Background and aims:The sodium taurocholate co-transporting polypeptide(NTCP)is a functional receptor for the hepatitis B virus(HBV),and it is critical for bile acid homeostasis.Previous studies of the association bet...Background and aims:The sodium taurocholate co-transporting polypeptide(NTCP)is a functional receptor for the hepatitis B virus(HBV),and it is critical for bile acid homeostasis.Previous studies of the association between the S267F variant and chronic hepatitis B(CHB)have generated conflicting results.This study analyzed the correlation between the NTCP S267F variant and CHB susceptibility by using a large sample of participants classified by gender and age,and this study also analyzed the relationship between this variant and the level of serum total bile acids.Methods:In total,543 patients with CHB and 429 control subjects underwent S267F variant genotyping using SNaPshot technology.Logistic regression was utilized to evaluate any association of the NTCP S267F variant with CHB susceptibility.Results:The S267F variant was inversely correlated with the risk of chronic HBV infection in both the dominant model(GG genotype vs.AG genotype:odds ratio(OR)=0.46,95%confidence interval(CI)0.30 -0.71,P<0.001)and the allele model(G allele vs.A allele:OR=0.50,95%CI 0.33-0.76,P=0.001),and this correlation was not affected by gender and age stratification.The carriers of the heterozygous NTCP variant exhibited higher total bile acids levels than the carriers of wild-type NTCP,regardless of whether they were control subjects or patients with CHB.Heterozygous carriers exhibited reduced hepatitis B e antigen(HBeAg)-positivity rates and had lower ALT,AST,and lg DNA concentrations compared with wild-type carriers in patients with CHB.Conclusions:The S267F variant of NTCP is a protective factor that reduces the risk of chronic HBV infection and exhibits a higher total bile acids level.Patients with CHB who carry this variant may have a better prognosis than those carrying wild-type NTCP.展开更多
BACKGROUND Sodium taurocholate cotransport polypeptide(NTCP)deficiency disease is a genetic metabolic disorder due to mutations in the SLC10A1 gene and impaired bile acid salt uptake by the basolateral membrane transp...BACKGROUND Sodium taurocholate cotransport polypeptide(NTCP)deficiency disease is a genetic metabolic disorder due to mutations in the SLC10A1 gene and impaired bile acid salt uptake by the basolateral membrane transport protein NTCP in hepatocytes.A variety of clinical manifestations and genetic mutation loci have been reported for this disease.However,specific therapeutic measures are lacking,and the long-term effects are unknown.CASE SUMMARY An infant with elevated bile acids and behavioral neurodevelopmental delay failed to respond to bile acid-lowering therapy.Genetic testing for metabolic liver disease revealed that the child had NTCP deficiency due to the SLC10A1 mutation:c.422dupA(p.Y141X),which is a novel mutation site.The current followup revealed a gradual decrease in bile acid levels after 1 year of age,but the child still had behavioral neurodevelopmental delays.CONCLUSION The clinical manifestations,genetic characteristics,treatment and long-term prognosis due to NTCP deficiency remain poorly defined and need to be further confirmed by more studies and reports.展开更多
Sodium taurocholate cotransporting polypeptide(NTCP)is identified as the functional receptor for HBV entry,which is responsible for upregulated HBV transcription in the HBV life cycle.Besides,NTCP is also implicated i...Sodium taurocholate cotransporting polypeptide(NTCP)is identified as the functional receptor for HBV entry,which is responsible for upregulated HBV transcription in the HBV life cycle.Besides,NTCP is also implicated in the progression of HBV-induced hepatocellular carcinoma(HCC).Thereby,NTCP-targeting entry inhibitors are proposed to suppress HBV infection and replication in HBV-induced hepatoma therapy.Herein,we integrated in silico screening and chemical synthesis to obtain a small-molecule NTCP inhibitor B7,which exhibited moderate anti-proliferative activities against HepG2 cells and anti-HBV activity in vitro.Additionally,CETSA assay,molecular docking,and MD simulation validated that B7 could bind to NTCP.Furthermore,western blot analysis demonstrated that B7 induced apoptosis with an increased expression of Bax and caspase 3 cleaving as well as a decreasing expression of Bcl-2 in HepG2 cells.Taken together,our study identified B7 as a novel NTCP inhibitor with anti-proliferation activities which might provide a new opportunity for HCC therapy.展开更多
