Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

NTCP (Sodium Taurocholate Cotransporting Polypeptide)

Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101735

Synonyms

Historical Background

A sodium-dependent transport system for conjugated bile salts was extensively characterized in early studies using perfused rat liver and isolated rat and human basolateral membranes. The factor responsible for the activity of the system was first identified by Dr. Meier’s group in 1990. In their seminal study, they injected rat liver poly (A)+ RNA into Xenopus laevis oocytes and observed the functional expression of sodium-dependent taurocholate uptake (Hagenbuch et al. 1990). Meier and coworkers size-fractionated and enriched the active mRNA, and showed that the 1.5∼3 Kb subfraction supported bile salt uptake. Following expression cloning of a rat cDNA library, they succeeded in cloning rat Ntcp, which consists of 1738 nucleotides that encode an open reading frame and whose expression produces a 362 aa polypeptide (Hagenbuch et al. 1991). NTCP was subsequently cloned from many species, including human, mouse, and rabbit (Stieger 2011). In addition to its function as a transporter of bile salts, NTCP was recently identified as an entry receptor for hepatitis B and D viruses by Dr. Li’s group (Yan et al. 2012).

Introduction

The solute carrier (SLC) 10 family comprises uptake transporters for bile salts, steroidal hormones, and various drugs. The SLC10 transporter family consists of seven members, including sodium taurocholate cotransporting polypeptide (NTCP, SLC10A1), apical sodium-dependent bile acid transporter (ASBT, SLC10A2), SLC10A3, SLC10A4, SLC10A5, sodium-dependent organic anion transporter (SOAT, SLC10A6), and SLC10A7 (Anwer and Stieger 2014). Of the family members, NTCP and ASBT have been extensively characterized as regulators for the enterohepatic circulation of bile salts. NTCP, the first identified SLC10 family member, is mainly distributed in the liver and its primary function in bile salt metabolism is to transport extracellular bile salts into hepatocytes (Fig. 1). NTCP also transports other xenobiotics, including statins, propranolol, furosemide, micafungin, and indocyanine green (Claro da Silva et al. 2013). In addition to this transporter function, NTCP was recently demonstrated to serve as an entry receptor for hepatitis B and D viruses (HBV and HDV) (Fig. 1) (Yan et al. 2012).
NTCP (Sodium Taurocholate Cotransporting Polypeptide), Fig. 1

NTCP’s functions as a transporter for bile salts (BS) and as an entry receptor for hepatitis B and D viruses (HBV, HDV). NTCP cotransports one molecule of extracellular BS together with two sodium ions to the hepatocytes. NTCP also essentially supports the entry of HBV and HDV into hepatocytes through the interaction with the preS1 region of the viral envelope protein

The human NTCP (hNTCP) gene produces a 349 aa protein with a mass of ∼56 kDa (Stieger 2011; Watashi and Wakita 2015). NTCP is expressed in not only human but also in other mammals such as chimpanzee, monkey, rabbit, rat, and mouse and in avians, reptiles, fishes, and potentially nematodes. The amino acid homologies of hNTCP to mouse (mNtcp), tupaia (tsNtcp), and crab-eating monkey Ntcp (mkNtcp) are 73.8%, 83.9%, and 96.3%, respectively. The NTCP gene product is a hydrophobic transmembrane protein. Its crystal structure remains to be solved, but a series of mutagenesis assays suggest that this protein has putative seven to nine transmembrane domains with a predicted topology of amino-terminal extracellular and carboxy-terminal intracellular sides. NTCP is distributed mainly on the basolateral membrane of hepatocytes and functions as an uptake transporter for bile salts. Its function is strictly regulated at both the transcriptional and posttranslational levels.

