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Titolo:
Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis
Autore:
Wang, RX; Salem, M; Yousef, IM; Tuchweber, B; Lam, P; Childs, SJ; Helgason, CD; Ackerley, C; Phillips, MJ; Ling, V;
Indirizzi:
British Columbia Canc Agcy, British Columbia Canc Res Ctr, Vancouver, BC V5Z 1L3, Canada British Columbia Canc Agcy Vancouver BC Canada V5Z 1L3 BC V5Z 1L3, Canada Univ Montreal, Dept Pharmacol, Montreal, PQ H3C 3J7, Canada Univ MontrealMontreal PQ Canada H3C 3J7 ol, Montreal, PQ H3C 3J7, Canada Univ Montreal, Dept Nutr, Montreal, PQ H3C 3J7, Canada Univ Montreal Montreal PQ Canada H3C 3J7 tr, Montreal, PQ H3C 3J7, Canada Hosp Ste Justine, Pediat Res Ctr, Montreal, PQ H3C 1C5, Canada Hosp Ste Justine Montreal PQ Canada H3C 1C5 Montreal, PQ H3C 1C5, Canada Hosp Sick Children, Dept Pathol, Toronto, ON M5G 1X8, Canada Hosp Sick Children Toronto ON Canada M5G 1X8 Toronto, ON M5G 1X8, Canada
Titolo Testata:
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
fascicolo: 4, volume: 98, anno: 2001,
pagine: 2011 - 2016
SICI:
0027-8424(20010213)98:4<2011:TIOSOP>2.0.ZU;2-Q
Fonte:
ISI
Lingua:
ENG
Soggetto:
BILE-ACID TRANSPORT; SALT EXPORT PUMP; NUCLEAR RECEPTOR; LIVER; PROTEIN; IDENTIFICATION; RESOLUTION; METABOLISM; SECRETION; MECHANISM;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
51
Recensione:
Indirizzi per estratti:
Indirizzo: Ling, V British Columbia Canc Agcy, British Columbia Canc Res Ctr, 601 W 10th Ave,Vancouver, BC V5Z 1L3, Canada British Columbia Canc Agcy 601 W 10thAve Vancouver BC Canada V5Z 1L3
Citazione:
R.X. Wang et al., "Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis", P NAS US, 98(4), 2001, pp. 2011-2016

Abstract

Mutations in the sister of P-glycoprotein (Spgp) or bile salt export pump (BSEP) are associated with Progressive Familial Intrahepatic Cholestasis (PFIC2). Spgp is predominantly expressed in the canalicular membranes of liver, Consistent with in vitro evidence demonstrating the involvement of Spgp in bile salt transport, PFIC2 patients secrete less than 1% of biliary bilesalts compared with normal infants. The disease rapidly progresses to hepatic failure requiring liver transplantation before adolescence. In this study, we show that the knockout of spgp gene in mice results in intrahepatic cholestasis, but with significantly less severity than PFIC2 in humans. Some unexpected characteristics are observed. Notably, although the secretion of cholic acid in mutant mice is greatly reduced (6% of wild-type), total bile salt output in mutant mice is about 30% of wild-type. Also, secretion of an unexpectedly large amount of tetra-hydroxylated bile acids (not detected in wild-type) is observed. These results suggest that hydroxylation and an alternative canalicular transport mechanism for bile acids compensate for the absence of Spgp function and protect the mutant mice from severe cholestatic damage. In addition, the Spgp(-/-) mice display a significant increase in the secretion of cholesterol and phospholipids into the bile. This latter observation in spgp(-/-) mice suggests that intrahepatic, rather thanintracanalicular, bile salts are the major driving force for the biliary lipid secretion, The spgp-/- mice thus provide a unique model for gaining new insights into therapeutic intervention for intrahepatic cholestasis and understanding mechanisms associated with lipid homeostasis.

ASDD Area Sistemi Dipartimentali e Documentali, Università di Bologna, Catalogo delle riviste ed altri periodici
Documento generato il 07/07/20 alle ore 22:07:01