Increased sulfation of bile acids in mice and human subjects with sodium taurocholate cotransporting polypeptide deficiency
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ABSTRACT:
PROVIDER: PRJNA510995 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR8360780_1.fastq.gz | Fastqsanger.gz | |||
| SRR8360780_2.fastq.gz | Fastqsanger.gz | |||
| SRR8360790.fastq.gz | Fastqsanger.gz | |||
| SRR8360800.fastq.gz | Fastqsanger.gz | |||
| SRR8360771_1.fastq.gz | Fastqsanger.gz |
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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:Sodium taurocholate cotransporting polypeptide (NTCP, encoded by Slc10a1/SLC10A1) deficiency can result in hypercholanemia but no obvious symptoms in both mice and humans. However, the consequence of and response to long-term hypercholanemia caused by NTCP deficiency remain largely unexplored. Here, we analyzed lifelong dynamics of serum total bile acid (TBA) levels in Slc10a1 -/- mice, and we also assessed changes of TBA levels in 33 young individuals with SLC10A1 loss-of-function variant p.Ser267Phe. We found that overall serum TBA levels tended to decrease gradually with age in both Slc10a1 -/- mice and p.Ser267Phe individuals. Liver mRNA profiling revealed notable transcription alterations in hypercholanemic Slc10a1 -/- mice, including inhibition of bile acid (BA) synthesis, enhancement of BA detoxification, and altered BA transport. Members of the sulfotransferase (SULT) family showed the most dramatic increases in livers of hypercholanemic Slc10a1 -/- mice, and one of their BA sulfates, taurolithocholic acid 3-sulfate, significantly increased. Importantly, consistent with the mouse studies, comprehensive profiling of 58 BA species in sera of p.Ser267Phe individuals revealed a markedly increased level of BA sulfates. Together, our findings indicate that the enhanced BA sulfation is a major mechanism for BA detoxification and elimination in both mice and humans with Slc10a1/SLC10A1 deficiency.
| S-EPMC6682732 | biostudies-literature
Project description:Sodium taurocholate co-transporting polypeptide deficiency attenuates hepatocarcinogenesis in mice
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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:The Na+ -taurocholate cotransporting polypeptide (NTCP/SLC10A1) is believed to be pivotal for hepatic uptake of conjugated bile acids. However, plasma bile acid levels are normal in a subset of NTCP knockout mice and in mice treated with myrcludex B, a specific NTCP inhibitor. Here, we elucidated which transport proteins mediate the hepatic uptake of conjugated bile acids and demonstrated intestinal sensing of elevated bile acid levels in plasma in mice. Mice or healthy volunteers were treated with myrcludex B. Hepatic bile acid uptake kinetics were determined in wild-type (WT), organic anion transporting polypeptide (OATP) knockout mice (lacking Slco1a/1b isoforms), and human OATP1B1-transgenic mice. Effects of fibroblast growth factor 19 (FGF19) on hepatic transporter mRNA levels were assessed in rat hepatoma cells and in mice by peptide injection or adeno-associated virus-mediated overexpression. NTCP inhibition using myrcludex B had only moderate effects on bile acid kinetics in WT mice, but completely inhibited active transport of conjugated bile acid species in OATP knockout mice. Cholesterol 7α-hydroxylase Cyp7a1 expression was strongly down-regulated upon prolonged inhibition of hepatic uptake of conjugated bile acids. Fgf15 (mouse counterpart of FGF19) expression was induced in hypercholanemic OATP and NTCP knockout mice, as well as in myrcludex B-treated cholestatic mice, whereas plasma FGF19 was not induced in humans treated with myrcludex B. Fgf15/FGF19 expression was induced in polarized human enterocyte-models and mouse organoids by basolateral incubation with a high concentration (1 mM) of conjugated bile acids.ConclusionNTCP and OATPs contribute to hepatic uptake of conjugated bile acids in mice, whereas the predominant uptake in humans is NTCP mediated. Enterocytes sense highly elevated levels of (conjugated) bile acids in the systemic circulation to induce FGF15/19, which modulates hepatic bile acid synthesis and uptake. (Hepatology 2017;66:1631-1643).
