NTCP Deficiency Affects the Levels of Circulating Bile Acids and Induces Osteoporosis

BackgroundThe p.Ser267Phe mutation in the SLC10A1 gene can cause NTCP deficiency. However, the full clinical presentation of p.Ser267Phe homozygous individuals and its long-term consequences remain unclear. Hence, in the present study, we characterized the phenotypic characteristics of NTCP deficiency and evaluated its long-term prognosis.MethodsTen NTCP p.Ser267Phe homozygous individuals were recruited and a comprehensive medical evaluation with a 5-year follow-up observation was performed. The phenotypic characteristics of NTCP deficiency were also demonstrated using an NTCP-global knockout mouse model.ResultsDuring the 5-year follow-up observation of 10 NTCP p.Ser267Phe homozygous adults, we found that the most common phenotypic features of NTCP deficiency in adults were hypercholanemia, vitamin D deficiency, bone loss, and gallbladder abnormalities. The profile of bile acids (BAs) in the serum was significantly altered in these individuals and marked by both elevated proportion and concentration of primary and conjugated BAs. Moreover, the NTCP deficiency led to increased levels of serum BAs, decreased levels of vitamin D, and aggravated the osteoporotic phenotype induced by estrogen withdrawal in mice.ConclusionsBoth mice and humans with NTCP deficiency presented hypercholanemia and were more prone to vitamin D deficiency and aggravated osteoporotic phenotype. Therefore, we recommend monitoring the levels of BAs and vitamin D, bone density, and abdominal ultrasounds in individuals with NTCP deficiency

Diverse Effects of the NTCP p.Ser267Phe Variant on Disease Progression During Chronic HBV Infection and on HBV preS1 Variability

The sodium taurocholate co-transporting polypeptide (NTCP) acts as a cellular receptor for the hepatitis B virus (HBV) infection on host hepatocytes. We aim to investigate how the NTCP p.Ser267Phe variant affects HBV-related disease progression and analyze viral genomic variability under a host genetic background carrying the p.Ser267Phe variant. A total of 3187 chronic hepatitis B (CHB) patients were enrolled and genotyped for the p.Ser267Phe variant. The variant's association with disease progression was evaluated by logistic regression analysis. We also enrolled 83 treatment-naive CHB patients to analyze the variability of the HBV preS1 region. The frequency of the NTCP p.Ser267Phe variant was significantly lower in patients diagnosed with acute-on-chronic liver failure [OR (95% CI) = 0.33 (0.18–0.58), P = 1.34 × 10−4], cirrhosis [OR (95% CI) = 0.47 (0.31–0.72), P = 4.04 × 10−4], and hepatocellular carcinoma [OR (95% CI) = 0.54 (0.34–0.86), P = 9.83 × 10−3] as compared with CHB controls under the additive model after adjustment. Furthermore, the percentage of amino acid mutations in HBV preS1 region was significantly higher in the NTCP p.Ser267Phe heterozygote group than in the NTCP wild type homozygote group (P < 0.05). We herein demonstrate that the NTCP p.Ser267Phe variant is a protective factor reducing CHB patient risk for liver failure, cirrhosis, and hepatocellular carcinoma. A host genetic background carrying NTCP p.Ser267Phe exerts selective pressure on the virus, leading to more variability