Transcriptional Regulation

Transcription of NTCP is regulated differently among species, and the molecular mechanisms of rat NTCP have been extensively characterized. Expression of NTCP is regulated by multiple transcription factors, especially nuclear hormone receptors (Fig. 2). In the rat, farnesoid X receptor (FXR), a nuclear receptor of bile salts, negatively regulates the transcription of NTCP: FXR activates the expression of small heterodimer partner (SHP), and SHP then represses the transcription of NTCP mRNA by interacting with the retinoic acid receptor (RAR)/retinoid X receptor (RXR) heterodimer, which induces the transcription of NTCP (Dawson et al. 2009). Upon the recognition of intracellular bile salts, FXR represses not only NTCP, but also other bile salt transporters such as ASBT and organic anion transporting polypeptide (OATP) 1B1 (Claro da Silva et al. 2013). In addition, FXR upregulates bile salt efflux transporters, such as bile salt export pump (BSEP) and OATP8, to prevent intracellular accumulation of cytotoxic bile salts. Activation of FXR reduces the expression level of cholesterol 7α-hydroxylase (CYP7A1), a key enzyme involved in bile acid biosynthesis. Another nuclear hormone receptor, glucocorticoid receptor (GR), is reported to transactivate mouse and human NTCP: Hepatocytes from GR knockout mice showed a decrease in the expression of NTCP, accompanied by a reduced bile volume in the gallbladder. Hepatocyte nuclear factor (HNF) 1 and HNF4 are also reported as positive regulators for rat NTCP transcription, while HNF3 represses the transcription of NTCP. Stimulation of cytokines, including tumor necrosis factor (TNF)α and interleukin (IL)-1β, has been reported to decrease the expression of NTCP by modulating the activity of the above transcription factors (Dawson et al. 2009; Urban et al. 2014).
NTCP (Sodium Taurocholate Cotransporting Polypeptide), Fig. 2

Transcriptional regulation and posttranslational modification of NTCP. NTCP expression is regulated by several nuclear hormone receptors. Farnesoid X receptor (FXR) is activated by stimulation of BS to upregulate small heterodimer partner (SHP). SHP then represses the transcription of NTCP. FXR also negatively regulate cholesterol-7-hydrogenase (CYP7A1), a key enzyme for BS synthesis. In addition, NTCP transcription is reported to be activated by glucocorticoid receptor (GR), hepatocyte nuclear factor 1 (HNF1), and HNF4, and negatively regulated by HNF3. After NTCP protein synthesis, its subcellular localization is regulated by posttranslational modification. Cyclic AMP (cAMP) triggers the phosphoinositide 3-kinase (PI3K) signaling and activates protein kinase C (PKC)δ and PKCζ. These PKCs promote the translocation of NTCP to the plasma membrane

Posttranslational Modification

After transcription and translation, NTCP is destined to be localized to the plasma membrane to work as a bile salt transporter. NTCP is mainly located on the basolateral membrane of hepatocytes. This localization is regulated by several posttranslational modification events (Fig. 2) (Anwer and Stieger 2014; Claro da Silva et al. 2013). Cyclic AMP (cAMP) affects NTCP localization on the plasma membrane and transporter activity by activating phosphoinositide-3-kinase (PI3K) and protein kinase C (PKC): cAMP triggers PI3K signaling and then activates PKCδ and PKCζ. These PKCs activate Rab4, which colocalizes with NTCP, to stimulate the motility of Rab4 and NTCP-containing vesicles on the microtubules leading to the plasma membrane. PKC activation is shown to translocate NTCP from the plasma membrane to the cytosol. These findings suggest that the serine/threonine phosphorylation of NTCP is a key determinant for its localization, although the mechanism as a whole remains to be understood. It is also reported that the glycosylation of NTCP alters its localization. The R252H point mutation of NTCP reduces the complex-glycosylated NTCP, resulting in a reduction in plasma membrane NTCP, although it is not clear whether this amino acid is the glycosylation site (Vaz et al. 2015). In addition, NTCP localization on the plasma membrane is modulated by S-nitrosylation (Anwer and Stieger 2014). Treatment with nitric oxide to induce S-nitrosylation decreases NTCP membrane localization and its transport activity. NTCP is also reported to be modified by ubiquitin, and ubiquitinated NTCP mediates the degradation through the proteasome pathway. The above transcriptional and posttranslational regulation mechanisms of NTCP play a key role in regulating bile salt circulation and metabolism.