| S-EPMC5698707 | biostudies-literature
Project description:UnlabelledThe Na(+) -taurocholate cotransporting polypeptide (NTCP) mediates uptake of conjugated bile acids (BAs) and is localized at the basolateral membrane of hepatocytes. It has recently been recognized as the receptor mediating hepatocyte-specific entry of hepatitis B virus and hepatitis delta virus. Myrcludex B, a peptide inhibitor of hepatitis B virus entry, is assumed to specifically target NTCP. Here, we investigated BA transport and Myrcludex B binding in the first Slc10a1-knockout mouse model (Slc10a1 encodes NTCP). Primary Slc10a1(-/-) hepatocytes showed absence of sodium-dependent taurocholic acid uptake, whereas sodium-independent taurocholic acid uptake was unchanged. In vivo, this was manifested as a decreased serum BA clearance in all knockout mice. In a subset of mice, NTCP deficiency resulted in markedly elevated total serum BA concentrations, mainly composed of conjugated BAs. The hypercholanemic phenotype was rapidly triggered by a diet supplemented with ursodeoxycholic acid. Biliary BA output remained intact, while fecal BA excretion was reduced in hypercholanemic Slc10a1(-/-) mice, explained by increased Asbt and Ostα/β expression. These mice further showed reduced Asbt expression in the kidney and increased renal BA excretion. Hepatic uptake of conjugated BAs was potentially affected by down-regulation of OATP1A1 and up-regulation of OATP1A4. Furthermore, sodium-dependent taurocholic acid uptake was inhibited by Myrcludex B in wild-type hepatocytes, while Slc10a1(-/-) hepatocytes were insensitive to Myrcludex B. Finally, positron emission tomography showed a complete abrogation of hepatic binding of labeled Myrcludex B in Slc10a1(-/-) mice.ConclusionThe Slc10a1-knockout mouse model supports the central role of NTCP in hepatic uptake of conjugated BAs and hepatitis B virus preS1/Myrcludex B binding in vivo; the NTCP-independent hepatic BA uptake machinery maintains a (slower) enterohepatic circulation of BAs, although it is occasionally insufficient to clear BAs from the circulation.
| S-EPMC4657468 | biostudies-literature
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.
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Project description:Enterococcus faecalis is a natural inhabitant of the human gastrointestinal tract. In a healthy physiological state of the gut (eubiosis), E. faecalis is a subdominant species in the intestinal microbiota. When the intestinal homeostasis is disrupted (dysbiosis), it becomes dominant species and can cause infections. The taurocholate bile acid (TCA) becomes prominent during dysbiosis. This experiment aimed to better understand how E. faecalis adapts to TCA. We showed that TCA reprograms genes involved in the pool management of amino acids and nucleotides.
2022-05-20 | GSE194009 | GEO
Project description:The liver bile acids transporter sodium taurocholate cotransporting polypeptide (NTCP) is responsible for the majority of sodium-dependent bile salts uptake by hepatocytes. NTCP also functions as a cellular receptor for viral entry of hepatitis B virus (HBV) and hepatitis D virus (HDV) through a specific interaction between NTCP and the pre-S1 domain of HBV large envelope protein. However, it remains unknown if these two functions of NTCP are independent or if they interfere with each other. Here we show that binding of the pre-S1 domain to human NTCP blocks taurocholate uptake by the receptor; conversely, some bile acid substrates of NTCP inhibit HBV and HDV entry. Mutations of NTCP residues critical for bile salts binding severely impair viral infection by HDV and HBV; to a lesser extent, the residues important for sodium binding also inhibit viral infection. The mutation S267F, corresponding to a single nucleotide polymorphism (SNP) found in about 9% of the East Asian population, renders NTCP without either taurocholate transporting activity or the ability to support HBV or HDV infection in cell culture. These results demonstrate that molecular determinants critical for HBV and HDV entry overlap with that for bile salts uptake by NTCP, indicating that viral infection may interfere with the normal function of NTCP, and bile acids and their derivatives hold the potential for further development into antiviral drugs.Human hepatitis B virus (HBV) and its satellite virus, hepatitis D virus (HDV), are important human pathogens. Available therapeutics against HBV are limited, and there is no drug that is clinically available for HDV infection. A liver bile acids transporter (sodium taurocholate cotransporting polypeptide [NTCP]) critical for maintaining homeostasis of bile acids serves as a functional receptor for HBV and HDV. We report here that the NTCP-binding lipopeptide that originates from the first 47 amino acids of the pre-S1 domain of the HBV L protein blocks taurocholate transport. Some bile salts dose dependently inhibit HBV and HDV infection mediated by NTCP; molecular determinants of NTCP critical for HBV and HDV entry overlap with that for bile acids transport. This work advances our understanding of NTCP-mediated HBV and HDV infection in relation to NTCP's physiological function. Our results also suggest that bile acids or their derivatives hold potential for development into novel drugs against HBV and HDV infection.
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Project description:Contrasted effects of deoxycholate and taurocholate bile acids on the gut pathobiont Enterococcus faecalis
| PRJNA798734 | ENA