Molecular mechanism of SHP/REV-ERBalpha/CYP4A axis in mediating alcohol-induced livery injury
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA564392 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR10082900.fastq.gz | Fastqsanger.gz | |||
| SRR10082901.fastq.gz | Fastqsanger.gz | |||
| SRR10082902.fastq.gz | Fastqsanger.gz | |||
| SRR10082903.fastq.gz | Fastqsanger.gz | |||
| SRR10082904.fastq.gz | Fastqsanger.gz |
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Project description:The molecular mechanisms of CYP4A in ALD pathogenesis has not been elucidated. In the current study, we found that hepatic Cyp4a10 and Cyp4a14 expression were significantly upregulated in WT, but not in Shp-/- mice fed with ethanol.
2020-12-31 | GSE137059 | GEO
Project description:Alcohol-associated liver disease (ALD) represents a spectrum of histopathological changes, including alcoholic steatosis, steatohepatitis, and cirrhosis. One of the early responses to excessive alcohol consumption is lipid accumulation in the hepatocytes. Lipid ω-hydroxylation of medium- and long-chain fatty acid metabolized by the cytochrome P450 4A (CYP4A) family is an alternative pathway for fatty acid metabolism. The molecular mechanisms of CYP4A in ALD pathogenesis have not been elucidated. In this study, WT and Shp-/- mice were fed with a modified ethanol-binge, National Institute on Alcohol Abuse and Alcoholism model (10 days of ethanol feeding plus single binge). Liver tissues were collected every 6 hours for 24 hours and analyzed using RNA-Seq. The effects of REV-ERBα agonist (SR9009, 100 mg/kg/d) or CYP4A antagonist (HET0016, 5 mg/kg/d) in ethanol-fed mice were also evaluated. We found that hepatic Cyp4a10 and Cyp4a14 expression were significantly upregulated in WT mice, but not in Shp-/- mice, fed with ethanol. ChIP quantitative PCR and promoter assay revealed that REV-ERBα is the transcriptional repressor of Cyp4a10 and Cyp4a14. Rev-Erbα-/- hepatocytes had a marked induction of both Cyp4a genes and lipid accumulation. REV-ERBα agonist SR9009 or CYP4A antagonist HET0016 attenuated Cyp4a induction by ethanol and prevented alcohol-induced steatosis. Here, we have identified a role for the SHP/REV-ERBα/CYP4A axis in the pathogenesis of ALD. Our data also suggest REV-ERBα or CYP4A as the potential therapeutic targets for ALD.
| S-EPMC8410014 | biostudies-literature
Project description:To explore the effect of Shp-1 deletion on single-cell resolution, we profiled Shp-1f/f and Shp-1Δ/Δ AML cells from the BM of MLL-AF9 mice with or without chemotherapy using single-cell RNA sequencing (scRNA-seq).
2023-11-22 | GSE244234 | GEO
Project description:Background: Fibroblast growth factor-19 (FGF19) is an intestinal hormone that mediates postprandial metabolic responses in the liver. The unusual orphan nuclear receptor, Small Heterodimer Partner (SHP), acts as a co-repressor for many transcriptional factors and has been implicated in diverse biological pathways including FGF19-mediated repression of bile acid synthesis. To explore global functions of SHP in mediating FGF19 action, we identify genome-wide SHP binding sites in hepatic chromatin in mice treated with vehicle or FGF19 by ChIP-seq analysis. Results: The overall pattern of SHP binding sites between these two groups is similar, but SHP binding is enhanced at the sites by addition of FGF19. SHP binding is detected preferentially in promoter regions that are enriched in motifs for unexpected non-nuclear receptors. We observe global co-localization of SHP sites with published sites for SREBP-2, a master transcriptional activator of cholesterol biosynthesis. FGF19 increases functional interaction between endogenous SHP and SREBP-2 and inhibits SREBP-2 target genes, and these effects were blunted in SHP-knockout mice. Furthermore, FGF19-induced phosphorylation of SHP at Thr-55 is shown to be important for its functional interaction with SREBP-2 and reduction of liver/serum cholesterol levels. Conclusion: This study reveals SHP as a global transcriptional partner of SREBP-2 in regulation of sterol biosynthetic gene networks and provides a potential mechanism for cholesterol-lowering action of FGF19. Genome-wide SHP binding profiles in hepatic chromatin in mice under treatment of FGF19 or vehicle were generated using high throughput sequencing followed by chromatin immunoprecipitation.
