Bile acids decrease hepatic paraoxonase 1 expression and plasma high-density lipoprotein levels via FXR-mediated signaling of FGFR4
Bile acids decrease hepatic paraoxonase 1 expression and plasma high-density lipoprotein levels via FXR-mediated signaling of FGFR4
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DOI：
10.1161/01.atv.0000195793.73118.b4
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发表时间：
2006-02-01
影响因子：
8.7
通讯作者：
Davis, RA
中科院分区：
文献类型：
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作者：
Gutierrez, A;Ratliff, EP;Davis, RA
目的：探讨膳食胆汁酸对肝脏对氧磷酶1(PON1)表达的抑制作用。方法与结果：对动脉粥样硬化易感性不同的C57BL/6和C3H/HeJ小鼠分别饲喂含牛磺胆酸盐的饲料和致动脉粥样硬化的饲料。与更易患动脉粥样硬化的C57BL/6小鼠相比，C3H/HeJ小鼠表现出对饮食中胆汁酸抑制肝脏PON1 mRNA的抵抗，并降低了高密度脂蛋白胆固醇。尽管Toll受体4的敲除不影响对牛磺胆酸盐的反应，但FXR或FGFR4的缺失都阻止了牛磺胆酸盐对PON1和CYP7A1的抑制。FGF19是人回肠表达FGFR4的激活剂，可降低人肝癌细胞PON1和CYP7A1的表达。在所有被研究的小鼠中，饮食中的牛磺胆酸盐增加了FXR诱导的人FGF19的小鼠FGF15的回肠表达。结论-胆汁酸通过FXR介导的FGF15的诱导抑制了肝脏PON1和CYP7A1的mRNA表达。因此，C3H/HeJ小鼠不能显示牛磺胆酸盐对PON1和CYP7A1 mRNAs的抑制并不是因为缺乏FGF15的诱导，而是因为FGF15-FGFR4关联的远端信号事件。
Objective - The purpose of this research was to determine how dietary bile acids repress hepatic expression of paraoxonase 1 (PON1).Methods and Results - C57BL/6 mice and C3H/HeJ mice, having different susceptibilities to atherosclerosis, were fed a chow diet and an atherogenic diet containing taurocholate. Compared with the more atherosclerosis - susceptible C57BL/6 mice, C3H/HeJ mice display resistance to dietary bile acid repression of hepatic PON1 mRNA and decreased high-density lipoprotein cholesterol. Whereas knockout of toll receptor 4 did not affect response to taurocholate, deletion of either FXR or FGFR4 blocked taurocholate repression of PON1 and CYP7A1. FGF19, an activator of FGFR4 expressed in human ileum, decreased expression of both PON1 and CYP7A1 expression by human hepatoma cells. In all of the mice studied, dietary taurocholate increased ileal expression of FGF15, a FXR-inducible murine homologue of human FGF19.Conclusions - Hepatic PON1 and CYP7A1 mRNA expression is repressed by bile acids via FXR-mediated induction of FGF15. Thus, the inability of C3H/HeJ mice to display taurocholate repression of PON1 and CYP7A1 mRNAs was not because of a lack of induction of FGF15 but rather signaling events distal to FGF15-FGFR4 association.