SLC10A1

Detailed Information

SLC10A1 Gene is located in the 14q24.2 region of human chromosome 14, spanning approximately 23 kb and containing five exons and four introns. Its mRNA transcript (NM_003049.3) encodes a 349-amino-acid transmembrane glycoprotein, Sodium Taurocholate Cotransporting Polypeptide (NTCP). The protein has a molecular weight of approximately 37 kDa (non-glycosylated form) to 55 kDa (glycosylated form), and is specifically expressed on the basolateral membrane of hepatocytes. NTCP contains nine transmembrane domains, with its N-terminus on the cytoplasmic side and C-terminus in the extracellular space, forming a typical solute carrier transporter topology. NTCP belongs to the solute carrier family 10 (SLC10). The serine residue at position 267 (p.Ser267) in the bile acid-binding domain plays a key role in transport function. Mutations at this site can significantly reduce its transport capacity. Immunofluorescence and Western blot studies confirm that NTCP expression levels in liver tissue are directly correlated with bile acid clearance efficiency. The antibody detection shows two bands at approximately 38 kDa and 50 kDa, reflecting different glycosylation modifications.

NTCP expression is regulated by various transcription factors, including hepatocyte nuclear factors (HNF) and CEBP-β. Its promoter region, about 1.2 kb, contains multiple cis-acting elements, ensuring its high and specific expression in hepatocytes. Evolutionary conservation analysis shows that the serine at position 267 is highly conserved across species, suggesting its critical role in maintaining protein function. Glycosylation modifications are crucial for NTCP's correct membrane localization in hepatocytes, and this process matures gradually after birth, becoming stable around the age of one. This correlates with the physiological changes in bile acid metabolism during infancy.

Biological Function and Physiological Significance

NTCP is a key transporter on the basolateral membrane of hepatocytes, efficiently taking up conjugated bile acids through a sodium-dependent mechanism, thus maintaining bile acid enterohepatic circulation homeostasis. Under normal physiological conditions, about 95% of bile acids are taken up by hepatocytes from portal venous blood via NTCP, and its transport efficiency directly influences cholesterol metabolism balance since bile acids are the main products of cholesterol catabolism. NTCP has broad affinity for several conjugated bile acids, such as taurocholate and glycocholate, and its transport follows the electrochemical gradient: for each bile acid molecule transported, two sodium ions are co-transported, which allows NTCP to function efficiently even in low bile acid concentrations.

Figure 1. Functional and structural analysis of NTCP. (Liu H, et al., 2022)

In addition to bile acid transport, NTCP is also involved in the liver uptake of various endogenous substances and drugs. Its substrate spectrum includes thyroid hormones (T4/T3), steroid hormones (such as estrone sulfate), and certain clinical drugs (such as statins). This pleiotropy makes NTCP a key molecule in hepatic drug disposition, and its functional state can influence pharmacokinetics and therapeutic efficacy. An important function of NTCP, discovered in 2012, is its role as a functional receptor for Hepatitis B Virus (HBV) and Hepatitis D Virus (HDV). The virus binds NTCP specifically via the pre-S1 domain of the large surface antigen (LHBs), mediating viral endocytosis. Notably, the p.Ser267Phe mutation not only impairs bile acid transport but also completely blocks HBV/HDV infection, providing a new target for antiviral therapy.

Hepatocytes also possess compensatory mechanisms for bile acid uptake, wherein the organic anion transporting polypeptides (OATP1B1/1B3) on the basolateral membrane play an important role in NTCP deficiency. These transporters uptake bile acids and bilirubin in a sodium-independent manner, but their expression is age-dependent—lower in neonates and gradually increasing with age, reaching adult levels around the age of seven. This developmental feature explains the age-related dynamic changes in bile acid levels in NTCP deficiency disease patients: significantly elevated in childhood and normalizing in adulthood. Animal studies show that even with Myrcludex B specifically inhibiting NTCP function, the compensatory action of OATP1B1/1B3 can maintain plasma bile acid levels close to normal.

