ABCB11 explained
ATP-binding cassette, sub-family B member 11 (ABCB11), also known as the bile salt export pump (BSEP), is a protein which in humans is encoded by the gene.[1]
Function
The product of the ABCB11 gene is an ABC transporter named BSEP (bile salt export pump), or sPgp (sister of P-glycoprotein). This membrane-associated protein is a member of the superfamily of ATP-binding cassette (ABC) transporters. ABC proteins transport various molecules across extra- and intra-cellular membranes. ABC genes are divided into seven distinct subfamilies (ABC1, MDR/TAP, MRP, ALD, OABP, GCN20, White).[2]
This protein is a member of the MDR/TAP subfamily. Some members of the MDR/TAP subfamily are involved in multidrug resistance. This particular protein is responsible for the transport of taurocholate and other cholate conjugates from hepatocytes (liver cells) to the bile. In humans, the activity of this transporter is the major determinant of bile formation and bile flow.[3] [4] [5] [6]
Clinical significance
ABCB11 is a gene associated with progressive familial intrahepatic cholestasis type 2 (PFIC2).[1] [7] [8] [9] PFIC2 caused by mutations in the ABCB11 gene increases the risk of hepatocellular carcinoma in early life.[10] Benign recurrent intrahepatic cholestasis (BRIC) is associated with episodic cholestatic jaundice and mutations in ATP8B1 or ABCB11.[11]
Bile salts from the cytoplasm of hepatocytes are transported by the bile salt export pump (BSEP) into bile canaliculi. When bile salt export is deficient due to mutation in the ABCB11 gene, this can lead to intrahepatic toxic accumulation of the bile salts. Individuals with such mutations have an increased incidence of hepatocellular carcinoma or cholangiocarcinoma.[12]
Further reading
- Guey LT, García-Closas M, Murta-Nascimento C, Lloreta J, Palencia L, Kogevinas M, Rothman N, Vellalta G, Calle ML, Marenne G, Tardón A, Carrato A, García-Closas R, Serra C, Silverman DT, Chanock S, Real FX, Malats N . 6 . Genetic susceptibility to distinct bladder cancer subphenotypes . European Urology . 57 . 2 . 283–292 . February 2010 . 19692168 . 3220186 . 10.1016/j.eururo.2009.08.001 .
- Weerachayaphorn J, Cai SY, Soroka CJ, Boyer JL . Nuclear factor erythroid 2-related factor 2 is a positive regulator of human bile salt export pump expression . Hepatology . 50 . 5 . 1588–1596 . November 2009 . 19821532 . 3013376 . 10.1002/hep.23151 .
- Rose CS, Grarup N, Krarup NT, Poulsen P, Wegner L, Nielsen T, Banasik K, Faerch K, Andersen G, Albrechtsen A, Borch-Johnsen K, Clausen JO, Jørgensen T, Vaag A, Pedersen O, Hansen T . 6 . A variant in the G6PC2/ABCB11 locus is associated with increased fasting plasma glucose, increased basal hepatic glucose production and increased insulin release after oral and intravenous glucose loads . Diabetologia . 52 . 10 . 2122–2129 . October 2009 . 19669124 . 10.1007/s00125-009-1463-z . free .
- Dixon PH, van Mil SW, Chambers J, Strautnieks S, Thompson RJ, Lammert F, Kubitz R, Keitel V, Glantz A, Mattsson LA, Marschall HU, Molokhia M, Moore GE, Linton KJ, Williamson C . 6 . Contribution of variant alleles of ABCB11 to susceptibility to intrahepatic cholestasis of pregnancy . Gut . 58 . 4 . 537–544 . April 2009 . 18987030 . 10.1136/gut.2008.159541 . 206948058 .
- Acalovschi M, Tirziu S, Chiorean E, Krawczyk M, Grünhage F, Lammert F . Common variants of ABCB4 and ABCB11 and plasma lipid levels: a study in sib pairs with gallstones, and controls . Lipids . 44 . 6 . 521–526 . June 2009 . 19408031 . 10.1007/s11745-009-3300-z . 4003830 .
