Severe cholestasis induced by cholic acid feeding in knockout mice of sister of P-glycoprotein
Severe cholestasis induced by cholic acid feeding in knockout mice of sister of P-glycoprotein
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DOI：
10.1016/j.hep.2003.09.037
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发表时间：
2003-12-01
期刊：
影响因子：
13.5
通讯作者：
Ling, V
中科院分区：
文献类型：
--
作者：
Wang, RX;Lam, P;Ling, V
肝内胆汁淤积症通常与胆汁胆汁酸分泌受损有关，这一过程由P-糖蛋白姊妹蛋白(SPgp或Abcb11)介导，也称为胆盐输出泵(BSEP)。在人类中，SPGP基因突变与一种致命的儿童疾病--2型进行性家族性肝内胆汁淤积症(PFIC2)有关。然而，在小鼠中，SPGP的“敲除”只会导致轻微的胆汁淤积。在这项研究中，我们用添加了胆酸(CA)的饲料喂养SPGP(-L/-)基因敲除小鼠，以确定是否可以诱导出更明显的PFIC2样表型。这些小鼠出现了严重的胆汁淤积，特征是黄疸、体重减轻、血浆胆汁酸升高、转氨酶升高、胆管病(胆管增生和胆管炎)、肝坏死、高死亡率和主要肝脏基因mRNA表达的广泛变化(16/36)。一个令人惊讶的观察是，CA喂养的突变小鼠的胆汁酸产量和胆汁流量显著高于预期。这表明SPGP(-/-)小鼠能够利用另一种胆盐转运系统。然而，与SPGP不同的是，尽管该系统容量很高，但不足以保护基因敲除小鼠免受胆汁淤积的影响。总之，SPGP(-/-)小鼠为研究与胆汁淤积和相关疾病相关的分子途径提供了一个独特的模型。
Intrahepatic cholestasis is often associated with impairment of biliary bile acid secretion, a process mediated by the sister of P-glycoprotein (Spgp or Abcb11) also known as the bile salt export pump (Bsep). In humans, mutations in the Spgp gene are associated with a fatal childhood disease, type 2 progressive familial intrahepatic cholestasis (PFIC2). However in mice, the "knockout" of Spgp only results in mild cholestasis. In this study, we fed spgp(-l/-) knockout mice with a cholic acid (CA)-supplemented diet to determine whether a more pronounced PFIC2-like phenotype could be induced. Such mice developed severe cholestasis characterized by jaundice, weight loss, elevated plasma bile acid, elevated transaminase, cholangiopathy (proliferation of bile ductules and cholangitis), liver necrosis, high mortality, and wide-ranging changes in the mRNA expression of major liver genes (16/36 examined). A surprising observation was that the bile acid output and bile flow in CA-fed mutant mice was significantly higher than anticipated. This suggests that the spgp(-/-) mice arc able to utilize an alternative bile salt transport system. However, unlike Spgp, this system is insufficient to protect the knockout mice from cholestasis despite its high capacity. In conclusion, the spgp(-/-) mice provide a unique model to investigate molecular pathways associated with cholestasis and related diseases.