Severe cholestasis induced by cholic acid feeding in knockout mice of sister of P-glycoprotein

被引:104
作者
Wang, RX
Lam, P
Liu, L
Forrest, D
Yousef, IM
Mignault, D
Phillips, MJ
Ling, V [1 ]
机构
[1] British Columbia Canc Agcy, British Columbia Canc Res Ctr, Vancouver, BC V5Z 1L3, Canada
[2] Univ Montreal, Dept Pharmacol, Montreal, PQ H3C 3J7, Canada
[3] Hosp St Justine, Pediat Res Ctr, Montreal, PQ, Canada
[4] Univ Toronto, Hosp Sick Children, Dept Pathol, Toronto, ON M5G 1X8, Canada
关键词
D O I
10.1016/j.hep.2003.09.037
中图分类号
R57 [消化系及腹部疾病];
学科分类号
摘要
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.
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页码:1489 / 1499
页数:11
相关论文
共 41 条
[1]  
ARIAS IM, 1988, LIVER BIOL PATHOBIOL, P1377
[2]   Adaptive regulation of hepatic bile salt transport: Role of bile salt hydrophobicity and microtubule-dependent vesicular pathway [J].
Arrese, M ;
Pizarro, M ;
Solis, N ;
Accatino, L .
JOURNAL OF HEPATOLOGY, 1997, 26 (03) :694-702
[3]   Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters [J].
Berge, KE ;
Tian, H ;
Graf, GA ;
Yu, LQ ;
Grishin, NV ;
Schultz, J ;
Kwiterovich, P ;
Shan, B ;
Barnes, R ;
Hobbs, HH .
SCIENCE, 2000, 290 (5497) :1771-1775
[4]   FIC1 and BSEP defects in Taiwanese patients with chronic intrahepatic cholestasis with low γ-glutamyltranspeptidase levels [J].
Chen, HL ;
Chang, PS ;
Hsu, HC ;
Ni, YH ;
Hsu, HY ;
Lee, JH ;
Jeng, YM ;
Shau, WY ;
Chang, MH .
JOURNAL OF PEDIATRICS, 2002, 140 (01) :119-124
[5]  
Childs S, 1998, CANCER RES, V58, P4160
[6]  
CHILDS S, 1995, CANCER RES, V55, P2029
[7]   REGULATION OF BILIARY LIPID SECRETION BY MDR2 P-GLYCOPROTEIN IN THE MOUSE [J].
ELFERINK, RPJO ;
OTTENHOFF, R ;
VANWIJLAND, M ;
SMIT, JJM ;
SCHINKEL, AH ;
GROEN, AK .
JOURNAL OF CLINICAL INVESTIGATION, 1995, 95 (01) :31-38
[8]  
Erlinger S, 1996, J HEPATOL, V24, P88
[9]   The endothelin antagonist bosentan inhibits the canalicular bile salt export pump: A potential mechanism for hepatic adverse reactions [J].
Fattinger, K ;
Funk, C ;
Pantze, M ;
Weber, C ;
Reichen, J ;
Stieger, B ;
Meier, PJ .
CLINICAL PHARMACOLOGY & THERAPEUTICS, 2001, 69 (04) :223-231
[10]   Effects of ursodeoxycholic and cholic acid feeding on hepatocellular transporter expression in mouse liver [J].
Fickert, P ;
Zollner, G ;
Fuchsbichler, A ;
Stumptner, C ;
Pojer, C ;
Zenz, R ;
Lammert, F ;
Stieger, B ;
Meier, PJ ;
Zatloukal, K ;
Denk, H ;
Trauner, M .
GASTROENTEROLOGY, 2001, 121 (01) :170-183