Sodium taurocholate co-transporting polypeptide deficiency attenuates hepatocarcinogenesis in mice
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PROVIDER: PRJNA655900 | ENA |
REPOSITORIES: ENA
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Project description:Sodium taurocholate co-transporting polypeptide (NTCP) is a liver specific bile acid (BA) transporter; this transporter also serves as a functional receptor for hepatitis B virus (HBV) and hepatitis D virus (HDV). Here, we generated mouse models to investigate the role of NTCP in hepatocarcinogenesis. We report that NTCP-deficient (Slc10a1-/-) mice with long-term hypercholanemia do not develop spontaneous hepatocellular carcinoma (HCC). Using a diethylnitrosamine (DEN)-induced mouse model of HCC, we found that Slc10a1-/- mice exhibited fewer liver tumors, while transgenic mice constitutively overexpressing mouse NTCP in hepatocytes Tg(mNTCP-C9) experienced increased tumor burdens. Intriguingly, the subset of male Slc10a1-/- mice with hypercholanemia exhibited a hepatic female-biased gene expression. Importantly, a majority of the human homologs of genes with significantly hepatic female-biased expression were found to be correlated with improved prognosis in human patients with liver cancer. Our findings indicate that pharmacological manipulation of NTCP function can have a clinical impact on decreasing risk of development or decreasing risk of death liver cancer.
2025-08-01 | GSE155870 | GEO
Project description:Increased sulfation of bile acids in mice and human subjects with sodium taurocholate cotransporting polypeptide deficiency
| PRJNA510995 | ENA
Project description:Purpose: To decipher the biochemical basis for the declining of total bile acids (TBA) levels in the late age of Slc10a1-/- mice, we performed a serial liver RNA-Seq analysis of mRNA expression with male mice at different ages. Methods: Liver mRNA profiles of 4-week, 8-week, 20-month-old wild-type (WT) and sodium taurocholate cotransporting polypeptide knockout (Slc10a1-/-) mice were generated by deep sequencing, in triplicate, quadruplicate or sextuplicate, using Illumina Hiseq-2500 platform. Clean mRNA-seq reads were aligned to the mouse reference genome (GRCm38) with TopHat (v2.0.13), guided by Ensembl gene annotation v83. Only uniquely aligned and properly paired reads were retained for further analysis. Gene-level read counts were calculated with HTseq (v0.6.1p1) with the union mode. Genes with less than a total of 11 non-normalized reads across all samples were excluded. Data normalization and statistical analysis of differential expression were performed with the DEseq2 (v1.10.0) R package. Pair-wise Spearman correlation between samples across all quantified genes used for hierarchical clustering. Results: At 4 weeks and 8 weeks, WT and Slc10a1-/- mice exhibited clear different pattern in terms of transcriptome similarity and were well separated, however, the difference was indistinguishable at 20 months.And changes of pathways involved in the metabolism of xenobiotics in Slc10a1-/- mice. Conclusions: Our study reveal that enhanced BA sulfation is a major mechanism for BA detoxification and elimination in Slc10a1-/- mice with hypercholanemia.
2019-06-13 | GSE124214 | GEO
Project description:miR-6126 downregulated expression level of sodium taurocholate cotransporting polypeptide (NTCP), a host cell receptor required for hepatitis B virus (HBV) entry.
2022-08-01 | GSE180543 | GEO
Project description:Impaired bile flow (cholestasis) leads to transcriptional downregulation of the bile acid importer Na+-taurocholate co-transporting protein (NTCP) and to ER-stress in the liver. Here, we show that ER-stress induction strongly reduces NTCP protein expression, plasma membrane abundance and NTCP-mediated bile acid uptake. This is not controlled via a single specific UPR-pathway but mainly depends on the interaction of NTCP with calnexin, an ER chaperone involved in folding of N-glycosylated proteins. In mice, expression of both Ntcp and calnexin was reduced by thapsigargin-induced ER-stress. Calnexin downregulation in HepG2 and U2OS cells results in a decreased NTCP expression and a reduced bile acid uptake. Calreticulin shows partial functional redundancy with calnexin as it also interacts with NTCP, and is downregulated upon ER-stress, but specifically in calnexin-depleted cells. In conclusion, ER stress-induced downregulation of calnexin provides an additional mechanism to dampen NTCP-mediated bile acid uptake during cholestasis.
