Sodium-dependent bile salt transporters of the SLC10A transporter family: more than solute transporters

Abstract

Summary The SLC10A transporter gene family consists of seven members and substrates transported by three members (SLC10A1, SLC10A2 and SLC10A6) are Na+-dependent. SLC10A1 (sodium taurocholate cotransporting polypeptide or NTCP) and SLC10A2 (apical sodium-dependent bile salt transporter or ASBT) transport bile salts and play an important role in maintaining enterohepatic circulation of bile salts. Solutes other than bile salts are also transported by NTCP. However, ASBT has not been shown to be a transporter for non-bile salt substrates. While the transport function of NTCP can potentially be used as liver function test, interpretation of such a test may be complicated by altered expression of NTCP in diseases and presence of drugs that may inhibit NTCP function. Transport of bile salts by NTCP and ASBT is inhibited by a number of drugs and it appears that ASBT is more permissive to drug inhibition than NTCP. The clinical significance of this inhibition in drug disposition and drug-drug interaction remains to be determined. Both NCTP and ASBT undergo post-translational regulations that involve phosphorylation/dephosphorylation, translocation to and retrieval from the plasma membrane and degradation by the ubiquitin-proteasome system. These posttranslational regulations are mediated via signaling pathways involving cAMP, calcium, nitric oxide, phosphoinositide-3-kinase (PI3K), protein kinase C (PKC) and protein phosphatases. There appears to be species difference in the substrate specificity and the regulation of plasma membrane localization of human and rodent NTCP. These differences should be taken into account when extrapolating rodent data for human clinical relevance and developing novel therapies. NTCP has recently been shown to play an important role in HBV and HDV infection by serving as a receptor for entry of these viruses into hepatocytes.

Regulation of Plasma Membrane Localization of the Na+-Taurocholate Cotransporting Polypeptide (Ntcp) by Hyperosmolarity and Tauroursodeoxycholate

“…These kinases are involved in the regulation of diverse cellular functions (70), including bile formation (35,71). It was suggested that choleretic and cholestatic effects may involve different PKC isoforms; however, the picture is not entirely consistent.…”

“…Ntcp is a serine/threonine phosphorylated protein (34) and underlies complex regulation (35). cAMP can induce an increase in TC uptake by insertion of Ntcp into the plasma membrane (36) via increases in intracellular Ca 2ϩ and subsequent activation of protein phosphatase 2B (PP2B) via Ca 2ϩ -calmodulin kinase (35). This is associated with a dephosphorylation of Ntcp at Ser-226 (37).…”

“…Also, taurochenodeoxycholate (TCDC) inhibits TC uptake at the sinusoidal membrane in a chelerythrine-and cypermethrin-dependent way (33). Ntcp is a serine/threonine phosphorylated protein (34) and underlies complex regulation (35). cAMP can induce an increase in TC uptake by insertion of Ntcp into the plasma membrane (36) via increases in intracellular Ca 2ϩ and subsequent activation of protein phosphatase 2B (PP2B) via Ca 2ϩ -calmodulin kinase (35).…”

Bile Acid Uptake Transporters as Targets for Therapy

“…Hepatic FXR activation by (semi-)synthetic FXR agonists has been successful in cholestatic animal models [44,45] in order to induce hepatic bile acid efflux and reduce bile acid uptake and such therapies are now being tested in phase II and III trials in PBC and primary sclerosing cholangitis [46]. In addition to FXR-dependent transcriptional repression of the bile acid uptake machinery, posttranscriptional regulation of the plasma membrane expression and function of NTCP is expected to be relevant during cholestasis, as reviewed elsewhere [47]. So far, the effectiveness of (further) inhibition of basolateral hepatic bile acid uptake in the context of cholestasis was only studied using OATP1A1 knockout mice, which were not protected against hepatic injury after bile-duct ligation [48].…”

A Novel Tricyclic Polyketide, Vanitaracin A, Specifically Inhibits the Entry of Hepatitis B and D Viruses by Targeting Sodium Taurocholate Cotransporting Polypeptide

“…Sodium taurocholate cotransporting polypeptide (NTCP), a hepatic membrane transporter for bile acid uptake (6)(7)(8), was recently reported to be an HBV entry receptor (9). The pre-S1 region of the HBV large surface protein (LHBs) interacts with NTCP, which is known to be essential for HBV infection, in mediating the viral entry process (9,10).…”