Ontology highlight
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PROVIDER: PRJNA1079501 | ENA |
REPOSITORIES: ENA
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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:We applied RNA sequencing (RNA-seq) to study the gene expression profile in the liver of GAN DIO-NASH-HCC mice (non-tumorous tissue samples, n=9; tumor samples, n=9) and chow-fed controls (healthy liver samples, n=5)). Comparing tumour tissue of GAN DIO-NASH-HCC mice to healthy chow-fed controls, we find that tumors of GAN DIO-NASH-HCC mice show widespread regulations of genes associated with human HCC. Human HCC can be classified into three categories (S1-S3). Using the human S1-S3 gene classification described by Hoshida Y. et al. (2009), we find that GAN DIO-NASH-HCC tumors resemble the human S1 class of proliferating HCC tumors with poor prognosis.
2024-01-02 | GSE243976 | GEO
Project description:Non-alcoholic steatohepatitis (NASH) is associated with hepatic steatosis, intralobular inflammation, and fibrosis. The degree of hepatic fibrosis, mainly caused by excessive production of extracellular matrix proteins, is the sole predictor of liver-related and overall mortality in NASH patients. The hepatic stellate cells (HSCs) are causally implicated in fibrogenesis during NASH development but as sinusoidal pericytes also vital for vascular homeostasis of the healthy liver. Using single-cell RNA-sequencing we have analyzed whole liver plasticity and interrogated the transition of HSCs from pericytes in the healthy liver to collagen-producing cells in a diet-induced murine model of advanced NASH. We show how postprandial cues are sensed and integrated by HSCs promoting their phenotypic stabilization and, through paracrine mediators, sinusoidal health. While dominant under healthy conditions the basis for this multimodal signaling through stellate cell-specific Gs protein-coupled receptors and the bile-acid receptor NR1H4/FXR deteriorates in activated HSCs of the NASH liver. Expression of key signaling components were validated in situ in human and murine liver tissue supporting the translatability of our findings and pharmacological relevance in treatment of chronic liver diseases as NASH.
2023-11-21 | GSE218297 | GEO
Project description:Liver zonation characterizes the separation of metabolic pathways along the lobules and is required for optimal hepatic function. Wnt signaling is a master regulator of spatial liver zonation. A perivenous-periportal Wnt activity gradient orchestrates metabolic zonation by activating genes in perivenous hepatocytes, while suppressing genes in their periportal counterparts. The understanding of liver gene zonation and zonation regulators in disease was limited. Non-alcoholic steatohepatitis (NASH) is a chronic liver disease characterized by fat accumulation, inflammation, and fibrosis. Here, we investigated the perturbation of liver gene zonation in a mouse NASH model by combination of spatial transcriptomics, bulk RNAseq and in situ hybridization. Wnt target genes represented a major subset of genes showing altered spatial expression in the NASH liver. The altered Wnt target gene expression level and zonation spatial pattern were in line with the upregulation of Wnt regulators and the augmentation of Wnt signaling. Particularly, we found that the Wnt activator Rspo3 expression was restricted to the perivenous zone in control livers, whereas expanded to the periportal zone in NASH livers. AAV8-mediated RSPO3 overexpression in controls resulted in a zonation change, and further amplified the disturbed zonation of Wnt target genes in NASH, but had no impacts on steatosis, inflammation and fibrosis. In summary, our study demonstrated the alteration of Wnt signaling in a mouse NASH model, leading to perturbed liver zonation.
2024-08-01 | GSE248077 | GEO
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:The goal of this study was to apply next-generation sequencing (NGS) analyses to identify genes and pathways regulated by the Foxk1 transcription factor in the liver and to see the effects of liver-specific Foxk1 deficiency in the diet-induced non-alcoholic steatohepatitis (NASH) model. Transcriptome and ChIP-seq analysis revealed that liver Foxk1 promotes the pathogenesis of NASH by regulating the expression of a series of molecules involved in hepatic lipid metabolism in an mTORC1-dependent manner.
