ArticleProceedings of the National Academy of Sciences of the United States of America2001
Targeted inactivation of sister of P-glycoprotein gene (spgp) in mice results in nonprogressive but persistent intrahepatic cholestasis.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2001. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 111 papers, 1 of them a synthesis that pooled it.
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Who cites it
111 citing papers in PubMed, 1 synthesis or guideline pooled it, 323 citations in OpenAlex.
- Bile Acids Transporters of Enterohepatic Circulation for Targeted Drug Delivery.Molecules (Basel, Switzerland) · 2022Pooled it
- Human cardiovascular disease IBC chip-wide association with weight loss and weight regain in the look AHEAD trial.Human heredity · 2013Trial
- Liver-directed gene therapy results in amelioration of progressive familial intrahepatic cholestasis type 2 in mice.Hepatology communications · 2026Article
- Farnesoid x Receptor Deficiency Promotes Hepatocytic Injury in Cyp2c70-Deficient Mice With a Human-Like Bile Acid Composition.Liver international : official journal of the International Association for the Study of the Liver · 2026Article
- Therapeutic potential of tetrahydroxylated bile acids in reducing liver injury: Insights from thePediatric investigation · 2026Article
- The history and future of bile acid therapies.Journal of hepatology · 2025Article
- Gly-βMCA modulates bile acid metabolism to reduce hepatobiliary injury inAmerican journal of physiology. Gastrointestinal and liver physiology · 2025Article
- Disrupting bile acid metabolism by suppressing Fxr causes hepatocellular carcinoma induced by YAP activation.Nature communications · 2025Article
- Liver fibrosis negatively impacts in vivo gene transfer to murine hepatocytes.Nature communications · 2025Article
- The acidic microenvironment in the perisinusoidal space critically determines bile salt-induced activation of hepatic stellate cells.Communications biology · 2024Article
- Coordinated action of a gut-liver pathway drives alcohol detoxification and consumption.Nature metabolism · 2024Article
- Rapid in vivo evaluation system for cholestasis-related genes in mice with humanized bile acid profiles.Hepatology communications · 2024Article
- Hepatic LGR4 aggravates cholestasis-induced liver injury in mice.American journal of physiology. Gastrointestinal and liver physiology · 2024Article
- Comprehensive Bile Acid Profiling of ABCB4-mutated Patients and the Prognostic Role of Taurine-conjugated 3α,6α,7α,12α-Tetrahydroxylated Bile Acid in Cholestasis.Journal of clinical and translational hepatology · 2024Article
- Bsep/Abcb11 knockout ameliorates Schistosoma mansoni liver pathology by reducing parasite fecundity.Liver international : official journal of the International Association for the Study of the Liver · 2023Article
- Case of Congenital Hemolytic Anemia withChildren (Basel, Switzerland) · 2023Article
- Poly-hydroxylated bile acids and their prognostic roles in Alagille syndrome.World journal of pediatrics : WJP · 2023Article
- Tetrahydroxylated bile acids improve cholestatic liver and bile duct injury in the Mdr2Hepatology communications · 2022Article
- The human ATP-binding cassette (ABC) transporter superfamily.Human mutation · 2022Review
- Depletion of Gut Microbiota Inhibits Hepatic Lipid Accumulation in High-Fat Diet-Fed Mice.International journal of molecular sciences · 2022Article
51 more citing papers are in PubMed but not listed here.
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Authors and funding
10 authors at 4 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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 bile salts 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 than intracanalicular, 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.
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