钠离子牛磺胆酸共转运多肽(sodium-taurocholate cotransporting polypeptide,NTCP)缺陷病是一种溶质载体家族10成员1(solute carrier family 10 member 1,SLC10A1)双等位基因突变引起的胆汁酸代谢障碍性疾病,分布具有区域和种族差异,其...钠离子牛磺胆酸共转运多肽(sodium-taurocholate cotransporting polypeptide,NTCP)缺陷病是一种溶质载体家族10成员1(solute carrier family 10 member 1,SLC10A1)双等位基因突变引起的胆汁酸代谢障碍性疾病,分布具有区域和种族差异,其中SLC10A1 c.800C>T(p.Ser267Phe)是我国的高频突变。NTCP缺陷病患儿主要表现为病理性黄疸,少部分有生长、运动和神经系统发育迟缓的表现,成年患者临床症状和体征不明显,生化检查提示血清总胆汁酸水平升高、部分伴有转氨酶和25-羟维生素D3水平降低。NTCP缺陷病性高胆汁酸血症需与乙型肝炎病毒感染、丁型肝炎病毒感染、自身免疫性肝炎及妊娠期肝内胆汁淤积症等鉴别,妊娠合并NTCP缺陷病性高胆汁酸血症对母胎的影响迄今少有相关报道。综述NTCP缺陷病的分子遗传机制、临床表现、实验室检查、诊断、治疗及其对母胎的影响,为该病患者的明确诊断和正确干预提供依据。展开更多
Currently, hepatitis B virus(HBV), upon attaching to human hepatocytes, is considered to interact first with heparan sulfate proteoglycan(HSPG) via an antigenic loop of HBV envelope S protein. Then, it is promptly tra...Currently, hepatitis B virus(HBV), upon attaching to human hepatocytes, is considered to interact first with heparan sulfate proteoglycan(HSPG) via an antigenic loop of HBV envelope S protein. Then, it is promptly transferred to the sodium taurocholate cotransporting polypeptide(NTCP) via the myristoylated N-terminal sequence of pre-S1 region(from Gly-2 to Gly-48, HBV genotype D), and it finally enters the cell by endocytosis. However, it is not clear how HSPG passes HBV to NTCP and how NTCP contributes to the cellular entry of HBV. Owing to the poor availability and the difficulty of manipulations, including fluorophore encapsulation, it has been nearly impossible to perform biochemical and cytochemical analyses using a substantial amount of HBV. A bio-nanocapsule(BNC), which is a hollow nanoparticle consisting of HBV envelope L protein, was efficiently synthesized in Saccharomyces cerevisiae. Since BNC could encapsulate payloads(drugs, genes, proteins) and specifically enter human hepatic cells utilizing HBV-derived infection machinery, it could be used as a model of HBV infection to elucidate the early infection machinery. Recently, it was demonstrated that the N-terminal sequence of pre-S1 region(from Asn-9 to Gly-24) possesses low p H-dependent fusogenic activity, which might play a crucial role in the endosomal escape of BNC payloads and in the uncoating process of HBV. In this minireview, we describe a model in which each domain of the HBV L protein contributes to attachment onto human hepatic cells through HSPG, initiation of endocytosis, interaction with NTCP in endosomes, and consequent provocation of membrane fusion followed by endosomal escape.展开更多
AIM To determine the variability/conservation of the domain of hepatitis B virus(HBV) pre S1 region that interacts with sodium-taurocholate cotransporting polypeptide(hereafter, NTCP-interacting domain) and the preval...AIM To determine the variability/conservation of the domain of hepatitis B virus(HBV) pre S1 region that interacts with sodium-taurocholate cotransporting polypeptide(hereafter, NTCP-interacting domain) and the prevalence of the rs2296651 polymorphism(S267 F, NTCP variant) in a Spanish population. METHODS Serum samples from 246 individuals were included and divided into 3 groups: patients with chronic HBV infection(CHB)(n = 41, 73% Caucasians), patients with resolved HBV infection(n = 100, 100% Caucasians) and an HBV-uninfected control group(n = 105, 100% Caucasians). Variability/conservation of the amino acid(aa) sequences of the NTCPinteracting domain,(aa 2-48 in viral genotype D) and a highly conserved pre S1 domain associated with virion morphogenesis(aa 92-103 in viral genotype D) were analyzed by next-generation sequencing and compared in 18 CHB patients with viremia > 4 log IU/mL. The rs2296651 polymorphism was determined in all individuals in all 3 groups using an in-house real-time PCR melting curve analysis.RESULTS The HBV pre S1 NTCP-interacting domain showed a high degree of conservation among the examined viral genomes especially between aa 9 and 21(in the genotype D consensus sequence). As compared with the virion morphogenesis domain, the NTCPinteracting domain had a smaller proportion of HBV genotype-unrelated changes comprising > 1% of the quasispecies(25.5% vs 31.8%), but a larger proportion of genotype-associated viral polymorphisms(34% vs 27.3%), according to consensus sequences from Gen Bank patterns of HBV genotypes A to H. Variation/conservation in both domains depended on viral genotype, with genotype C being the most highly conserved and genotype E the most variable(limited finding, only 2 genotype E included). Of note, proline residues were highly conserved in both domains, and serine residues showed changes only to threonine or tyrosine in the virion morphogenesis domain. The rs2296651 polymorphism was not detected in any participant.CONCLUSION In our CHB population, the NTCP-interacting domain was highly conserved, particularly the proline residues and essential amino acids related with the NTCP interaction, and the prevalence of rs2296651 was low/null.展开更多
基金This study was funded by the Natural Science Foundation of Fujian Province(No.2021J011447)Ningde Science and Technology Plan Project(No.20170032).