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Project description:Background: Fibroblast growth factor-19 (FGF19) is an intestinal hormone that mediates postprandial metabolic responses in the liver. The unusual orphan nuclear receptor, Small Heterodimer Partner (SHP), acts as a co-repressor for many transcriptional factors and has been implicated in diverse biological pathways including FGF19-mediated repression of bile acid synthesis. To explore global functions of SHP in mediating FGF19 action, we identify genome-wide SHP binding sites in hepatic chromatin in mice treated with vehicle or FGF19 by ChIP-seq analysis. Results: The overall pattern of SHP binding sites between these two groups is similar, but SHP binding is enhanced at the sites by addition of FGF19. SHP binding is detected preferentially in promoter regions that are enriched in motifs for unexpected non-nuclear receptors. We observe global co-localization of SHP sites with published sites for SREBP-2, a master transcriptional activator of cholesterol biosynthesis. FGF19 increases functional interaction between endogenous SHP and SREBP-2 and inhibits SREBP-2 target genes, and these effects were blunted in SHP-knockout mice. Furthermore, FGF19-induced phosphorylation of SHP at Thr-55 is shown to be important for its functional interaction with SREBP-2 and reduction of liver/serum cholesterol levels. Conclusion: This study reveals SHP as a global transcriptional partner of SREBP-2 in regulation of sterol biosynthetic gene networks and provides a potential mechanism for cholesterol-lowering action of FGF19.
2015-11-12 | GSE74913 | GEO
Project description:Bile acid (BA) homeostasis is maintained through a feedback loop operated by the nuclear hormone receptors FXR and SHP. Here we show that contrary to the current models placing FXR upstream of SHP in a linear regulatory pathway, the phenotypic consequence of the combined loss of both receptors is much more severe than the relatively modest impact of the loss of either Fxr or Shp alone. This is highlighted by the dramatic elevation of hepatic and serum BA levels in the double knockout (DKO) mice as early as three weeks of age coupled with a commensurate increase in Cyp7A1 expression and alterations in BA homeostatic genes. In addition, we find several genes necessary for C21 steroid biosynthetic pathway as novel targets for FXR and SHP. The elevated BAs result in severe hepato-pathology but the DKO mice surprisingly do not develop complete liver failure and live for over a year. Their survival is accompanied by an adaptive proliferation of the resident liver progenitor cell population, known as oval cells. Overall, these data demonstrate that FXR and SHP function coordinately to maintain BA homeostasis, and identify DKO mice as a novel genetic model for juvenile cholestatic disorders and for oval cell activation. Liver samples collected from FXR-/-, SHP-/-, and FXR-/-/SHP-/- animals at 3 or 5 weeks were hybridized to Illumina mouse REF-8 v1.1 arrays in duplicate.
2010-12-10 | E-GEOD-20599 | biostudies-arrayexpress
Project description:The protein-tyrosine phosphatase SHP-1 (PTPN6) is an important glucose homeostasis modulator. Besides negatively regulating insulin signaling, the specific role of SHP-1 in metabolic control remains poorly understood. We show that SHP-1 acts as a co-activator for transcription of the phosphoenolpyruvate carboxykinase 1 (PCK1) gene, thereby modulating basal gluconeogenesis in hepatocytes. SHP-1 interacts with RNA polymerase II-subunits and signal transducer and activator of transcription 5 (STAT5), and localizes to the nucleus, where a sub-fraction of SHP-1 associates with chromatin. While SHP-1 binds to the PCK1-promoter, its loss affects RNA polymerase II-recruitment to this and other promoters of genes enriched for glucose metabolism-related functions. SHP-1-downregulation, and similarly STAT5 pharmacological inhibition reduce PCK1-transcript levels correlating with blunted gluconeogenesis. Overall, we identified a novel molecular SHP-1-function, that of a regulator of PCK1-transcription and subsequently hepatic gluconeogenesis, through physical interaction with the transcription machinery, mediated by an Akt-independent mechanism, but independent of STAT5 tyrosine-phosphorylation status.
