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Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection.

ABSTRACT: Hepatocyte proliferation could result in the loss of covalently closed circular DNA (cccDNA) and the emergence of cccDNA-cleared nascent hepatocytes, which appear refractory to hepatitis B virus (HBV) reinfection with unknown mechanism(s). Sodium taurocholate cotransporting polypeptide (NTCP) is the functional receptor for HBV entry. In this study, down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes was found to prevent HBV infection in HepG2-NTCP-tet cells and in liver-humanized mice. In patients, lower NTCP protein expression was correlated well with higher levels of hepatocyte proliferation and less HBsAg expression in HBV-related focal nodular hyperplasia (FNH) tissues. Clinically, significantly lower NTCP protein expression was correlated with more active hepatocyte proliferation in CHB patients with severe active necroinflammation and better antiviral treatment outcome. Mechanistically, the activation of cell cycle regulatory genes p53, S-phase kinase-associated protein 2 (SKP2) and cyclin D1 during cell proliferation, as well as proliferative and inflammatory cytokine Interleukin-6 (IL-6) could transcriptionally down-regulate NTCP expression. From these aspects, we conclude that within the milieu of hepatocyte proliferation, down-regulation of cell membrane localized NTCP expression level renders nascent hepatocytes resistant to HBV reinfection. This may accelerate virus clearance during immune-mediated cell death and compensatory proliferation of survival hepatocytes.

SUBMITTER: Yan Y

PROVIDER: S-EPMC6567113 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection.

Yan Ying Y Allweiss Lena L Yang Danli D Kang Jingting J Wang Jianwen J Qian Xiangjun X Zhang Ting T Liu Hui H Wang Lu L Liu Shuhong S Sui Jianhua J Chen Xiangmei X Dandri Maura M Zhao Jingmin J Lu Fengmin F

Emerging microbes & infections 20190101 1

Hepatocyte proliferation could result in the loss of covalently closed circular DNA (cccDNA) and the emergence of cccDNA-cleared nascent hepatocytes, which appear refractory to hepatitis B virus (HBV) reinfection with unknown mechanism(s). Sodium taurocholate cotransporting polypeptide (NTCP) is the functional receptor for HBV entry. In this study, down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes was found to prevent HBV infection in HepG2-NTCP-tet cells an ...[more]

PMID: 31179847

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Project description:BACKGROUND:SLC10A1 gene codes NTCP, a receptor through which the hepatitis B virus (HBV) gets access into hepatocytes - a stage of the viral cycle necessary for replication. Polymorphism variants of SLC10A1 play roles in HBV infection, viral clearance, treatment outcome, and complications, in diverse ethnic groups and countries. However, no such study has been conducted in the Ghanaian population, a country with HBV endemicity. Therefore, an exploratory study was conducted to investigate the presence of three (3) single nucleotide polymorphisms (SNPs) in the SLC10A1 gene (rs2296651, rs61745930, and rs4646287) and assessed the risk of HBV infection among the Ghanaian population. METHOD:Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method was used to determine the presence of the SNPs among 292 participants comprising 146 HBV infected persons as case-subjects and 146 HBV non-infected persons as control-subjects. RESULTS:The minor allele frequency (T) of rs2296651 was present in a significantly high proportion of cases compared with the control group (11.6% vs. 3.1%, p?<?0.0001). The homozygote recessive variant of rs61745930 was present in 2.7% of the control group and 5.5% of the case group. Moreover, the minor allele frequencies of rs4646287 were 9.3 and 8.2% among the control and the case group, respectively (p?=?0.767). Under the dominant (CC) genetic model of inheritance, rs2296651 was found to be protective of HBV infection [OR?=?0.18 (0.07-0.44)], whereas under the co-dominant and additive model, rs2296651 was a potential risk factor for HBV infection [OR?=?5.2 (95%CI: 2.1-12.8); 3.5 (95%CI: 1.6-7.6], respectively. Variants of rs61745930 and rs4646287 were not associated with HBV infection (p?>?0.05). Polymorphisms in SLC10A1, however, did not show any significant association with HBV infectivity (p?>?0.05). CONCLUSION:The study highlights some polymorphism proof that variants rs2296651, rs61745930, and rs4646287 exist in HBV-infected individuals in Ghana. Although variant rs2296651 was found to be associated with HBV infection, this association warrants more studies. Polymorphisms in SLC10A1 were not associated with HBV infectivity among the Ghanaian population. Further investigation is warranted to assess the offensive role of the relationship between rs2296651 and HBV infectivity.