- Chen HL, Liu YJ, Su YN, Wang NY, Wu SH, Ni YH, Hsu HY, Wu TC, Chang MH . 6 . Diagnosis of BSEP/ABCB11 mutations in Asian patients with cholestasis using denaturing high performance liquid chromatography . The Journal of Pediatrics . 153 . 6 . 825–832 . December 2008 . 18692205 . 10.1016/j.jpeds.2008.06.034 . Chang Mei-hwei .
- Thompson R, Strautnieks S . BSEP: function and role in progressive familial intrahepatic cholestasis . Seminars in Liver Disease . 21 . 4 . 545–550 . November 2001 . 11745042 . 10.1055/s-2001-19038 . 36313859 .
- Kim SR, Saito Y, Itoda M, Maekawa K, Kawamoto M, Kamatani N, Ozawa S, Sawada J . 6 . Genetic variations of the ABC transporter gene ABCB11 encoding the human bile salt export pump (BSEP) in a Japanese population . Drug Metabolism and Pharmacokinetics . 24 . 3 . 277–281 . 2009 . 19571440 . 10.2133/dmpk.24.277 .
- Saito A, Kawamoto M, Kamatani N . Association study between single-nucleotide polymorphisms in 199 drug-related genes and commonly measured quantitative traits of 752 healthy Japanese subjects . Journal of Human Genetics . 54 . 6 . 317–323 . June 2009 . 19343046 . 10.1038/jhg.2009.31 . free .
- Hosgood HD, Menashe I, He X, Chanock S, Lan Q . PTEN identified as important risk factor of chronic obstructive pulmonary disease . Respiratory Medicine . 103 . 12 . 1866–1870 . December 2009 . 19625176 . 2783799 . 10.1016/j.rmed.2009.06.016 .
- Hosgood HD, Menashe I, Shen M, Yeager M, Yuenger J, Rajaraman P, He X, Chatterjee N, Caporaso NE, Zhu Y, Chanock SJ, Zheng T, Lan Q . 6 . Pathway-based evaluation of 380 candidate genes and lung cancer susceptibility suggests the importance of the cell cycle pathway . Carcinogenesis . 29 . 10 . 1938–1943 . October 2008 . 18676680 . 2722857 . 10.1093/carcin/bgn178 .
- Ross CJ, Katzov-Eckert H, Dubé MP, Brooks B, Rassekh SR, Barhdadi A, Feroz-Zada Y, Visscher H, Brown AM, Rieder MJ, Rogers PC, Phillips MS, Carleton BC, Hayden MR . 6 . Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy . Nature Genetics . 41 . 12 . 1345–1349 . December 2009 . 19898482 . 10.1038/ng.478 . 21293339 .
- Lu Y, Dollé ME, Imholz S, van 't Slot R, Verschuren WM, Wijmenga C, Feskens EJ, Boer JM . 6 . Multiple genetic variants along candidate pathways influence plasma high-density lipoprotein cholesterol concentrations . Journal of Lipid Research . 49 . 12 . 2582–2589 . December 2008 . 18660489 . 10.1194/jlr.M800232-JLR200 . free .
- Byrne JA, Strautnieks SS, Ihrke G, Pagani F, Knisely AS, Linton KJ, Mieli-Vergani G, Thompson RJ . 6 . Missense mutations and single nucleotide polymorphisms in ABCB11 impair bile salt export pump processing and function or disrupt pre-messenger RNA splicing . Hepatology . 49 . 2 . 553–567 . February 2009 . 19101985 . 10.1002/hep.22683 . 9236795 . free .
