Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity
Complementary roles of farnesoid X receptor, pregnane X receptor, and constitutive androstane receptor in protection against bile acid toxicity
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DOI：
10.1074/jbc.m307145200
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发表时间：
2003-11-14
影响因子：
4.8
通讯作者：
Sinal, CJ
中科院分区：
文献类型：
--
作者：
Guo, GL;Lambert, G;Sinal, CJ
核受体farnesoid X受体（FXR）和pregnane X受体（PXR）在维持胆汁酸稳态中起重要作用。B6杂交在体内同时缺失FXR和PXR129-Fxr(tm1Gonz) （FXR-null）和B6；129-Pxr(tm1gsk - wellcome) （PXR-null）小鼠显示B6中胆汁酸、胆固醇和脂质稳态更严重的破坏；129-Fxr(tm1Gonz) Pxr(tm1gsk - wellcome) （FXR-PXR双空或fpxr -空）小鼠饲喂1%胆酸（CA）日粮。在饲喂CA的FXR-和fpxr -阴性小鼠中，诱导肝内组成型雄甾受体（CAR）及其靶基因的表达。为了测试CAR的上调是否代表了一种防止胆汁酸毒性的手段，以补偿FXR和PXR的损失，动物使用CAR激活剂，苯巴比妥或1,4-双[2-（3,5-二氯吡啶氧基）]苯（TCPOBOP）预处理，然后使用CA饮食。经苯巴比妥或TCPOBOP预处理后，血清胆汁酸和胆红素浓度显著降低，参与胆汁酸和/或胆红素代谢和排泄的肝脏基因（CYP2B、CYP3A、MRP2、MRP3、UGT1A和谷胱甘肽s -转移酶α）表达升高，证实了CAR对胆汁酸毒性的保护作用。综上所述，本研究表明FXR和PXR在维持体内胆汁酸以及胆固醇和脂质稳态方面具有重要的联合作用。此外，FXR、PXR和CAR以一种互补的方式保护肝脏免受胆汁酸毒性，表明它们作为冗余但不同的防御层，防止胆汁淤积期间胆汁酸对肝脏的明显损害。
The nuclear receptors, farnesoid X receptor (FXR) and pregnane X receptor (PXR), are important in maintaining bile acid homeostasis. Deletion of both FXR and PXR in vivo by cross-breeding B6;129-Fxr(tm1Gonz) (FXR-null) and B6;129-Pxr(tm1Glaxo-Wellcome) (PXR-null) mice revealed a more severe disruption of bile acid, cholesterol, and lipid homeostasis in B6;129-Fxr(tm1Gonz) Pxr(tm1Glaxo-Wellcome) (FXR-PXR double null or FPXR-null) mice fed a 1% cholic acid (CA) diet. Hepatic expression of the constitutive androstane receptor (CAR) and its target genes was induced in FXR- and FPXR-null mice fed the CA diet. To test whether up-regulation of CAR represents a means of protection against bile acid toxicity to compensate for the loss of FXR and PXR, animals were pretreated with CAR activators, phenobarbital or 1,4- bis[2-(3,5-dichlorpyridyloxy)] benzene (TCPOBOP), followed by the CA diet. A role for CAR in protection against bile acid toxicity was confirmed by a marked reduction of serum bile acid and bilirubin concentrations, with an elevation of the expression of the hepatic genes involved in bile acid and/or bilirubin metabolism and excretion (CYP2B, CYP3A, MRP2, MRP3, UGT1A, and glutathione S-transferase alpha), following pretreatment with phenobarbital or TCPOBOP. In summary, the current study demonstrates a critical and combined role of FXR and PXR in maintaining not only bile acid but also cholesterol and lipid homeostasis in vivo. Furthermore, FXR, PXR, and CAR protect against hepatic bile acid toxicity in a complementary manner, suggesting that they serve as redundant but distinct layers of defense to prevent overt hepatic damage by bile acids during cholestasis.