Premium
Severe cholestasis induced by cholic acid feeding in knockout mice of sister of P‐glycoprotein
Author(s) -
Wang Renxue,
Lam Ping,
Liu Lin,
Forrest Dana,
Yousef Ibrahim M.,
Mignault Diane,
Phillips M. James,
Ling Victor
Publication year - 2003
Publication title -
hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.488
H-Index - 361
eISSN - 1527-3350
pISSN - 0270-9139
DOI - 10.1016/j.hep.2003.09.037
Subject(s) - cholestasis , progressive familial intrahepatic cholestasis , cholic acid , bile acid , medicine , knockout mouse , endocrinology , bile salt export pump , gene knockout , liver disease , biology , neonatal cholestasis , biochemistry , gene , transporter , biliary atresia , receptor , transplantation , liver transplantation
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 −/− 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 are 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.