- Ho RH, Leake BF, Kilkenny DM, Meyer Zu Schwabedissen HE, Glaeser H, Kroetz DL, Kim RB . Polymorphic variants in the human bile salt export pump (BSEP; ABCB11): functional characterization and interindividual variability . Pharmacogenetics and Genomics . 20 . 1 . 45–57 . January 2010 . 20010382 . 2883163 . 10.1097/FPC.0b013e3283349eb0 .
- Takeuchi F, Katsuya T, Chakrewarthy S, Yamamoto K, Fujioka A, Serizawa M, Fujisawa T, Nakashima E, Ohnaka K, Ikegami H, Sugiyama T, Nabika T, Kasturiratne A, Yamaguchi S, Kono S, Takayanagi R, Yamori Y, Kobayashi S, Ogihara T, de Silva A, Wickremasinghe R, Kato N . 6 . Common variants at the GCK, GCKR, G6PC2-ABCB11 and MTNR1B loci are associated with fasting glucose in two Asian populations . Diabetologia . 53 . 2 . 299–308 . February 2010 . 19937311 . 10.1007/s00125-009-1595-1 . free .
- Ohno M, Kunimoto M, Nishizuka M, Osada S, Imagawa M . Ku proteins function as corepressors to regulate farnesoid X receptor-mediated gene expression . Biochemical and Biophysical Research Communications . 390 . 3 . 738–742 . December 2009 . 19833092 . 10.1016/j.bbrc.2009.10.040 .
- Andreotti G, Menashe I, Chen J, Chang SC, Rashid A, Gao YT, Han TQ, Sakoda LC, Chanock S, Rosenberg PS, Hsing AW . 6 . Genetic determinants of serum lipid levels in Chinese subjects: a population-based study in Shanghai, China . European Journal of Epidemiology . 24 . 12 . 763–774 . 2009 . 19888660 . 2885778 . 10.1007/s10654-009-9402-3 .
- Sabatti C, Service SK, Hartikainen AL, Pouta A, Ripatti S, Brodsky J, Jones CG, Zaitlen NA, Varilo T, Kaakinen M, Sovio U, Ruokonen A, Laitinen J, Jakkula E, Coin L, Hoggart C, Collins A, Turunen H, Gabriel S, Elliot P, McCarthy MI, Daly MJ, Järvelin MR, Freimer NB, Peltonen L . 6 . Genome-wide association analysis of metabolic traits in a birth cohort from a founder population . Nature Genetics . 41 . 1 . 35–46 . January 2009 . 19060910 . 2687077 . 10.1038/ng.271 .
- Kosters A, Karpen SJ . Bile acid transporters in health and disease . Xenobiotica; the Fate of Foreign Compounds in Biological Systems . 38 . 7–8 . 1043–1071 . July 2008 . 18668439 . 2823065 . 10.1080/00498250802040584 .
Notes and References
- Strautnieks SS, Bull LN, Knisely AS, Kocoshis SA, Dahl N, Arnell H, Sokal E, Dahan K, Childs S, Ling V, Tanner MS, Kagalwalla AF, Németh A, Pawlowska J, Baker A, Mieli-Vergani G, Freimer NB, Gardiner RM, Thompson RJ . 6 . A gene encoding a liver-specific ABC transporter is mutated in progressive familial intrahepatic cholestasis . Nature Genetics . 20 . 3 . 233–238 . November 1998 . 9806540 . 10.1038/3034 . 21339613 .
- Web site: Entrez Gene: ABCB11 .
- Noé J, Stieger B, Meier PJ . Functional expression of the canalicular bile salt export pump of human liver . Gastroenterology . 123 . 5 . 1659–1666 . November 2002 . 12404240 . 10.1053/gast.2002.36587 . free .
- Arrese M, Ananthanarayanan M . The bile salt export pump: molecular properties, function and regulation . Pflügers Archiv . 449 . 2 . 123–131 . November 2004 . 15578267 . 10.1007/s00424-004-1311-4 . free . 21771483 . 10533/175746 .