Function

Bile salts are important physiological agents for the intestinal digestion of fat and absorption of fat-soluble vitamins. They also function as intracellular signaling molecules through G protein-coupled receptors (GPCRs) and nuclear hormone receptors to regulate cellular physiological events, including lipid, glucose, energy, and metabolic homeostasis. Bile salts are synthesized mainly in the liver using cholesterol or oxysterols as starting materials via stepwise reactions involving cytochrome P450 (CYP) family enzymes. The synthesized primary bile salts can be then conjugated with either glycine or taurine to produce conjugated bile salts. These bile salts are secreted from hepatocytes into the bile and travel down the intestine, where they function to promote nutrient digestion and absorption (Fig. 3). Most of the bile salts are then carried in the portal circulation back to the liver for uptake and resecretion into bile. This cycle of bile salts is called enterohepatic circulation, and this circulation system involves several transporters, such as NTCP and the OATP family that take up bile salts from portal blood into hepatocytes, BSEP (which secretes bile salts into the bile), and ASBT and organic solute transporter alpha-beta (OSTα/β), which mediate the uptake and efflux of bile salts from enterocytes (Kosters and Karpen 2008; Stieger 2011).
NTCP (Sodium Taurocholate Cotransporting Polypeptide), Fig. 3

Enterohepatic circulation of bile salts. BS are synthesized mainly in the liver and can be conjugated with either glycine or taurine. The BS are secreted from hepatocytes into the bile canaliculi through transport by bile salt export pump (BSEP) and then flow into gallbladder to travel down the small intestine. More than 90% of BS are reabsorbed into enterocytes within the terminal ileum via transport by apical sodium-dependent bile salt transporter (ASBT). BS are then secreted into the portal vein by organic solute transporter (OSTα/β) and travel back to the liver. In the liver, BS are transported into the hepatocytes by NTCP or organic anion-transporting polypeptide family (OATPs)

The uptake of bile salts by NTCP occurs in a sodium-dependent manner (Figs. 1, 3). NTCP cotransports one bile salt molecule together with two sodium ions to the intracellular side using the energy provided by the out-to-in sodium gradient generated by Na+/K+-ATPase on the basolateral plasma membrane. NTCP predominantly transports taurine- or glycine-conjugated bile salts and shows higher affinity for dihydroxy bile salts (e.g., taurochenodeoxycholate and taurodeoxycholate) than for trihydroxy bile salts (e.g., taurocholate, cholate) (Kosters and Karpen 2008; Stieger 2011). A recent NTCP knockout analysis showed that about 30% of NTCP-deficient mice remarkably accumulated conjugated bile salt in the serum (up to 500-fold compared with normal mice) and had significantly reduced body weights (Slijepcevic et al. 2015). Another NTCP knockout study reported that in addition to the elevation of serum bile salt levels, some mice developed gallbladder diseases and impaired liver function at an early age, together with altered lipid metabolism (Hou et al. 2015). These observations clearly demonstrate the critical role of NTCP in bile salt metabolism and its related physiological events. Many drugs and small molecules have been reported to interact with and impair the transporter activity of NTCP. Inhibition of the transporter activity of NTCP by these compounds may elevate serum bile salts levels and thus cause significant adverse effects. OATPs, which are other sodium-dependent bile salt transporters, can partially compensate for the inhibition of NTCP, but some of these compounds inhibit both NTCP and OATP transporters.

Polymorphism

Several single-nucleotide polymorphisms (SNPs) associate with the transporter activity of NTCP have been reported. A SNPs analysis of 90 European Americans, 90 African-Americans, 100 Chinese Americans, and 90 Hispanic Americans identified seven SNPs in the NTCP coding region, including four nonsynonymous SNPs, which resulted in the I223T, S267F, I279T, and K314E substitutions in NTCP (Ho et al. 2004). The I223T variant, seen in 5.5% of African-Americans, showed an equivalent level of total NTCP protein expression in cells compared with the wild type, but significantly reduced NTCP expression on the cell surface: consequently, bile salt uptake was impaired. I223 is therefore likely to be important for NTCP trafficking to the cell surface. The S267F variant, seen in 7.5% of Chinese Americans, exhibited almost complete loss of both conjugated- and unconjugated-bile salt uptake, but possessed normal transport activity for another substrate, estron sulfate, suggesting that S267 is critical for bile salt binding/recognition. The I279T and K314E polymorphisms were relatively rare and were found in 0.5% of Chinese Americans and in 0.55% of Hispanic Americans, respectively. A recent paper reported other minor variants (I88T, L131 V, V200 M, L222S, M256 T, A323P, and A333T) seen in less than 0.5% of the Chinese populations. Although these variants in the NTCP gene are unlikely to cause serious diseases in individuals, a recent report analyzing a child case who showed growth retardation and motor developmental delay found the R252H polymorphism of NTCP and an extremely elevated serum bile salt level (up to mM levels) (Vaz et al. 2015). This case demonstrates the essential role of NTCP in the uptake of conjugated bile salts in human liver.

