Inhibition of the mineralocorticoid Receptor reduces Cirrhosis associated changes of hepatocyte Glucose and Lipid Metabolism in hepatocytes
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1076131 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:Background & aims: Recent studies have suggested that mineralocorticoid receptor (MR) activation may contribute to the progression of liver cirrhosis. Hypoxia, a common feature in liver cirrhosis, has been found to induce MR activation hepatocytes. However, the impact of non-physiological MR activation remains poorly understood. In this study, we investigate the effect of cirrhosis-induced MR activation in hepatocytes. Methods: RNA sequencing followed by gene ontology term enrichment analysis was performed on liver samples from rats treated for 12 weeks with or without CCl4 and for the last four weeks with or without eplerenone (MR antagonist). We investigated if these changes can be mimicked by hypoxia and if those changes lead to alterations of glucose and lipid metabolism in primary rat hepatocytes (pRH) and human HepG2 cells.
2024-12-27 | GSE255673 | GEO
Project description:Gene profiling of hepatocytes in early and advanced cirrhotic Rats Two-condition experiment, Advanced cirrhosis vs Control liver, Advanced cirrhosis vs Early cirrhosis. Biological replicates: 5 Advanced cirrhosis, 5 Early cirrhosis, 5 control liver. Each hepatocyte was isolated independently. One replicate per array.
2011-11-02 | E-GEOD-22977 | biostudies-arrayexpress
Project description:Cirrhosis is a late stage of fibrosis that fatally impairs liver function. Unfortunately, genetic animal models mimicking human cirrhosis are lacking and the molecular mechanisms remain unknown. Here we report the first murine genetic model recapitulating clinical features of cirrhosis, which are induced by hepatocyte-specific elimination of microspherule protein 1 (MCRS1), a member of the non-specific lethal (NSL) and INO80 chromatin modifier complexes. Deregulation of bile acid (BA) transporter expression, revealed by proteomic analysis of MCRS1-depleted mouse livers, with pronounced downregulation of the Na+-taurocholate cotransporting polypeptide (NTCP), causes BA accumulation in liver sinusoids. Genetic ablation of the BA receptor FXR in hepatic stellate cells (HSCs) suppresses bile duct ligation (BDL)-induced fibrosis in mice. Moreover, in vitro experiments demonstrate that fibrotic marker expression is reduced in FXR-depleted HSCs cultured in conditioned medium containing high BAs from MCRS1-depleted hepatocytes. Additionally, hepatocytic MCRS1 overexpression increases their NTCP levels, and consequently protects mice against BDL-induced liver fibrosis. Deletion of a putative SANT domain in MCRS1, also revealed by protein sequence analysis and essential for histone H3 (H3) binding, disrupts H3/HDAC1 complex formation. This evicts MCRS1 and HDAC1 from their H3 anchoring sites and increases histone lysine acetylation of BA transporter genes, independently of the NSL or INO80 complexes. Taken together, our data reveal a previously unrecognized function of MCRS1 as a novel histone acetylation regulator that binds to H3, and recruits a novel chromatin-modifying complex that maintains gene expression homeostasis and liver health. Accordingly, loss of nuclear MCRS1 correlates with increased histone acetylation in human cirrhosis samples. Regulation of histone acetylation might thus be central to cirrhotic development.
2022-05-19 | PXD023026 | Pride
Project description:Cell therapy shows great promise as an alternative therapy for the cirrhotic liver. We have previously developed an approach for efficient expansion of both murine and human hepatocyte-derived liver progenitor-like cells (HepLPCs) in vitro without genetic modification. The current study aimed to apply HepLPCs to treatment of liver cirrhosis. The effects of allogeneic HepLPCs transplantation were studied in rat models of liver cirrhosis induced by carbon tetrachloride (CCl4) . Liver tissues were collected and analyzed by RNA sequencing array to analyze changes in histology or gene expression patterns. Transplantation of HepLPCs reduced active fibrogenesis and net fibrosis in model of liver cirrhosis. Apoptosis of hepatic stellate cells (HSCs) was observed in vivo after HepLPCs treatment.
2024-04-10 | GSE200550 | GEO
Project description:The escalating demand for liver transplantation, coupled with the scarcity of donor organs and inherent transplantation risks, underscores the urgent need for innovative cirrhosis treatments. To address this, we have developed a protocol for transforming human primary hepatocytes into expandable Hepatocyte-Derived Liver Progenitor-Like Cells (HepLPCs). In animal models, these cells exhibited anti-fibrotic properties and facilitated liver regeneration. This study comprises a pre-clinical phase and an inaugural clinical trial involving nine cirrhosis patients to assess the feasibility and safety of HepLPC treatment. The HepLPCs infusion was well-tolerated, devoid of transfusion reactions or dose-limiting toxicities. Primary outcome measures, encompassing safety and feasibility, were successfully met. Notably, the results revealed enhanced liver function following HepLPCs infusion, indicating significant improvements in cirrhosis indicators over a 6-month observation period. These promising findings advocate for the therapeutic potential of HepLPCs as an innovative strategy for liver cirrhosis, warranting further exploration through clinical trials, particularly in decompensated cirrhosis and acute-on-chronic liver failure patients.
2024-12-30 | GSE248227 | GEO
Project description:Cirrhosis and cancers of the upper digestive tract, colorectal and ENT share common risk factors. Liver cirrhosis can change the elimination of cancer drugs.
Precise data on management and outcome of patients with liver cirrhosis undergoing chemotherapy are lacking. Most patients have been excluded from clinical trials evaluating conventional therapies.
The study of tolerance, side effects, and outcome in patients with cirrhosis could help improve chemotherapy management for better tolerance and efficacy.
The main objective is to estimate the frequency of liver cirrhosis among patients evaluated in CPR for ENT, upper digestive or colorectal cancer.
Secondary objective includes the evaluation ofthe impact of cirrhosis on the management of chemotherapy by comparing cirrhotic patients’ outcomes with a control group of matched non-cirrhotic patients.
| 2323209 | ecrin-mdr-crc
Project description:One in five heavy drinkers develop alcohol-associated cirrhosis. Metabolism, inflammation, signaling, gut microbiome and genetic variations have all been tied to pathogenesis but alcohol-associated cirrhosis (AC) models in rodents are limited by differences between rodent species and humans in genetic background and bioenergetics. Here, we used iPSC derived hepatocytes (iHLCs) as a tool to understand mechanisms of AC injury, hypothesizing that iHLC’s derived from patients would preserve genetic and bioenergetic differences leading to AC, and as compared to iHLC’s from patients free of liver disease. Bioenergetically, AC iHLCs had lower spare capacity for mitochondrial respiration and produced less ATP. Metabolic capacities of AC iHLC mitochondria for glutamine and fatty acids were reduced. Together with genome wide association (GWAS) studies, these metabolic and histologic profiles of AC derived iHLCs suggest that differences in mitochondrial oxidative phosphorylation and lipid droplet formation predispose to AC.
2024-02-29 | GSE254610 | GEO
Project description:Gene expression analysis of hearts from double transgenic mice with conditional, cardiomyocyte-specific, overexpression of the mineralocorticoid (MR) or of the glucocorticoid receptor (GR).
2010-06-18 | GSE20525 | GEO