Project description:BackgroundSingle nucleotide polymorphisms (SNPs) in the sodium taurocholate co-transporting polypeptide (NTCP) have been showed to be associated with natural history of hepatitis B virus (HBV) infection. However, it is unclear whether the SNPs are related to the clinical outcome of HBV infection in Thai individuals.MethodsThe rs2296651 and rs4646287 polymorphisms of NTCP were determined by allelic discrimination using commercial TaqMan probes in blood samples of 1021 Thai individuals. These subjects included 610 patients with chronic HBV infection [CHB, 305 with hepatocellular carcinoma (HCC) and 305 without HCC], 206 subjects with spontaneous HBV clearance and 205 healthy controls who were age and gender-matched.ResultsThe frequencies of rs2296651 A minor allele in the CHB group, the HBV clearance group and healthy controls were 7.8, 7.3 and 13.9%, respectively. For rs4646287, the frequencies of T minor allele of the corresponding groups were 10.4, 8.0 and 9.5%, respectively. Compared with healthy controls, the frequencies of rs2296651 GA + AA genotypes were significantly lower in the CHB group (P < 0.001) and in the HBV clearance group (P = 0.001). There was no difference in their distribution between the HBV clearance and CHB groups. Among the CHB group, the distribution of GA + AA genotypes in patients with HCC were significantly lower than in patients without HCC (P = 0.014). The frequencies of HBeAg positivity in patients harboring GG and GA + AA genotypes were 39.8 and 23.5%, respectively (P = 0.004). Among patients with HCC, the mean HBV DNA of the corresponding genotypes were 4.9 ± 1.3 vs. 2.7 ± 1.0 log10 IU/mL, respectively (P < 0.001). There was no difference in genotype and allele frequencies of rs4646287 polymorphism among all studied groups.ConclusionsOur results showed that rs2296651 polymorphism was associated with a decreased risk of susceptibility to HBV infection and the development of HCC. These data suggest that the NTCP polymorphism might have an influence on natural history of HBV infection in Thai individuals. This abstract was partly presented at the American Association for the Study of Liver Diseases (AASLD) Meeting 2018, November 9-13, 2018, in San Francisco, CA, USA and was published in Hepatology 2018; 68:1237A-1238A.

Project description:BackgroundNaturally occurring variation in Membrane-bound O-acyltransferase domain-containing 7 (MBOAT7), encoding for an enzyme involved in phosphatidylinositol acyl-chain remodelling, has been associated with fatty liver and hepatic disorders. Here, we examined the relationship between hepatic Mboat7 down-regulation and fat accumulation.MethodsHepatic MBOAT7 expression was surveyed in 119 obese individuals and in experimental models. MBOAT7 was acutely silenced by antisense oligonucleotides in C57Bl/6 mice, and by CRISPR/Cas9 in HepG2 hepatocytes.FindingsIn obese individuals, hepatic MBOAT7 mRNA decreased from normal liver to steatohepatitis, independently of diabetes, inflammation and MBOAT7 genotype. Hepatic MBOAT7 levels were reduced in murine models of fatty liver, and by hyper-insulinemia. In wild-type mice, Mboat7 was down-regulated by refeeding and insulin, concomitantly with insulin signalling activation. Acute hepatic Mboat7 silencing promoted hepatic steatosis in vivo and enhanced expression of fatty acid transporter Fatp1. MBOAT7 deletion in hepatocytes reduced the incorporation of arachidonic acid into phosphatidylinositol, consistently with decreased enzymatic activity, determining the accumulation of saturated triglycerides, enhanced lipogenesis and FATP1 expression, while FATP1 deletion rescued the phenotype.InterpretationMBOAT7 down-regulation by hyper-insulinemia contributes to hepatic fat accumulation, impairing phosphatidylinositol remodelling and up-regulating FATP1.FundingLV was supported by MyFirst Grant AIRC n.16888, Ricerca Finalizzata Ministero della Salute RF-2016-02,364,358, Ricerca corrente Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico; LV and AG received funding from the European Union Programme Horizon 2020 (No. 777,377) for the project LITMUS-"Liver Investigation: Testing Marker Utility in Steatohepatitis". MM was supported by Fondazione Italiana per lo Studio del Fegato (AISF) 'Mario Coppo' fellowship.

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Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection.

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Down-regulation of cell membrane localized NTCP expression in proliferating hepatocytes prevents hepatitis B virus infection.

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