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The Lipid Raft Component Stomatin Interacts with the Na+ Taurocholate Cotransporting Polypeptide (NTCP) and Modulates Bile Salt Uptake

1
Amsterdam UMC, University of Amsterdam, Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology, Endocrinology and Metabolism, 1105 BK Amsterdam, The Netherlands
2
Center for Molecular Medicine, Molecular Cancer Research Section, University Medical Center, 3584 CX Utrecht, The Netherlands
3
Amsterdam UMC, Department of Gastroenterology and Hepatology, University of Amsterdam, Amsterdam Gastroenterology, Endocrinology and Metabolism, Amsterdam 1105 AZ, The Netherlands
*
Author to whom correspondence should be addressed.
Shared the first authorship.
Cells 2020, 9(4), 986; https://doi.org/10.3390/cells9040986
Received: 17 March 2020 / Revised: 13 April 2020 / Accepted: 14 April 2020 / Published: 16 April 2020
The sodium taurocholate cotransporting polypeptide (NTCP) is expressed at the basolateral membrane of hepatocytes, where it mediates the uptake of conjugated bile acids and forms the hepatocyte entry receptor for the hepatitis B and D virus. Here, we aimed to identify novel protein–protein interactions that could play a role in the regulation of NTCP. To this end, NTCP was precipitated from HA-tagged hNTCP-expressing HepG2 cells, and chloride channel CLIC-like 1 (CLCC1) and stomatin were identified as interacting proteins by mass spectrometry. Interaction was confirmed by co-immunoprecipitation. NTCP, CLCC1 and stomatin were found at the plasma membrane in lipid rafts, as demonstrated by a combination of immunofluorescence, cell surface biotinylation and isolation of detergent-resistant membranes. Neither CLCC1 overexpression nor its knockdown had an effect on NTCP function. However, both stomatin overexpression and knockdown increased NTCP-mediated taurocholate uptake while NTCP abundance at the plasma membrane was only increased in stomatin depleted cells. These findings identify stomatin as an interactor of NTCP and show that the interaction modulates bile salt transport. View Full-Text
Keywords: bile acid; lipid raft; enterohepatic circulation; cholestasis; ASBT; BSEP; OATP; protein–protein interaction; transporter bile acid; lipid raft; enterohepatic circulation; cholestasis; ASBT; BSEP; OATP; protein–protein interaction; transporter
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Appelman, M.D.; Robin, M.J.; Vogels, E.W.; Wolzak, C.; Vos, W.G.; Vos, H.R.; Van Es, R.M.; Burgering, B.M.; Van de Graaf, S.F. The Lipid Raft Component Stomatin Interacts with the Na+ Taurocholate Cotransporting Polypeptide (NTCP) and Modulates Bile Salt Uptake. Cells 2020, 9, 986.

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