌合小鼠在基线时表现出血清LDL胆固醇（LDL-C）与HDL胆固醇（HDL-C）的类人比。嵌合小鼠中的OCA处理可增加循环中的LDL-C并降低循环中的HDL-C水平，表明这些小鼠密切模拟了人类FXR激活的胆固醇作用。从机理上讲，OCA处理可增加嵌合小鼠的肝胆固醇，但不增加对照小鼠的肝胆固醇。该增加与SREBP-2活性和靶基因表达的降低相关，包括LDL受体蛋白的显着降低。与阿托伐他汀共同治疗可降低总胆固醇，挽救LDL受体蛋白水平，并使血清LDL-C标准化。用两种临床相关的非类固醇FXR激动剂进行的治疗在嵌合小鼠中引起相似的脂蛋白和肝细胞变化，表明循环中LDL-C的增加是FXR激活的一类作用。

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