文摘Background and aims:The sodium taurocholate co-transporting polypeptide(NTCP)is a functional receptor for the hepatitis B virus(HBV),and it is critical for bile acid homeostasis.Previous studies of the association between the S267F variant and chronic hepatitis B(CHB)have generated conflicting results.This study analyzed the correlation between the NTCP S267F variant and CHB susceptibility by using a large sample of participants classified by gender and age,and this study also analyzed the relationship between this variant and the level of serum total bile acids.Methods:In total,543 patients with CHB and 429 control subjects underwent S267F variant genotyping using SNaPshot technology.Logistic regression was utilized to evaluate any association of the NTCP S267F variant with CHB susceptibility.Results:The S267F variant was inversely correlated with the risk of chronic HBV infection in both the dominant model(GG genotype vs.AG genotype:odds ratio(OR)=0.46,95%confidence interval(CI)0.30 -0.71,P<0.001)and the allele model(G allele vs.A allele:OR=0.50,95%CI 0.33-0.76,P=0.001),and this correlation was not affected by gender and age stratification.The carriers of the heterozygous NTCP variant exhibited higher total bile acids levels than the carriers of wild-type NTCP,regardless of whether they were control subjects or patients with CHB.Heterozygous carriers exhibited reduced hepatitis B e antigen(HBeAg)-positivity rates and had lower ALT,AST,and lg DNA concentrations compared with wild-type carriers in patients with CHB.Conclusions:The S267F variant of NTCP is a protective factor that reduces the risk of chronic HBV infection and exhibits a higher total bile acids level.Patients with CHB who carry this variant may have a better prognosis than those carrying wild-type NTCP.
基金Yunnan Science Foundation Project,No.2019-81960102.
文摘BACKGROUND Sodium taurocholate cotransport polypeptide(NTCP)deficiency disease is a genetic metabolic disorder due to mutations in the SLC10A1 gene and impaired bile acid salt uptake by the basolateral membrane transport protein NTCP in hepatocytes.A variety of clinical manifestations and genetic mutation loci have been reported for this disease.However,specific therapeutic measures are lacking,and the long-term effects are unknown.CASE SUMMARY An infant with elevated bile acids and behavioral neurodevelopmental delay failed to respond to bile acid-lowering therapy.Genetic testing for metabolic liver disease revealed that the child had NTCP deficiency due to the SLC10A1 mutation:c.422dupA(p.Y141X),which is a novel mutation site.The current followup revealed a gradual decrease in bile acid levels after 1 year of age,but the child still had behavioral neurodevelopmental delays.CONCLUSION The clinical manifestations,genetic characteristics,treatment and long-term prognosis due to NTCP deficiency remain poorly defined and need to be further confirmed by more studies and reports.
基金supported by National Science and Technology Major Project of the Ministry of Science and Technology of China(No.2018ZX09735005)the National Natural Science Foundation of China(Nos.81922064,81874290,81673290,81803347 and 81903502)+1 种基金the Natural Science Foundation of Guangdong Province(No.2018A030313707)Post-Doctor Research Project,West China Hospital,Sichuan University(No.2019HXBH034)。
文摘Sodium taurocholate cotransporting polypeptide(NTCP)is identified as the functional receptor for HBV entry,which is responsible for upregulated HBV transcription in the HBV life cycle.Besides,NTCP is also implicated in the progression of HBV-induced hepatocellular carcinoma(HCC).Thereby,NTCP-targeting entry inhibitors are proposed to suppress HBV infection and replication in HBV-induced hepatoma therapy.Herein,we integrated in silico screening and chemical synthesis to obtain a small-molecule NTCP inhibitor B7,which exhibited moderate anti-proliferative activities against HepG2 cells and anti-HBV activity in vitro.Additionally,CETSA assay,molecular docking,and MD simulation validated that B7 could bind to NTCP.Furthermore,western blot analysis demonstrated that B7 induced apoptosis with an increased expression of Bax and caspase 3 cleaving as well as a decreasing expression of Bcl-2 in HepG2 cells.Taken together,our study identified B7 as a novel NTCP inhibitor with anti-proliferation activities which might provide a new opportunity for HCC therapy.