Clinically Relevant Diseases and Translational Applications

NTCP functional deficiency causes a genetic disorder called NTCP Deficiency Syndrome (OMIM: 619998), which is caused by pathogenic mutations in both alleles of the SLC10A1 gene and follows an autosomal recessive inheritance pattern. The core biochemical feature of the disease is persistent hypercholanemia, but clinical manifestations are highly heterogeneous. In children, common symptoms include neonatal hyperbilirubinemia (50% of cases) or cholestasis in infancy, which may be associated with vitamin D deficiency (reduced 25-hydroxyvitamin D) and an increased incidence of gallbladder polyps/gallstones. Adult patients are often asymptomatic, with only mild bile acid elevation, but some female patients are misdiagnosed with intrahepatic cholestasis of pregnancy (ICP). Liver pathology changes are minimal, showing hepatocyte swelling, mild cholestasis, and portal tract inflammatory cell infiltration, but no progressive liver fibrosis or cirrhosis has been reported.

The mutation spectrum of SLC10A1 shows significant ethnic differences. In East Asian populations, the c.800C>T (p.Ser267Phe) mutation is a hotspot, with allele frequencies of 8% in the Han population of South China, 12% in the Dai ethnic group, and approximately 11% in Vietnamese populations. This mutation causes a loss of over 99% of NTCP's bile acid transport capacity, with a homozygous theoretical disease prevalence of around 1.37%. Other rare mutations include c.263T>C (p.Ile88Thr) and c.615_618delCTCT (p.Ser206Profs*12). Diagnosis requires genetic testing, but it should be noted that next-generation sequencing often misclassifies p.Ser267Phe as a benign polymorphism, leading to misdiagnosis. Therefore, targeted SLC10A1 sequencing is recommended for patients with unexplained hypercholanemia, especially those with prolonged jaundice or pregnancy-related cholestasis.

Currently, there is no specific treatment for NTCP deficiency syndrome, and treatment is symptomatic and supportive. Ursodeoxycholic acid (UDCA) can improve liver function in some patients but cannot correct hypercholanemia. It is noteworthy that pregnancy complicated by NTCP deficiency syndrome may increase fetal risk (such as low birth weight and growth restriction), but current data is limited (one stillbirth among three reported cases). Basic research suggests that a high bile acid environment may affect placental function by activating the pregnane X receptor (PXR), but the exact mechanism needs further exploration.

NTCP's viral receptor function has opened up new directions for the development of anti-HBV/HDV drugs. Myrcludex B (Bulevirtide), an NTCP-binding inhibitor, has been approved in the EU for treating HDV infection, with Phase II clinical trials showing a viral response rate exceeding 70%. Additionally, gene therapy strategies based on the p.Ser267Phe mutation (such as CRISPR/Cas9-mediated targeted editing) are in preclinical research, aiming to simulate the natural antiviral state. In diagnostic technology, a suspended magnetic bead-based liquid-phase chip reagent kit targeting common SLC10A1 mutations has achieved multiplex detection of eight sites, significantly improving screening efficiency.

Research Challenges and Future Directions

The core challenge of NTCP research currently lies in elucidating the molecular coordination mechanism of its dual functions (transport and viral receptor). Structural biology studies using cryo-electron microscopy have revealed high-resolution structures of NTCP-bile acid and NTCP-pre-S1 complexes, providing a blueprint for rational drug design. Another unresolved issue is the long-term outcome of NTCP deficiency syndrome: although short-term prognosis is favorable, whether lifelong hypercholanemia increases risks for colorectal cancer or cardiovascular diseases remains to be determined by large cohort studies. The NTCP deficiency registry system in Guangdong Province shows that about 30% of adult patients have gallbladder abnormalities (polyps or stones), suggesting the need for long-term follow-up.

In the field of precision medicine, NTCP expression levels may serve as a prognostic marker for liver cancer. Bioinformatics analyses have found that SLC10A1 expression is significantly downregulated in hepatocellular carcinoma (HCC), with low expression associated with shortened overall survival (hazard ratio HR=1.53). The mechanism involves bile acid metabolism dysregulation (CAR pathway abnormality) and immune microenvironment remodeling (reduced cytotoxic T cell infiltration). These findings provide a theoretical basis for NTCP-based molecular subtyping of liver cancer.