The discovery that NTCP functions as an entry receptor for HBV and HDV (see the next paragraph) prompted the analysis of SNPs that associate with HBV infection, the pathogenesis of chronic hepatitis B, and eventual hepatocellular carcinoma. In an analysis of 1899 chronic hepatitis B patients and 1828 healthy controls of Taiwanese Han Chinese individuals, the S267F NTCP variant was significantly associated with resistance to chronic hepatitis B (4.1–4.6% of the population with chronic hepatitis B vs. 10.8–11.1% of healthy individuals) and a lower incidence of acute-on-chronic liver failure (Peng et al. 2015). No other NTCP SNPs were identified in this paper showing association with hepatitis B. Another study from Taiwan on 3801 chronic hepatitis B patients and a cohort of HBV-negative individuals also consistently showed an association between the S267F variant and resistance to HBV infection and decreased risk of resultant cirrhosis and hepatocellular carcinoma (Hu et al. 2016). Although other papers showed no such association of this genetic variation with HBV infection, a relatively small number of individuals were analyzed in these studies. Cell culture analysis showed that the S267F mutation in NTCP severely impaired the function of the protein as an entry receptor for HBV and HDV (Yan et al. 2014), thus explaining the molecular basis for these epidemiological findings. However, it is interesting that some S267F individuals can still develop chronic hepatitis B in spite of the almost complete loss of receptor function observed in cell culture analysis, suggesting the existence of another entry receptor or of an HBV variant that can overcome the loss of function of NTCP (S267F). Additionally, a genetic variant located in intron 1 of NTCP (rs4646287) was shown to have association with the risk of HBV infection, although its variant effect on the NTCP expression level was not clear. Thus, NTCP polymorphisms affect susceptibility of HBV infection and HBV-related pathogenesis in addition to bile salt metabolism.

NTCP as an HBV/HDV Receptor

NTCP as a Virus Entry Receptor

Fifty years after the discovery of HBV, the cellular receptor for HBV has remained unknown despite intense efforts to analyze the viral entry process. In 2012, NTCP was revealed to function as an entry receptor for HBV and HDV (Fig. 1) (Yan et al. 2012). The liver-specific distribution of NTCP apparently accounts for some, if not all, of the hepatotropism of HBV and HDV. An HBV particle contains three types of surface envelope proteins: small (SHBs), middle (MHBs), and large surface proteins (LHBs). These proteins share a common carboxyl-terminal domain, termed the S region. SHBs comprises only the S region, while MHBs have an amino-terminal extension, referred to as the preS2 region, and LHBs carries a further amino-terminal region upstream of preS2 and S, called the preS1 region (Urban et al. 2014). A series of analyses using neutralizing antibodies and mutagenesis suggest that both the preS1 and the S regions play pivotal roles in HBV infection, and that the 2–48 aa region of preS1 is especially essential for interaction with a cellular receptor that had remained unidentified. Recently, Yan et al. used an affinity purification method to identify NTCP as a binding protein for the 2–48 aa region of preS1. Subsequent analysis showed that knockdown of NTCP in HBV-susceptible cells impaired HBV susceptibility, and ectopic expression of NTCP rendered HBV nonsusceptible human hepatocyte cell lines susceptible to HBV infection. These data demonstrate that NTCP is an HBV entry receptor. Furthermore, it was shown that NTCP is essential for the entry of HDV, which shares the same envelope proteins as HBV. This discovery represents a major breakthrough in HBV/HDV research in this decade.

Residues Responsible for Binding with Viruses, Bile Salts, and Sodium

The precise mechanisms by which NTCP mediates viral entry are currently largely unknown, but it is speculated that NTCP triggers the endocytosis of HBV/HDV through engagement of the preS1 region during the early entry process. Limited information about its molecular basis indicates which NTCP residues are required to support viral entry (Watashi and Wakita 2015; Yan et al. 2015): especially, it was shown that hNTCP and tsNtcp, but not mkNtcp, support infection of HBV and HDV. Comparison of the sequences of these three proteins suggests that 157–165 aa of hNTCP are required for viral entry. The introduction of mutations (KGIVISLVL) in the 157–165 aa region of hNTCP abolished preS1 binding, although the data could not exclude the possibility that the mutations caused a major conformational change of NTCP. Another study compared the sequence of hNTCP with that of mNtcp, which does not support HBV/HDV entry, and identified 84–87 aa (RLKN) as critical residues in hNTCP for viral entry. It is interesting that mice carrying the RLKN hNTCP mutation in the 84–87 aa region of mNtcp became susceptible to infection by HDV. Modeling analysis suggested that both the 157–165 aa and 84–87 aa regions reside on the extracellular surface or in the transmembrane region, although the precise mechanisms by which these regions support HBV/HDV entry remain to be clarified.

