Compensatory Induction of Liver Efflux Transporters in Response to ANIT-Induced Liver Injury Is Impaired in FXR-Null Mice
Compensatory Induction of Liver Efflux Transporters in Response to ANIT-Induced Liver Injury Is Impaired in FXR-Null Mice
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DOI：
10.1093/toxsci/kfp094
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发表时间：
2009-07-01
影响因子：
3.8
通讯作者：
Klaassen, Curtis D.
中科院分区：
文献类型：
--
作者：
Cui, Yue J.;Aleksunes, Lauren M.;Klaassen, Curtis D.
α-萘异硫氰酸酯（ANIT）是一种肝毒性物质，可引起啮齿动物急性肝内胆汁淤积。法尼醇X受体（FXR）和胆烷X受体（PXR）是肝脏中两种主要的胆汁酸感受器。本研究的目的是表征在ANIT诱导的肝损伤期间FXR和PXR对肝转运蛋白的调节。向野生型、FXR缺失和PXR缺失小鼠施用ANIT（75 mg/kg，po），48 h后评价肝毒性和基底外侧摄取的信使RNA（mRNA）表达（牛磺胆酸钠共转运多肽、有机阴离子转运多肽[Oatp] 1a 1、Oatp 1a 4、Oatp 1b 2）和外排转运蛋白（有机溶质转运蛋白[Ost] α、Ost β、多药耐药相关蛋白[Mrp] 3、Mrp 4）以及小管转运蛋白（胆盐输出泵[Bsep]，Mrp 2，多药耐药蛋白2 [Mdr 2]，ATP酶，I类，8B型，成员1 [Atp 8b 1]）。ANIT后48小时，野生型和PXR缺失小鼠的肝脏具有可比的多灶性坏死。然而，ANIT处理的FXR-null小鼠比野生型小鼠具有更少和更小的坏死灶，但在整个肝脏中具有分散的单细胞肝细胞坏死。血清丙氨酸转氨酶，碱性磷酸酶（ALP），和直接胆红素增加，在所有基因型，更高的ALP水平在FXR-null小鼠。ANIT处理的FXR缺失小鼠的血清和肝脏非结合胆汁酸高于其他两种基因型。ANIT诱导野生型和PXR缺失小鼠中Mdr 2、Bsep和Atp 8b 1的mRNA表达，但未能上调FXR缺失小鼠中这些基因的表达。ANIT处理后，所有基因型肝脏摄取转运蛋白的mRNA表达均下降。ANIT增加了野生型和PXR缺失小鼠肝脏中的Ost β和Mrp 3 mRNA，但没有改变FXR缺失小鼠中的Ost β mRNA。总之，FXR缺乏增强了小鼠对ANIT诱导的肝损伤的易感性，这可能是肝胆外排转运蛋白诱导受损和随后未结合胆汁酸肝脏蓄积的结果。
Alpha-naphthyl isothiocyanate (ANIT) is a hepatotoxicant that produces acute intrahepatic cholestasis in rodents. Farnesoid X receptor (FXR) and pregnane X receptor (PXR) are two major bile acid sensors in liver. The purpose of this study was to characterize the regulation of hepatic transporters by FXR and PXR during ANIT-induced liver injury. Wild-type, FXR-null, and PXR-null mice were administered ANIT (75 mg/kg, po) and evaluated 48 h later for hepatotoxicity and messenger RNA (mRNA) expression of basolateral uptake (sodium taurocholate-cotransporting polypeptide, organic anion transporting polypeptide [Oatp] 1a1, Oatp1a4, Oatp1b2) and efflux transporters (organic solute transporter [Ost] alpha, Ost beta, multidrug resistance-associated protein [Mrp] 3, Mrp4), as well as canalicular transporters (bile salt export pump [Bsep], Mrp2, multidrug resistance protein 2 [Mdr2], ATPase, class I, type 8B, member 1 [Atp8b1]). Livers from wild-type and PXR-null mice had comparable multifocal necrosis 48 h after ANIT. However, ANIT-treated FXR-null mice have fewer and smaller necrotic foci than wild-type mice but had scattered single-cell hepatocyte necrosis throughout the liver. Serum alanine transaminase, alkaline phosphatase (ALP), and direct bilirubin were increased in all genotypes, with higher ALP levels in FXR-null mice. Serum and liver unconjugated bile acids were higher in ANIT-treated FXR-null mice than the other two genotypes. ANIT induced mRNA expression of Mdr2, Bsep, and Atp8b1 in wild-type and PXR-null mice but failed to upregulate these genes in FXR-null mice. mRNA expression of uptake transporters declined in livers of all genotypes following ANIT treatment. ANIT increased Ost beta and Mrp3 mRNA in livers of wild-type and PXR-null mice but did not alter Ost beta mRNA in FXR-null mice. In conclusion, FXR deficiency enhances susceptibility of mice to ANIT-induced liver injury, likely a result of impaired induction of hepatobiliary efflux transporters and subsequent hepatic accumulation of unconjugated bile acids.