Xenobiotic Nuclear Receptor Signaling Determines Molecular Pathogenesis of Progressive Familial Intrahepatic Cholestasis.
Xenobiotic Nuclear Receptor Signaling Determines Molecular Pathogenesis of Progressive Familial Intrahepatic Cholestasis.
复制标题
外源性核受体信号传导决定进行性家族性肝内胆汁淤积症的分子发病机制。
DOI：
10.1210/en.2018-00110
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发表时间：
2018-06-01
期刊：
影响因子：
4.8
通讯作者：
Moore DD
中科院分区：
文献类型：
--
作者：
Kim KH;Choi JM;Li F;Arizpe A;Wooton-Kee CR;Anakk S;Jung SY;Finegold MJ;Moore DD
进行性家族性肝内胆汁淤积症(PFIC)是一种遗传性异质性疾病，由于胆小管运输异常或胆汁酸(BA)代谢受损而导致胆汁流动中断，导致BA过度蓄积和肝功能衰竭。我们之前报道了一种基于法尼醇X受体(FXR；NR1H4)和一个小的异源二聚体伙伴(SHP；NR0B2)[双基因敲除(DKO)]功能丧失的肝内胆汁淤积症小鼠模型，该模型与人PFIC5有很强的相似性。我们将DKO肝脏与另一种肝内胆汁淤积模型BSEP−/−的发病机制进行了比较，BSEP PIC2代表了人PFIC2。两种模型均表现出严重的肝肿大和肝脏BA蓄积，但DKO表现为更大的循环BA和肝损伤，而BSEP−/−的表型较轻。BAS的分子图谱显示，胆酸(CA)来源的BA在DKO肝脏中具有特异性富集性，而鹅去氧胆酸盐来源的BAS在BSEP−/−肝脏中具有特异性富集性。转录学和蛋白质组学分析显示，DKO特异性地激活了CA的合成和BA的基底外侧转运，而Bsep−/−则增加了鹅去氧胆酸的合成和小管的转运。DKO肝组织中雄烷受体(CAR)/孕烷X受体(PXR)-CYP2B/CYP2C轴被激活，但在其他胆汁淤积模型中不被激活。在Fxr：SHP：Car：PxR四重敲除中该轴的丢失阻止了Cyp2b/Cyp2c基因的诱导，损害了胆红素的结合/消除，并增加了肝脏损伤。在DKO和BSEP−/−中的差异表达在人肝组织中进行了概括。总之，FXR/SHP的缺失导致了不同的分子发病机制和CAR/PXR的激活，促进了Cyp2b/Cyp2c基因的转录和胆红素的清除。在Bsep−/−小鼠和PfIC2患者中未观察到CAR/PxR的激活。这些发现加深了对肝内胆汁淤积的异质性的理解。在PFIC5小鼠模型(FXR−/−；SHP−/−)的分子发病机制中，CAR/PXR-CYP2B/CYP2C轴的激活是特异的，而在PFIC2小鼠模型(BSEP−/−)中它是受损的。
Progressive familial intrahepatic cholestasis (PFIC) is a genetically heterogeneous disorder of bile flow disruption due to abnormal canalicular transport or impaired bile acid (BA) metabolism, causing excess BA accumulation and liver failure. We previously reported an intrahepatic cholestasis mouse model based on loss of function of both farnesoid X receptor (FXR; NR1H4) and a small heterodimer partner (SHP; NR0B2) [double knockout (DKO)], which has strong similarities to human PFIC5. We compared the pathogenesis of DKO livers with that of another intrahepatic cholestasis model,Bsep−/−, which represents human PFIC2. Both models exhibit severe hepatomegaly and hepatic BA accumulation, but DKO showed greater circulating BA and liver injury, andBsep−/− had milder phenotypes. Molecular profiling of BAs uncovered specific enrichment of cholic acid (CA)–derived BAs in DKO livers but chenodeoxycholate-derived BAs inBsep−/− livers. Transcriptomic and proteomic analysis revealed specific activation of CA synthesis and alternative basolateral BA transport in DKO but increased chenodeoxycholic acid synthesis and canalicular transport inBsep−/−. The constitutive androstane receptor (CAR)/pregnane X receptor (PXR)–CYP2B/CYP2C axis is activated in DKO livers but not in other cholestasis models. Loss of this axis inFxr:Shp:Car:Pxr quadruple knockouts blockedCyp2b/Cyp2c gene induction, impaired bilirubin conjugation/elimination, and increased liver injury. Differential CYP2B expression in DKO andBsep−/− was recapitulated in human PFIC5 and PFIC2 livers. In conclusion, loss of FXR/SHP results in distinct molecular pathogenesis and CAR/PXR activation, which promotesCyp2b/Cyp2c gene transcription and bilirubin clearance. CAR/PXR activation was not observed inBsep−/− mice or PFIC2 patients. These findings provide a deeper understanding of the heterogeneity of intrahepatic cholestasis. Activation of the CAR/PXR-CYP2B/CYP2C axis is specific for molecular pathogenesis of the PFIC5 mouse model (Fxr−/−;Shp−/−), whereas it is impaired in the PFIC2 mouse model (Bsep−/−).