Sodium/bile acid cotransporter also known as the Na+-taurocholate cotransporting polypeptide (NTCP) or liver bile acid transporter (LBAT) is a protein that in humans is encoded by the SLC10A1 (solute carrier family 10 member 1) gene.[5][6]
| SLC10A1 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | SLC10A1, NTCP, solute carrier family 10 member 1, FHCA2 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 182396; MGI: 97379; HomoloGene: 31126; GeneCards: SLC10A1; OMA:SLC10A1 - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Structure
editSodium/bile acid cotransporters are integral membrane glycoproteins. Human NTCP contains 349 amino acids and has a mass of 56 kDa.[7]
Function
editBile acid:sodium symporters participate in the enterohepatic circulation of bile acids. Two homologous transporters are involved in the reabsorption of bile acids. One of these absorbs bile acids from the intestinal lumen, the bile duct, and the kidney with an apical localization (ileal sodium/bile acid cotransporter). The other is this protein and is expressed in the basolateral membranes of hepatocytes (NTCP).[7]
As a cotransporter, NTCP binds two sodium ions and one (conjugated) bile salt molecule, thereby providing a hepatic influx of bile salts. Other transported molecules include steroid hormones, thyroid hormones and various xenobiotics:[7]
Hepatitis virus entry
editNTCP is a cell surface receptor necessary for the entry of hepatitis B and hepatitis D virus.[8] This entry mechanism is inhibited by myrcludex B,[9] cyclosporin A, progesterone, propranolol, bosentan, ezetimibe, bexarotene[10] as well as NTCP substrates like taurocholate, tauroursodeoxycholate and bromosulfophthalein.[7]
SLC10A1-deficiency
editIndividuals that lack functional NTCP have been identified.[11] These individuals display highly elevated bile salt levels in plasma, but without a clear phenotype. In areas of the world with a high prevalence of HBV, there are multiple individuals who carry the NTCP p.S267F polymorphism on both alleles; this makes NTCP inactive as a bile acid transporter, but provides protection against HBV infection.[12]
NTCP-deficient mice have also been created. These mice have reduced hepatic bile salt uptake but plasma bile salt levels are less clearly elevated, as the rodent-specific OATP1a/1b transporters provide can partially replace the function of NTCP.[13] Nevertheless, this NTCP-knockout animal model pointed to possible additional (non-HBV) aspects of NTCP-deficiency. NTCP-deficient mice are partially protected against the problems associated with a high-calorie diet, including excessive weight gain[14] and to liver damage in cholestasis.[15] These effects of NTCP deficiency have not yet been replicated in humans.
See also
editReferences
edit- ^ a b c GRCh38: Ensembl release 89: ENSG00000100652 – Ensembl, May 2017
- ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000021135 – Ensembl, May 2017
- ^ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
- ^ "Entrez Gene: SLC10A1 solute carrier family 10 (sodium/bile acid cotransporter family), member 1".
- ^ Hagenbuch B, Meier PJ (March 1994). "Molecular cloning, chromosomal localization, and functional characterization of a human liver Na+/bile acid cotransporter". The Journal of Clinical Investigation. 93 (3): 1326–1331. doi:10.1172/JCI117091. PMC 294097. PMID 8132774.
- ^ a b c d Watashi K, Urban S, Li W, Wakita T (February 2014). "NTCP and beyond: opening the door to unveil hepatitis B virus entry". International Journal of Molecular Sciences. 15 (2): 2892–2905. doi:10.3390/ijms15022892. PMC 3958888. PMID 24557582.
- ^ Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, et al. (November 2012). "Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus". eLife. 1: e00049. doi:10.7554/eLife.00049. PMC 3485615. PMID 23150796.
- ^ H. Spreitzer (14 September 2015). "Neue Wirkstoffe – Myrcludex B". Österreichische Apothekerzeitung (in German) (19/2015): 12.
- ^ Gad SA, Sugiyama M, Tsuge M, Wakae K, Fukano K, Oshima M, et al. (March 2022). "The kinesin KIF4 mediates HBV/HDV entry through the regulation of surface NTCP localization and can be targeted by RXR agonists in vitro". PLOS Pathogens. 18 (3): e1009983. doi:10.1371/journal.ppat.1009983. PMC 8970526. PMID 35312737.
- ^ Vaz FM, Paulusma CC, Huidekoper H, de Ru M, Lim C, Koster J, et al. (January 2015). "Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: conjugated hypercholanemia without a clear clinical phenotype". Hepatology. 61 (1): 260–267. doi:10.1002/hep.27240. PMID 24867799.
- ^ Peng L, Zhao Q, Li Q, Li M, Li C, Xu T, et al. (April 2015). "The p.Ser267Phe variant in SLC10A1 is associated with resistance to chronic hepatitis B". Hepatology. 61 (4): 1251–1260. doi:10.1002/hep.27608. PMID 25418280. S2CID 205895418.
