Sodium/bile acid cotransporter explained

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.[1] [2]

Structure

Sodium/bile acid cotransporters are integral membrane glycoproteins. Human NTCP contains 349 amino acids and has a mass of 56 kDa.

Function

s 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).

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:

Hepatitis virus entry

NTCP is a cell surface receptor necessary for the entry of hepatitis B and hepatitis D virus.[3] This entry mechanism is inhibited by myrcludex B,[4] cyclosporin A, progesterone, propranolol, bosentan, ezetimibe, bexarotene[5] as well as NTCP substrates like taurocholate, tauroursodeoxycholate and bromosulfophthalein.

SLC10A1-deficiency

Individuals that lack functional NTCP have been identified.[6] 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.[7]

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.[8] 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[9] and to liver damage in cholestasis.[10] These effects of NTCP deficiency have not yet been replicated in humans.

See also

Further reading

s

Notes and References

  1. Web site: Entrez Gene: SLC10A1 solute carrier family 10 (sodium/bile acid cotransporter family), member 1.
  2. Hagenbuch B, Meier PJ . Molecular cloning, chromosomal localization, and functional characterization of a human liver Na+/bile acid cotransporter . The Journal of Clinical Investigation . 93 . 3 . 1326–1331 . March 1994 . 8132774 . 294097 . 10.1172/JCI117091 .
  3. Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, Huang Y, Qi Y, Peng B, Wang H, Fu L, Song M, Chen P, Gao W, Ren B, Sun Y, Cai T, Feng X, Sui J, Li W . 6 . Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus . eLife . 1 . e00049 . November 2012 . 23150796 . 3485615 . 10.7554/eLife.00049 . free .
  4. H. Spreitzer. 14 September 2015. Neue Wirkstoffe – Myrcludex B. Österreichische Apothekerzeitung. 19/2015. 12. de.
  5. Gad SA, Sugiyama M, Tsuge M, Wakae K, Fukano K, Oshima M, Sureau C, Watanabe N, Kato T, Murayama A, Li Y, Shoji I, Shimotohno K, Chayama K, Muramatsu M, Wakita T, Nozaki T, Aly HH . 6 . 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 . March 2022 . 35312737 . 10.1371/journal.ppat.1009983 . 8970526 . free .
  6. Vaz FM, Paulusma CC, Huidekoper H, de Ru M, Lim C, Koster J, Ho-Mok K, Bootsma AH, Groen AK, Schaap FG, Oude Elferink RP, Waterham HR, Wanders RJ . 6 . Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: conjugated hypercholanemia without a clear clinical phenotype . Hepatology . 61 . 1 . 260–267 . January 2015 . 24867799 . 10.1002/hep.27240 . free .
  7. Peng L, Zhao Q, Li Q, Li M, Li C, Xu T, Jing X, Zhu X, Wang Y, Li F, Liu R, Zhong C, Pan Q, Zeng B, Liao Q, Hu B, Hu ZX, Huang YS, Sham P, Liu J, Xu S, Wang J, Gao ZL, Wang Y . 6 . The p.Ser267Phe variant in SLC10A1 is associated with resistance to chronic hepatitis B . Hepatology . 61 . 4 . 1251–1260 . April 2015 . 25418280 . 10.1002/hep.27608 . 205895418 .
  8. Slijepcevic D, Kaufman C, Wichers CG, Gilglioni EH, Lempp FA, Duijst S, de Waart DR, Elferink RP, Mier W, Stieger B, Beuers U, Urban S, van de Graaf SF . 6 . Impaired uptake of conjugated bile acids and hepatitis b virus pres1-binding in na(+) -taurocholate cotransporting polypeptide knockout mice . Hepatology . 62 . 1 . 207–219 . July 2015 . 25641256 . 4657468 . 10.1002/hep.27694 .
  9. Donkers JM, Kooijman S, Slijepcevic D, Kunst RF, Roscam Abbing RL, Haazen L, de Waart DR, Levels JH, Schoonjans K, Rensen PC, Oude Elferink RP, van de Graaf SF . 6 . NTCP deficiency in mice protects against obesity and hepatosteatosis . JCI Insight . 5 . 14 . June 2019 . 31237863 . 6675549 . 10.1172/jci.insight.127197 .
  10. Slijepcevic D, Roscam Abbing RL, Fuchs CD, Haazen LC, Beuers U, Trauner M, Oude Elferink RP, van de Graaf SF . 6 . Na+ -taurocholate cotransporting polypeptide inhibition has hepatoprotective effects in cholestasis in mice . Hepatology . 68 . 3 . 1057–1069 . September 2018 . 29572910 . 6175374 . 10.1002/hep.29888 .

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