2022-03-01 | GSE197324 | GEO
Project description:Immunotherapy has opened hitherto unknown possibilities to treat cancer. Whereas some cancer types (e.g. melanoma) can be efficiently treated, others lack measurable positive effects (e.g. PDAC). Moreover, stratification of responders/non-responders is only possible in some cancer types (e.g. melanoma). Hepatocellular carcinoma (HCC) has a dismal prognosis, limited treatment options and survival benefit, and represents a potential cancer entity for successful immunotherapy. Here, we investigated NASH-triggered HCC in the context PD-1-targeted immunotherapy. Using flow cytometry, single cell RNA sequencing, immunohistochemistry and mass spectrometric analyses, we found a progressive increase of CD8+PD-1+ effector T-cells with a unique profile of exhaustion and activation markers rising with murine and human NASH severity. Notably, late-stage HCC treatment with PD-1-targeted immunotherapy enhanced hepatic carcinogenesis in mice. Dissecting potential mechanisms of action during tumor-initiation and -progression we analyzed the effects of PD-1-targeted immunotherapy at HCC initiation. PD-1-targeted immunotherapy induced a pro-tumorigenic environment, enhanced necro-inflammation and increased NAFLD-activation score (NAS), leading to increased liver cancer incidence, tumor number and nodule size. In contrast, anti-CD8 or anti-CD8/anti-NK1.1 treatment reduced NAS and abrogated the development of liver cancer, thus identifying CD8+PD-1+ T-cells as drivers of liver cancer in NASH-triggered HCC. Increased apoptotic signaling, STAT3 phosphorylation and hepatic proliferation were detected in intra-tumoral liver tissue upon PD-1-targeted immunotherapy. In line, PD-1-/- mice challenged with a NASH diet displayed early onset of hepatocarcinogenesis, corroborating the pro-tumorigenic role of absent or reduced PD-1. Mechanistically PD-1-targeted immunotherapy mainly affected hepatic abundance of CD8+PD-1+ T-cells, instead of altering the quality of Tox+CXCR6+ expressing CD8+PD-1+TNF+CD39+Gzmb+ T-cells found in NASH livers, leading to an aggressive, pro-tumorigenic liver environment. Single-cell mapping of human NASH-, borderline NASH- or unaffected livers corroborated our preclinical NASH results. Moreover, in human NASH livers a correlation of hepatic CD8+, PD-1+, TNF+ T-cells with fibrosis and NASH severity was observed. Accordingly, HCC patients with NASH etiology display a sharp increase in intra- and peri-tumoral CD8+ PD-1+ T-cells. In a cohort of 65 patients recruited across 6 centers in Germany and Austria, patients with NAFLD/NASH-driven HCC responded worse to PD-1-targeted immunotherapy by Nivolumab or Pembrolizumab compared to non-NAFLD patients. This resulted in significant reduced overall survival, in trends of faster disease progression and reduced progression free survival. Histological analysis of livers derived from HCC patients treated with PD-1-targeted immunotherapy displayed high levels of intra and peri-tumoral CD8+ PD-1+ T-cells and Ki67+ hepatocytes. Taken together, these data indicate that PD-1-targeted immunotherapy induces immune-related adverse effects in NAFLD/NASH-driven HCC through CD8+PD-1+ T-cells. Our data call for stratification of HCC patients subjected to PD-1-targeted immunotherapy, with NAFLD being a negative predictor.
2021-03-03 | PXD017236 | Pride
Project description:OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is closely associated with metabolic syndrome and increases the risk for end-stage liver disease, such as cirrhosis and hepatocellular carcinoma. Despite this, the molecular events that influence NASH pathogenesis remain poorly understood. The objectives of the current study are to delineate the transcriptomic and proteomic signatures of NASH liver, to identify potential pathogenic pathways and factors, and to critically assess their role in NASH pathogenesis. METHODS: We performed RNA sequencing and quantitative proteomic analyses on the livers from healthy and diet-induced NASH mice. We examined the association between plasma levels of TSK, a newly discovered hepatokine, and NASH pathologies and reversal in response to dietary switch in mice. Using TSK knockout mouse model, we determined how TSK deficiency modulates key aspects of NASH pathogenesis. RESULTS: RNA sequencing and quantitative proteomic analyses revealed that diet-induced NASH triggers concordant reprogramming of the liver transcriptome and proteome in mice. NASH pathogenesis is linked to elevated plasma levels of the hepatokine TSK, whereas dietary switch reverses NASH pathologies and reduces circulating TSK concentrations. Finally, TSK inactivation protects mice from diet-induced NASH and liver transcriptome remodeling. CONCLUSIONS: Global transcriptomic and proteomic profiling of healthy and NASH livers revealed the molecular signatures of diet-induced NASH and dysregulation of the liver secretome. Our study illustrates a novel pathogenic mechanism through which elevated TSK in circulation promotes NASH pathologies, thereby revealing a potential target for therapeutic intervention.
2019-01-08 | GSE119340 | GEO
Project description:Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease worldwide. Nonalcoholic steatohepatitis (NASH), the progressive form of NAFLD, and advanced fibrosis are associated with poor outcomes but their molecular pathogenesis is not fully elucidated. Global RNA sequencing of snap frozen liver tissue from 98 patients with biopsy-proven NAFLD was performed. Unsupervised hierarchical clustering well-distinguished NASH from NAFL, and NASH patients exhibited molecular abnormalities reflecting their pathological features. Transcriptomic analysis identified multiple secreted proteins upregulated in NASH and/or advanced fibrosis
2021-05-31 | GSE167523 | GEO
Project description:Non-alcoholic steatohepatitis (NASH) is associated with hepatic steatosis, intralobular inflammation, and fibrosis. The degree of hepatic fibrosis, mainly caused by excessive production of extracellular matrix proteins, is the sole predictor of liver-related and overall mortality in NASH patients. The hepatic stellate cells (HSCs) are causally implicated in fibrogenesis during NASH development but as sinusoidal pericytes also vital for vascular homeostasis of the healthy liver. Using single-cell RNA-sequencing we have analyzed whole liver plasticity and interrogated the transition of HSCs from pericytes in the healthy liver to collagen-producing cells in a diet-induced murine model of advanced NASH. We show how postprandial cues are sensed and integrated by HSCs promoting their phenotypic stabilization and, through paracrine mediators, sinusoidal health. While dominant under healthy conditions the basis for this multimodal signaling through stellate cell-specific Gs protein-coupled receptors and the bile-acid receptor NR1H4/FXR deteriorates in activated HSCs of the NASH liver. Expression of key signaling components were validated in situ in human and murine liver tissue supporting the translatability of our findings and pharmacological relevance in treatment of chronic liver diseases as NASH.
2023-11-21 | GSE218299 | GEO