- Stieger B, Meier Y, Meier PJ . The bile salt export pump . Pflügers Archiv . 453 . 5 . 611–620 . February 2007 . 17051391 . 10.1007/s00424-006-0152-8 . free .
- Zinchuk VS, Okada T, Akimaru K, Seguchi H . Asynchronous expression and colocalization of Bsep and Mrp2 during development of rat liver . American Journal of Physiology. Gastrointestinal and Liver Physiology . 282 . 3 . G540–G548 . March 2002 . 11842005 . 10.1152/ajpgi.00405.2001 .
- Jansen PL, Strautnieks SS, Jacquemin E, Hadchouel M, Sokal EM, Hooiveld GJ, Koning JH, De Jager-Krikken A, Kuipers F, Stellaard F, Bijleveld CM, Gouw A, Van Goor H, Thompson RJ, Müller M . 6 . Hepatocanalicular bile salt export pump deficiency in patients with progressive familial intrahepatic cholestasis . Gastroenterology . 117 . 6 . 1370–1379 . December 1999 . 10579978 . 10.1016/S0016-5085(99)70287-8 . free .
- van Mil SW, van der Woerd WL, van der Brugge G, Sturm E, Jansen PL, Bull LN, van den Berg IE, Berger R, Houwen RH, Klomp LW . 6 . Benign recurrent intrahepatic cholestasis type 2 is caused by mutations in ABCB11 . Gastroenterology . 127 . 2 . 379–384 . August 2004 . 15300568 . 10.1053/j.gastro.2004.04.065 . 22906105 . free .
- Noe J, Kullak-Ublick GA, Jochum W, Stieger B, Kerb R, Haberl M, Müllhaupt B, Meier PJ, Pauli-Magnus C . 6 . Impaired expression and function of the bile salt export pump due to three novel ABCB11 mutations in intrahepatic cholestasis . Journal of Hepatology . 43 . 3 . 536–543 . September 2005 . 16039748 . 10.1016/j.jhep.2005.05.020 .
- Knisely AS, Strautnieks SS, Meier Y, Stieger B, Byrne JA, Portmann BC, Bull LN, Pawlikowska L, Bilezikçi B, Ozçay F, László A, Tiszlavicz L, Moore L, Raftos J, Arnell H, Fischler B, Németh A, Papadogiannakis N, Cielecka-Kuszyk J, Jankowska I, Pawłowska J, Melín-Aldana H, Emerick KM, Whitington PF, Mieli-Vergani G, Thompson RJ . 6 . Hepatocellular carcinoma in ten children under five years of age with bile salt export pump deficiency . Hepatology . 44 . 2 . 478–486 . August 2006 . 16871584 . 10.1002/hep.21287 . 22994215 .
- Kalaranjini KV, Glaxon JA, Vasudevan S, Arunkumar ML . Benign recurrent intrahepatic cholestasis - 2 (BRIC-2)/ABCB11 deficiency in a young child - Report from a tertiary care center in South India . Indian Journal of Pathology & Microbiology . 64 . Supplement . S146–S148 . June 2021 . 34135158 . 10.4103/IJPM.IJPM_254_20 . free .
- Strautnieks SS, Byrne JA, Pawlikowska L, Cebecauerová D, Rayner A, Dutton L, Meier Y, Antoniou A, Stieger B, Arnell H, Ozçay F, Al-Hussaini HF, Bassas AF, Verkade HJ, Fischler B, Németh A, Kotalová R, Shneider BL, Cielecka-Kuszyk J, McClean P, Whitington PF, Sokal E, Jirsa M, Wali SH, Jankowska I, Pawłowska J, Mieli-Vergani G, Knisely AS, Bull LN, Thompson RJ . 6 . Severe bile salt export pump deficiency: 82 different ABCB11 mutations in 109 families . Gastroenterology . 134 . 4 . 1203–1214 . April 2008 . 18395098 . 10.1053/j.gastro.2008.01.038 . free .