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Bioenergetic mechanisms of alcohol-associated cirrhosis in patient derived hepatocytes

ABSTRACT: Bioenergetic mechanisms of alcohol-associated cirrhosis in patient derived hepatocytes

PROVIDER: PRJNA1071132 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR27789024_1.fastq.gz	Fastqsanger.gz
	SRR27789024_2.fastq.gz	Fastqsanger.gz
	SRR27789025_1.fastq.gz	Fastqsanger.gz
	SRR27789025_2.fastq.gz	Fastqsanger.gz
	SRR27789026_1.fastq.gz	Fastqsanger.gz

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Bioenergetic mechanisms of alcohol-associated cirrhosis in patient derived hepatocytes

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.

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Rat hepatocytes: Advanced cirrhosis vs Control liver, Advanced cirrhosis vs Early cirrhosis

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.

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YAP overexpression in hepatocytes influences a specific fibrosis profile in alcohol-related hepatitis

Project description:Objective: YAP impairs hepatocyte regeneration in alcohol-related hepatitis (AH) but its impact on fibrogenesis remains unknown. Our aim was to describe fibrogenesis during AH and the relationship between impaired hepatocyte regeneration and fibrogenesis. Design: Fibrosis distribution and colocalization of YAP and αSMA were assessed by immunostaining. Extracellular matrix (ECM) composition in patients with severe AH (n=22) or alcohol-related cirrhosis (Cirrh, n=24) and healthy livers (Ctrl, n=15) was assessed by bulk and spatial proteomics and PCR. We generated organoids from AH and Cirrh livers and evaluated their impact on myofibroblasts in a 3D coculture model. Cirrh organoids were transduced with an active YAP and cocultured with myofibroblasts. Myofibroblasts were also cultured with medium from transduced (YAP medium) or not-transduced hepatocytes (CTRL medium).

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Inhibition of the mineralocorticoid Receptor reduces Cirrhosis associated changes of hepatocyte Glucose and Lipid Metabolism in hepatocytes

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.

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MCRS1 is a histone acetylation regulator whose loss in hepatocytes promotes cirrhosis

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.

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Hepatocytes cyclooxygenase-2 deficiency improves liver injury via inhibition of endoplasmic reticulum stress and epithelial-mesenchymal transition

Project description:The mechanism underlying the loss of normal liver tissues in liver cirrhosis, mainly hepatocytes, is not well-characterized. Endoplasmic reticulum (ER) stress-induced cell death has emerged as a potential mechanism for chronic liver diseases. We have previously demonstrated that cyclooxygenase-2 (COX-2) is closely related to the progress of liver cirrhosis. In this study, we aimed to verify whether hepatocytes COX-2 deficiency could protect liver injury via inducing ER stress in liver cirrhosis.

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Sex specific role of KDM5B demethylase in Alcohol-associated Liver Disease development and resolution

Project description:Alcohol-associated liver disease (ALD) is a major cause of alcohol related mortality. Recently we identified hepatic demethylases KDM5B and KDM5C as important sex-specific epigenetic regulators of alcohol response in the liver. In this study we aimed to study the molecular mechanisms of KDM5-dependent ALD development and resolution. We found that alcohol induces pathological changes in cell-cell communication in the liver that are in part mediated by epigenetic changes in hepatocytes mediated by histone demethylase KDM5B. Using cell type specific knockout mice, we found that KDM5B histone demethylase was a key regulator of alcohol-induced epigenetic changes in hepatocytes. Moreover, it regulated hepatocytes-non-parenchymal cell crosstalk that promoted inflammation and fibrosis development in ALD. This mechanism was specific to females. In males KDM5B deficiency was not sufficient to prevent fibrosis development. In contrast KDM5B demethylase loss promoted fibrosis resolution in both males and females. This mechanism involved changes in hepatocyte-macrophage crosstalk and LXRα activation, which we identified to be critical for the fibrosis resolution process. CONCLUSION: In summary, KDM5B demethylase is a regulator of cell-cell crosstalk involved in disease progression in females and in disease resolution in both sexes.

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