Shp-deletion induces dissociation of steatosis and inflammation in NASH
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ABSTRACT:
PROVIDER: PRJNA551941 | ENA |
REPOSITORIES: ENA
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2019-12-10 | GSE133566 | GEO
Project description:Non-alcoholic fatty liver disease (NAFLD) is characterized by a series of pathological changes that can progress from simple fatty liver disease to non-alcoholic steatohepatitis (NASH). The objective of this study is to describe changes in global gene expression associated with the progression of NAFLD. This study is focused on the expression levels of genes responsible for the absorption, distribution, metabolism and excretion (ADME) of drugs. Differential gene expression between three clinically defined pathological groups; normal, steatosis and NASH was analyzed. The samples were diagnosed as normal, steatotic, NASH with fatty liver (NASH fatty) and NASH without fatty liver (NASH NF). Genome-wide mRNA levels in samples of human liver tissue were assayed with Affymetrix GeneChipM-. Human 1.0ST arrays
2011-07-12 | E-MEXP-3291 | biostudies-arrayexpress
Project description:Non-alcoholic fatty liver disease (NAFLD) encompasses a spectrum of disease that ranges from simple steatosis, to inflammatory form non-alcoholic steatohepatitis (NASH), cirrhosis, and up to hepatocellular carcinoma. While NASH usually takes decades to develop at a rate of one stage per seven years, in the case of post-trasplant NASH (pt-NASH) develops fibrosis much more rapidly, with almost 50% of liver transplant recipients presenting stage 3 fibrosis by 5 years post-transplant. Archived fresh-frozen transplanted liver biopsy samples from four liver biopsy samples with evidence of NASH (2 recurrent and 2 de novo), two with simple steatosis (both de novo), and five with normal histology as controls had their transcriptome sequenced in two batches for deeper coverage.
2022-05-09 | E-MTAB-11688 | biostudies-arrayexpress
Project description:Following 21-week of high fat diet (HFD)-feeding, obese mice were classified into two groups termed as isolated steatosis and NASH based on H&E staining of liver
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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.
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Project description:Non-alcoholic fatty liver disease (NAFLD) is a predominant form of chronic liver disease, affecting nearly 25 % of the global population. The progression from steatosis to nonalcoholic steatohepatitis (NASH) in NAFLD patients is one of the major causes of liver-related death worldwide. We assessed the miRNA expression profiles of the exosomes derived from the peripheral blood of NASH patients or healthy controls.
2022-06-01 | GSE202167 | GEO
Project description:Hepatocellular carcinoma (HCC), which accounts for 90% of all primary livers tumors, is the fourth most common cancer in the world. The development of HCC is a long-term and complex process, and uncovering the molecular mechanisms associated with HCC development is critical for the disease diagnosis, prevention, and treatment. Exploring these mechanisms using human HCC samples is desirable, but frequently impractical, with a number of limitations and shortcomings. The STAMTM (Stelic Institute & Co, Tokyo, Japan) mouse model of NASH-associated liver carcinogenesis is considered a useful and relevant model for investigating the molecular pathogenesis of NASH-derived HCC. This model resembles the human HCC development associated with progression from simple steatosis to NASH, fibrosis, and HCC. In the present study, by using high-throughput whole genome microarrays (SurePrint G3 Mouse Gene Expression v2, 8x60K; Agilent Technologies, Santa Clara, CA), we examined the transcriptomic profiles in the livers of STAMTM mice at different stages of liver carcinogenesis, including steatosis (6 week time interval), NASH (8 weeks), fibrotic stage (12 weeks), and in full-fledged HCC (20 weeks). The results of microarray analyses showed significant progressive changes in hepatic gene expression during the development of HCC. A total of 970, 1462, 2742, and 2857 of differentially expressed genes were identified in the livers at 6, 8, 12, and 20 weeks, respectively. Detailed analysis of these differentially expressed genes will benefit the understanding of the underlying mechanisms of non-alcoholic fatty liver disease-derived HCC. Transcriptomic profile in the liver of STAM mice at 6 weeks (steatosis; n=3), 8 weeks (steatohepatitis; n=3) 12 weeks (fibrosis; n=4) and 20 weeks (HCC-stage tumor tissue, n=4) weeks. Age-matched control samples were also analyzed.
2016-06-22 | E-GEOD-83596 | biostudies-arrayexpress
Project description:We generated mice with conditional targeting of the Ptpn11 gene (encoding for Shp-2) in T cells (Shp-2fl/flLckCre) or myeloid cells (Shp-2fl/flLysMCre). Although no difference in tumor growth was observed between Shp-2fl/flLckCre and control mice and both groups were similarly benefitted by PD-1 blockade, Shp-2fl/flLysMCre mice had significantly diminished tumor growth that was not further decreased by anti-PD-1 treatment. As revealed by RNA-seq, myeloid-specific Shp-2 ablation was paralleled by expansion of activated myeloid cells and macrophages with molecular signatures of enhanced neutrophil and macrophage differentiation, phagocytosis, antigen-presenting function, TLR and type I IFN signaling, chemokine production, and expression of immunostimulatory molecules, which promoted T cell recruitment and activation.
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