文摘钠离子牛磺胆酸共转运多肽(sodium-taurocholate cotransporting polypeptide,NTCP)缺陷病是一种溶质载体家族10成员1(solute carrier family 10 member 1,SLC10A1)双等位基因突变引起的胆汁酸代谢障碍性疾病,分布具有区域和种族差异,其中SLC10A1 c.800C>T(p.Ser267Phe)是我国的高频突变。NTCP缺陷病患儿主要表现为病理性黄疸,少部分有生长、运动和神经系统发育迟缓的表现,成年患者临床症状和体征不明显,生化检查提示血清总胆汁酸水平升高、部分伴有转氨酶和25-羟维生素D3水平降低。NTCP缺陷病性高胆汁酸血症需与乙型肝炎病毒感染、丁型肝炎病毒感染、自身免疫性肝炎及妊娠期肝内胆汁淤积症等鉴别,妊娠合并NTCP缺陷病性高胆汁酸血症对母胎的影响迄今少有相关报道。综述NTCP缺陷病的分子遗传机制、临床表现、实验室检查、诊断、治疗及其对母胎的影响,为该病患者的明确诊断和正确干预提供依据。
文摘Currently, hepatitis B virus(HBV), upon attaching to human hepatocytes, is considered to interact first with heparan sulfate proteoglycan(HSPG) via an antigenic loop of HBV envelope S protein. Then, it is promptly transferred to the sodium taurocholate cotransporting polypeptide(NTCP) via the myristoylated N-terminal sequence of pre-S1 region(from Gly-2 to Gly-48, HBV genotype D), and it finally enters the cell by endocytosis. However, it is not clear how HSPG passes HBV to NTCP and how NTCP contributes to the cellular entry of HBV. Owing to the poor availability and the difficulty of manipulations, including fluorophore encapsulation, it has been nearly impossible to perform biochemical and cytochemical analyses using a substantial amount of HBV. A bio-nanocapsule(BNC), which is a hollow nanoparticle consisting of HBV envelope L protein, was efficiently synthesized in Saccharomyces cerevisiae. Since BNC could encapsulate payloads(drugs, genes, proteins) and specifically enter human hepatic cells utilizing HBV-derived infection machinery, it could be used as a model of HBV infection to elucidate the early infection machinery. Recently, it was demonstrated that the N-terminal sequence of pre-S1 region(from Asn-9 to Gly-24) possesses low p H-dependent fusogenic activity, which might play a crucial role in the endosomal escape of BNC payloads and in the uncoating process of HBV. In this minireview, we describe a model in which each domain of the HBV L protein contributes to attachment onto human hepatic cells through HSPG, initiation of endocytosis, interaction with NTCP in endosomes, and consequent provocation of membrane fusion followed by endosomal escape.
基金Supported by Instituto de Salud Carlos Ⅲ,No.PI14/01416 and No.PI15/00856cofinanced by the European Regional Development Fund(ERDF)the Gilead Fellowship Program,No.GLD14-00296
文摘AIM To determine the variability/conservation of the domain of hepatitis B virus(HBV) pre S1 region that interacts with sodium-taurocholate cotransporting polypeptide(hereafter, NTCP-interacting domain) and the prevalence of the rs2296651 polymorphism(S267 F, NTCP variant) in a Spanish population. METHODS Serum samples from 246 individuals were included and divided into 3 groups: patients with chronic HBV infection(CHB)(n = 41, 73% Caucasians), patients with resolved HBV infection(n = 100, 100% Caucasians) and an HBV-uninfected control group(n = 105, 100% Caucasians). Variability/conservation of the amino acid(aa) sequences of the NTCPinteracting domain,(aa 2-48 in viral genotype D) and a highly conserved pre S1 domain associated with virion morphogenesis(aa 92-103 in viral genotype D) were analyzed by next-generation sequencing and compared in 18 CHB patients with viremia > 4 log IU/mL. The rs2296651 polymorphism was determined in all individuals in all 3 groups using an in-house real-time PCR melting curve analysis.RESULTS The HBV pre S1 NTCP-interacting domain showed a high degree of conservation among the examined viral genomes especially between aa 9 and 21(in the genotype D consensus sequence). As compared with the virion morphogenesis domain, the NTCPinteracting domain had a smaller proportion of HBV genotype-unrelated changes comprising > 1% of the quasispecies(25.5% vs 31.8%), but a larger proportion of genotype-associated viral polymorphisms(34% vs 27.3%), according to consensus sequences from Gen Bank patterns of HBV genotypes A to H. Variation/conservation in both domains depended on viral genotype, with genotype C being the most highly conserved and genotype E the most variable(limited finding, only 2 genotype E included). Of note, proline residues were highly conserved in both domains, and serine residues showed changes only to threonine or tyrosine in the virion morphogenesis domain. The rs2296651 polymorphism was not detected in any participant.CONCLUSION In our CHB population, the NTCP-interacting domain was highly conserved, particularly the proline residues and essential amino acids related with the NTCP interaction, and the prevalence of rs2296651 was low/null.