2019-01-07 | PXD007948 | Pride
Project description:Human sodium taurocholate co-transporting polypeptide (NTCP) is the main bile acid uptake transporter in the liver with the capability to translocate xenobiotics. While its inhibitor requirements have been recently characterized, its substrate requirements have not. The objectives of this study were (a) to elucidate NTCP substrate requirements using native bile acids and bile acid analogs, (b) to develop the first pharmacophore for NTCP substrates and compare it with the inhibitor pharmacophores, and (c) to identify additional NTCP novel substrates. Thus, 18 native bile acids and two bile acid conjugates were initially assessed for NTCP inhibition and/or uptake, which suggested a role of hydroxyl pattern and steric interaction in NTCP binding and translocation. A common feature pharmacophore for NTCP substrate uptake was developed, using 14 native bile acids and bile acid conjugates, yielding a model which featured three hydrophobes, one hydrogen bond donor, one negative ionizable feature and three excluded volumes. This model was used to search a database of FDA approved drugs and retrieved the majority of the known NTCP substrates. Among the retrieved drugs, irbesartan and losartan were identified as novel NTCP substrates, suggesting a potential role of NTCP in drug disposition.
| S-EPMC4430447 | biostudies-literature
Project description:Non-coding small RNA expression analysis of rat pancreatic acinar cells(AR42J) treated with sodium taurocholate
| PRJNA750677 | ENA
Project description:Sodium taurocholate cotransporting polypeptide (NTCP) is a carrier protein encoded by the human SLC10A1 gene, acting as the principal transporter of conjugated bile salts from the plasma into hepatocytes. Although NTCP was cloned as early as in 1994 and its function has been studied extensively, clinical description of NTCP deficiency remains rather limited thus far. The patients in this paper were 2 female monozygotic twins, who were referred to our hospital at the age 2 years with the complaint of persistently-raised total bile acids (TBA) for 21 months. At age 3 months, they were both diagnosed to have cholestatic liver disease due to raised serum TBA and direct bilirubin (DBIL) with the fraction >20% of the elevated total bilirubin (TBIL). Thereafter, their jaundice subsided and the DBIL levels recovered gradually, while serum TBA remained raised persistently. In view of their refractory hypercholanemia but negative symptoms and signs, SLC10A1 genetic analysis was performed for all family members to evaluate the possibility of NTCP deficiency. As a result, the twins were both homozygotes, while the parents, carriers, of the reportedly pathogenic variant c.800C>T (p.Ser267Phe). These findings suggested that NTCP deficiency may be a unique genetic factor causing transient cholestasis in early infancy, as well as, persistent hypercholanemia in pediatric patients.
| S-EPMC6256173 | biostudies-literature
Project description:Acute pancreatitis (AP) is a common digestive disorder with high morbidity and mortality. At present, the pathogenic mechanisms of AP remain unclear. Pancreatic acinar intracellular trypsinogen activation is considered to be an important cause of AP and is an important event in the early stages of AP. The activation of trypsinogen is a key factor for the pancreas to maintain normal function and that the abnormal activation of trypsinogen in pancreatic acinar cells is an initiating factor for the occurrence of AP. In the past decade, microRNA-related research results suggest that small non-coding RNAs play an important role in AP. Recently, endogenous transfer RNA-derived small RNA (tsRNA), a newly identified non-coding small RNA, is reported to be associated with multiple diseases. tsRNAs can be broadly classified into two main groups: tiRNAs (tRNA halves) and tRFs (tRNA-derived fragments). tiRNAs are produced by specific cleavage in the anticodon loop under various stress conditions (29-50 nucleotides). tRFs are separated to 4 subtypes by their sites of origin in pre-tRNA or mature tRNA, and generally shorter than tiRNAs (16-28 nucleotides). Similar to the function of microRNA, tsRNA can inhibit their functions by binding to target genes. However, the role of tsRNA in regulating AP pathogenesis has not been investigated. In this experiment, sodium taurocholate was used to treat the rat pancreatic acinar cell (AR42J) to establish the AP-related intracellular activation of trypsinogen model. Then we used RNA sequencing to identify the differentially expressed non-coding small RNAs including microRNA and tsRNA in the cell model.
2023-09-17 | GSE181092 | GEO
Project description:Presence of taurocholate (TC), a constituent of bile, confers resistance of Candida albicans to antifungals like Caspofungin and Amphotericin B. Transcriptional profiles in presence and absence of TC were compared to determine whether an upregulation of known resistance genes is responsible for this effect. No upregulation was found, and the resistance seemed to be rather based on a direct interaction of TC with the antifungals.
2017-02-15 | E-MTAB-5277 | biostudies-arrayexpress