Kim Kang Ho, Choi Jong Min, Li Feng, Dong Bingning, Wooton-Kee Clavia Ruth, Arizpe Armando, Anakk Sayeepriyadarshini, Jung Sung Yun, Hartig Sean M, Moore David D
Department of Molecular and Cellular Biology Baylor College of Medicine Houston TX.
Center for Drug Discovery Baylor College of Medicine Houston TX.
Hepatol Commun. 2018 Dec 4;3(1):147-159. doi: 10.1002/hep4.1274. eCollection 2019 Jan.
Bile acid (BA) homeostasis is tightly regulated by multiple transcription factors, including farnesoid X receptor (FXR) and small heterodimer partner (SHP). We previously reported that loss of the FXR/SHP axis causes severe intrahepatic cholestasis, similar to human progressive familial intrahepatic cholestasis type 5 (PFIC5). In this study, we found that constitutive androstane receptor (CAR) is endogenously activated in double knockout (DKO) mice. To test the hypothesis that CAR activation protects DKO mice from further liver damage, we generated ;; triple knockout (TKO) mice. In TKO mice, residual adenosine triphosphate (ATP) binding cassette, subfamily B member 11 (ABCB11; alias bile salt export pump [BSEP]) function and fecal BA excretion are completely impaired, resulting in severe hepatic and biliary damage due to excess BA overload. In addition, we discovered that pharmacologic CAR activation has different effects on intrahepatic cholestasis of different etiologies. In DKO mice, CAR agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP; here on TC) treatment attenuated cholestatic liver injury, as expected. However, in the PFIC2 model knockout (BKO) mice, TC treatment exhibited opposite effects that reflect increased BA accumulation and liver injury. These contrasting results may be linked to differential regulation of systemic cholesterol homeostasis in DKO and BKO livers. TC treatment selectively up-regulated hepatic cholesterol levels in BKO mice, supporting BA synthesis. CAR activation in DKO mice is generally protective against cholestatic liver injury in these mice, which model PFIC5, but not in the PFIC2 model BKO mice. Our results emphasize the importance of the genetic and physiologic background when implementing targeted therapies to treat intrahepatic cholestasis.
胆汁酸（BA）稳态受到多种转录因子的严格调控，包括法尼酯X受体（FXR）和小异二聚体伴侣（SHP）。我们之前报道过，FXR/SHP轴的缺失会导致严重的肝内胆汁淤积，类似于人类5型进行性家族性肝内胆汁淤积症（PFIC5）。在本研究中，我们发现组成型雄烷受体（CAR）在双敲除（DKO）小鼠中被内源性激活。为了验证CAR激活可保护DKO小鼠免受进一步肝损伤这一假设，我们构建了三敲除（TKO）小鼠。在TKO小鼠中，残余的三磷酸腺苷（ATP）结合盒亚家族B成员11（ABCB11；别名胆盐输出泵[BSEP]）功能和粪便BA排泄完全受损，由于BA过载导致严重的肝脏和胆道损伤。此外，我们发现药物性CAR激活对不同病因的肝内胆汁淤积有不同影响。在DKO小鼠中，正如预期的那样，CAR激动剂1,4-双[2-(3,5-二氯吡啶氧基)]苯（TCPOBOP；以下简称TC）治疗减轻了胆汁淤积性肝损伤。然而，在PFIC2模型敲除（BKO）小鼠中，TC治疗表现出相反的效果，即反映出BA积累增加和肝损伤加重。这些截然不同的结果可能与DKO和BKO肝脏中全身胆固醇稳态的差异调节有关。TC治疗选择性地上调了BKO小鼠的肝脏胆固醇水平，促进了BA合成。在模拟PFIC5的DKO小鼠中，CAR激活通常对胆汁淤积性肝损伤具有保护作用，但在PFIC2模型BKO小鼠中则不然。我们的结果强调了在实施靶向治疗肝内胆汁淤积时遗传和生理背景的重要性。