- ^ Slijepcevic D, Kaufman C, Wichers CG, Gilglioni EH, Lempp FA, Duijst S, et al. (July 2015). "Impaired uptake of conjugated bile acids and hepatitis b virus pres1-binding in na(+) -taurocholate cotransporting polypeptide knockout mice". Hepatology. 62 (1): 207–219. doi:10.1002/hep.27694. PMC 4657468. PMID 25641256.
- ^ Donkers JM, Kooijman S, Slijepcevic D, Kunst RF, Roscam Abbing RL, Haazen L, et al. (June 2019). "NTCP deficiency in mice protects against obesity and hepatosteatosis". JCI Insight. 5 (14). doi:10.1172/jci.insight.127197. PMC 6675549. PMID 31237863.
- ^ Slijepcevic D, Roscam Abbing RL, Fuchs CD, Haazen LC, Beuers U, Trauner M, et al. (September 2018). "Na+ -taurocholate cotransporting polypeptide inhibition has hepatoprotective effects in cholestasis in mice". Hepatology. 68 (3): 1057–1069. doi:10.1002/hep.29888. PMC 6175374. PMID 29572910.
Further reading
edit- Trauner M, Boyer JL (April 2003). "Bile salt transporters: molecular characterization, function, and regulation". Physiological Reviews. 83 (2): 633–671. doi:10.1152/physrev.00027.2002. PMID 12663868. S2CID 5911966.
- Shiao T, Iwahashi M, Fortune J, Quattrochi L, Bowman S, Wick M, et al. (October 2000). "Structural and functional characterization of liver cell-specific activity of the human sodium/taurocholate cotransporter". Genomics. 69 (2): 203–213. doi:10.1006/geno.2000.6329. PMID 11031103.
- Müller O, Schalla C, Scheibner J, Stange EF, Fuchs M (February 2002). "Expression of liver plasma membrane transporters in gallstone-susceptible and gallstone-resistant mice". The Biochemical Journal. 361 (Pt 3): 673–679. doi:10.1042/0264-6021:3610673. PMC 1222351. PMID 11802798.
- Hallén S, Mareninova O, Brändén M, Sachs G (June 2002). "Organization of the membrane domain of the human liver sodium/bile acid cotransporter". Biochemistry. 41 (23): 7253–7266. doi:10.1021/bi012152s. PMID 12044156.
- Ho RH, Leake BF, Roberts RL, Lee W, Kim RB (February 2004). "Ethnicity-dependent polymorphism in Na+-taurocholate cotransporting polypeptide (SLC10A1) reveals a domain critical for bile acid substrate recognition". The Journal of Biological Chemistry. 279 (8): 7213–7222. doi:10.1074/jbc.M305782200. PMID 14660639.
- Jung D, Hagenbuch B, Fried M, Meier PJ, Kullak-Ublick GA (May 2004). "Role of liver-enriched transcription factors and nuclear receptors in regulating the human, mouse, and rat NTCP gene". American Journal of Physiology. Gastrointestinal and Liver Physiology. 286 (5): G752–G761. doi:10.1152/ajpgi.00456.2003. PMID 14701722. S2CID 1101720.
- Alrefai WA, Sarwar Z, Tyagi S, Saksena S, Dudeja PK, Gill RK (May 2005). "Cholesterol modulates human intestinal sodium-dependent bile acid transporter". American Journal of Physiology. Gastrointestinal and Liver Physiology. 288 (5): G978–G985. doi:10.1152/ajpgi.00379.2004. PMID 15604201. S2CID 633434.
- Chen HL, Chen HL, Liu YJ, Feng CH, Wu CY, Shyu MK, et al. (September 2005). "Developmental expression of canalicular transporter genes in human liver". Journal of Hepatology. 43 (3): 472–477. doi:10.1016/j.jhep.2005.02.030. PMID 15922475.
- Anwer MS, Gillin H, Mukhopadhyay S, Balasubramaniyan N, Suchy FJ, Ananthanarayanan M (September 2005). "Dephosphorylation of Ser-226 facilitates plasma membrane retention of Ntcp". The Journal of Biological Chemistry. 280 (39): 33687–33692. doi:10.1074/jbc.M502151200. PMID 16027164.
- Eloranta JJ, Jung D, Kullak-Ublick GA (January 2006). "The human Na+-taurocholate cotransporting polypeptide gene is activated by glucocorticoid receptor and peroxisome proliferator-activated receptor-gamma coactivator-1alpha, and suppressed by bile acids via a small heterodimer partner-dependent mechanism". Molecular Endocrinology. 20 (1): 65–79. doi:10.1210/me.2005-0159. PMID 16123152.
- Dias V, Ribeiro V (August 2007). "The expression of the solute carriers NTCP and OCT-1 is regulated by cholesterol in HepG2 cells". Fundamental & Clinical Pharmacology. 21 (4): 445–450. doi:10.1111/j.1472-8206.2007.00517.x. PMID 17635184. S2CID 46522965.
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