Most bile salts, including primary and secondary bile salts, inhibit the binding of NTCP with preS1 and subsequent infection of HBV and HDV (Watashi and Wakita 2015; Yan et al. 2015). These results suggest that the binding region of HBV/HDV and that of bile salts to NTCP are overlapped. This possibility is further supported by point mutation analyses in bile salt-binding residues, as described below. The bile salt and sodium binding sites on hNTCP have been predicted based on previous information obtained from rat Ntcp mapping and from the crystal structure of ASBT. Mutagenesis assays indicated that N262, Q293/L294, and S267 (described above) are all critical regions for bile salt binding. The introduction of mutations in any of these regions strongly impaired the ability of NTCP to bind to preS1 and thus support HBV/HDV infection. Thus, HBV/HDV interaction and bile salt binding share common molecular determinants on NTCP, at least based on the evidence available to date. Mutations in the reported or predicted sites for sodium binding, namely, Q68, S105/N106, E257 and Q261 of NTCP, also reduce viral receptor function, although to a lesser extent than mutations in the bile salt binding sites (Yan et al. 2014). Solving the NTCP protein structure is essential for fully understanding the molecular basis of NTCP function.

NTCP as a Target for Developing Anti-HBV Drugs

Approximately 240 million people worldwide are chronically infected with HBV, and this elevates their risk for developing liver cirrhosis and hepatocellular carcinoma. HDV coinfects the liver with HBV and clinically aggravates the natural history of HBV-related diseases. These viruses constitute a major public health problem worldwide and thus there is urgent need for new drugs against HBV/HDV infection. Identification of NTCP as an HBV/HDV receptor has facilitated research on developing anti-HBV/HDV agents. To date, NTCP substrates such as bile salts, including taurocholate, tauroursodeoxycholate, and taurochenodeoxycholate, and other xenobiotic substrates, including bromosulfophthalein, have been reported to inhibit HBV/HDV infection. Furthermore, compounds known to inhibit NTCP-mediated bile acid uptake, including cyclosporin A, ezetimibe, and irbesartan, were shown to inhibit HBV entry (Yan et al. 2015). Additionally, newly identified HBV entry inhibitors such as vanitaracin A identified using cell-based chemical screening have been demonstrated to directly target NTCP and inhibit both its viral receptor function and transporter activity. These data suggest that NTCP can serve as a new target for developing anti-HBV agents (Iwamoto and Watashi 2016). In fact, myrcludex B, which is an optimized synthetic lipopeptide of the myristoylated 2–48 aa region of preS1 and is proved to bind to NTCP, strongly inhibits HBV infection in both cell culture and in in vivo mouse models. A recent report of a phase Ib/IIa clinical study demonstrated the antiviral potential of myrcludex B for anti-HBV/HDV treatment in patients (Bogomolov et al. 2016). Currently, the adverse effects of long-term administration of myrcludex B, and its inhibition of NTCP transporter and modulation of bile salt metabolism, remain unclear. Optimizing strategies for using NTCP as a drug target will require further analysis of the mechanism underlying NTCP-mediated viral entry.

Summary

NTCP transports bile salts and other xenobiotics into hepatocytes that play a critical role in the enterohepatic circulation of bile salts. Knockout mice and gene polymorphism analyses clearly demonstrate the essential role of NTCP in bile salt metabolism. In addition, NTCP was recently identified as an entry receptor for HBV/HDV, making NTCP an attractive target for the development of antiviral agents. Although the molecular mechanisms by which NTCP supports HBV/HDV infection remain largely unknown, it is likely that NTCP supports HBV/HDV entry in a manner different from that used to transport bile salts because viral particles are much larger than the pore size of NTCP. Further mechanistic analysis of NTCP-mediated HBV/HDV entry will provide new insights into NTCP function.

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Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Senko Tsukuda
    • 1
  • Masashi Iwamoto
    • 1
  • Koichi Watashi
    • 1
  1. 1.Department of Virology IINational Institute of Infectious DiseasesTokyoJapan