School of Pharmaceutical Science and Technology, Tianjin University, Tianjin 300072, China.
Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas 66160.
Toxicol Sci. 2017 Dec 1;160(2):351-360. doi: 10.1093/toxsci/kfx191.
Fibrates and their receptor, namely peroxisome proliferator-activated receptor α (PPARα), have been reported to regulate bile acid (BA) synthesis and transport. However, the effect of fibrate treatment and PPARα activation on BA homeostasis remains controversial. In this study, both wild-type (WT) and PPARα-null male mice were treated with clofibrate (CLOF) for 4 days to evaluate the effects of short-term PPARα activation on BA homeostasis. Although a decrease in total BAs (ΣBAs) was observed in livers of CLOF-treated WT mice, it was not observed in PPARα-null mice. CLOF-mediated decrease in ΣBAs in the liver was not likely due to the reduction in BA synthesis or BA uptake, as evidenced by an increase in the BA synthetic enzyme (Cyp7a1) and 2 BA uptake transporters (Na (+)-taurocholate cotransporting polypeptide [Ntcp] and organic anion transporting polypeptide [Oatp]1b2). Instead, the decrease in liver BAs by CLOF is largely a result of increased biliary excretion of BAs, which was associated with a significant induction of the canalicular efflux transporter (bile salt export pump [Bsep]) in the liver. The PPARα-mediated increase in Cyp7a1 in CLOF-treated WT mice was not due to farnesoid X receptor (Fxr)-small heterodimer partner (Shp) signaling in the liver, but due to suppression of Fxr- fibroblast growth factor15 signaling in the ileum. Additionally, CLOF also suppressed intestinal BA transporters (apical sodium-dependent bile acid transporter and organic solute transporterβ) and cholesterol efflux transporters (Abcg5 and Abcg8) in a PPARα-dependent manner. In summary, this study provides the first comprehensive analysis on the effect of a short-term CLOF treatment on BA homeostasis, and revealed an essential role of PPARα in regulating BA synthesis, transport and signaling.
贝特类药物及其受体，即过氧化物酶体增殖物激活受体α（PPARα），已被报道可调节胆汁酸（BA）的合成和转运。然而，贝特类药物治疗和 PPARα 激活对 BA 动态平衡的影响仍存在争议。在这项研究中，我们用氯贝特（CLOF）处理野生型（WT）和 PPARα 敲除雄性小鼠 4 天，以评估短期 PPARα 激活对 BA 动态平衡的影响。尽管 CLOF 处理的 WT 小鼠肝脏中的总胆汁酸（ΣBAs）减少，但在 PPARα 敲除小鼠中没有观察到。CLOF 介导的 WT 小鼠肝脏中 ΣBAs 的减少不太可能是由于 BA 合成或 BA 摄取减少所致，这是因为 BA 合成酶（Cyp7a1）和 2 种 BA 摄取转运体（Na（+）-牛磺胆酸钠共转运多肽[Ntcp]和有机阴离子转运多肽[Oatp]1b2）增加。相反，CLOF 引起的肝脏 BAs 减少主要是由于胆汁中 BAs 的排泄增加所致，这与肝脏中胆汁盐输出泵（Bsep）的显著诱导有关。CLOF 处理的 WT 小鼠中 PPARα 介导的 Cyp7a1 增加不是由于肝脏中的法尼醇 X 受体（Fxr）-小异二聚体伴侣（Shp）信号，而是由于回肠中的 Fxr-成纤维细胞生长因子 15 信号受到抑制。此外，CLOF 还以 PPARα 依赖的方式抑制肠道 BA 转运体（顶端钠依赖性胆汁酸转运体和有机溶质转运体β）和胆固醇外排转运体（Abcg5 和 Abcg8）。总之，本研究首次全面分析了短期 CLOF 处理对 BA 动态平衡的影响，揭示了 PPARα 在调节 BA 合成、转运和信号中的重要作用。