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Project description:Anticancer T cells acquire a dysfunctional state characterized by poor effector function and expression of inhibitory receptors, such as programmed cell death protein 1 (PD-1). Blockade of PD-1 signalling leads to T cell reinvigoration and is increasingly applied as an effective anticancer treatment. Recent work challenged the commonly held view that the phosphatase Src homology 2 (SH2) domain–containing phosphatase (SHP)-2 is essential for the molecular cascade downstream PD-1, suggesting functional redundancy with the homologous phosphatase SHP-1. Therefore, we investigated the effect of concomitant SHP-1 and 2 deletion in T cells by knocking out these phosphatases under the CD4cre promoter. In vivo results not only indicate that Shp-1/2 deletion is insufficient to ameliorate tumour control, but also that it impairs the therapeutic effects of anti-PD1 treatment, affecting tumour-infiltrating CD8+ T cells. Notably, acute deletion of Shp-1/2 in effector T cells also fails to improve tumour control. In vitro results show that Shp-1/2-deleted CD8+ T cells exhibit impaired expansion due to a survival defect and proteomics analysis reveals substantial alterations in their proteome, including in apoptosis-related pathways. This data indicates that concomitant ablation of SHP-1/2 in polyclonal T cells fails to improve their anticancer properties, implying that caution shall be taken when considering their inhibition for immunotherapeutic approaches.
2022-09-29 | PXD034897 | Pride
Project description:Bile acid (BA) homeostasis is maintained through a feedback loop operated by the nuclear hormone receptors FXR and SHP. Here we show that contrary to the current models placing FXR upstream of SHP in a linear regulatory pathway, the phenotypic consequence of the combined loss of both receptors is much more severe than the relatively modest impact of the loss of either Fxr or Shp alone. This is highlighted by the dramatic elevation of hepatic and serum BA levels in the double knockout (DKO) mice as early as three weeks of age coupled with a commensurate increase in Cyp7A1 expression and alterations in BA homeostatic genes. In addition, we find several genes necessary for C21 steroid biosynthetic pathway as novel targets for FXR and SHP. The elevated BAs result in severe hepato-pathology but the DKO mice surprisingly do not develop complete liver failure and live for over a year. Their survival is accompanied by an adaptive proliferation of the resident liver progenitor cell population, known as oval cells. Overall, these data demonstrate that FXR and SHP function coordinately to maintain BA homeostasis, and identify DKO mice as a novel genetic model for juvenile cholestatic disorders and for oval cell activation.
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Project description:THEMIS is critical for conventional T cell development but its precise molecular function remains elusive. Here we show that THEMIS constitutively associates with the phosphatases SHP-1 and SHP-2. This complex requires the adapter GRB2, which bridges SHP to Themis in a Tyr-phosphorylation-independent fashion. Rather, SHP1 and THEMIS engage with the N-SH3 and C-SH3 domains of GRB2, respectively, a configuration that allows GRB2-SH2 to recruit the complex onto LAT. Coherent with THEMIS-mediated recruitment of SHP to the TCR signalosome, THEMIS knockdown increased TCR-induced TCR- phosphorylation, Erk activation and CD69 expression, however not Lck phosphorylation. This generalized TCR signalling increase led to augmented apoptosis, a phenotype mirrored by SHP-1 knockdown. Remarkably, a KI mutation of Lck Ser59, previously suggested to be key in ERK-mediated resistance towards SHP-1 negative feedback, did not affect TCR signalling nor ligand discrimination in vivo. Thus, THEMIS:SHP complex dampens early TCR signalling by a previously unknown molecular mechanism that favors T cell survival. We discuss possible implications of this mechanism in modulating TCR output signals towards conventional T cell development and differentiation.
2015-01-07 | PXD001410 | Pride