Distinct Metabolic Adaptation of Liver Circadian Pathways to Acute and Chronic Patterns of Alcohol Intake
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE132103 | GEO | 2019/11/30
REPOSITORIES: GEO
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Project description:In the U.S., alcohol-associated liver disease (ALD) impacts millions of people and is a major healthcare burden. While the pathology of ALD is unmistakable, the molecular mechanisms underlying ethanol hepatotoxicity are not fully understood. Hepatic ethanol metabolism is intimately linked with alterations in extracellular and intracellular metabolic processes, specifically oxidation/reduction reactions. The xenobiotic detoxification of ethanol leads to significant disruptions in glycolysis, β-oxidation, and the TCA cycle, as well as oxidative stress. Perturbation of these regulatory networks impacts the redox status of critical regulatory protein thiols throughout the cell. Integrating these key concepts, our goal was to apply a cutting-edge approach toward understanding mechanisms of ethanol metabolism in disrupting hepatic thiol redox signaling. Utilizing a chronic murine model of ALD, we applied a cysteine targeted click chemistry enrichment coupled with quantitative nHPLC-MS/MS to assess the thiol redox proteome. Our strategy reveals that ethanol metabolism largely reduces the cysteine proteome, with 593 cysteine residues significantly reduced and 8 significantly oxidized cysteines. Ingenuity Pathway Analysis demonstrates that ethanol metabolism reduces specific cysteines throughout ethanol metabolism (Adh1, Cat, Aldh2), antioxidant pathways (Prx1, Mgst1, Gsr), as well as many other biochemical pathways. Further research is needed to determine how a reduced cysteine proteome impacts individual protein activity across these protein targets and pathways. Additionally, understanding how a complex array of cysteine-targeted post-translational modifications (e.g., S-NO, S-GSH, S-OH) are integrated to regulate redox signaling and control throughout the cell is key to the development of redox-centric therapeutic agents targeted to ameliorate the progression of ALD.
2024-09-19 | PXD042070 | Pride
Project description:Distinct Metabolic Adaptation of Liver Circadian Pathways to Acute and Chronic Patterns of Alcohol Intake
| PRJNA545952 | ENA
Project description:Alcohol-associated liver disease (ALD) results from excessive alcohol consumption and is more severe in females. The prenane X receptor (PXR), a xenobiotic nuclear receptor essential for toxin defense, has been implicated in ALD, but the underlying mechanisms remain unclear. Due to species differences in ligand specificty, humanized PXR (hPXR) mouse models are necessary to investigate its role in the sexual dimorphism of ALD in humans. Ethanol exposure caused the most severe hepatoxicity in female hPXR mice with microarray analysis identifying 442 genes uniquely regulated by ethanol in female hPXR mice, implicated with ethanol-induced liver damage.
2024-10-31 | GSE280478 | GEO
Project description:BACKGROUND & AIMS: There is mounting evidence that microbes resident in the human intestine contribute to diverse alcohol-associated liver diseases (ALD) including the most deadly form known as alcoholic hepatitis (AH). However, mechanisms by which gut microbiota synergize with excessive alcohol intake to promote liver injury are poorly understood. Furthermore, whether drugs that selectively target gut microbial metabolism can improve ALD has never been tested. METHODS: We used liquid chromatography tandem mass spectrometry to quantify the levels of microbe and host choline co-metabolites in healthy controls and AH patients, and identified the metabolite trimethylamine (TMA) as a gut microbe-derived biomarker of AH. In subsequent studies, we treated mice with non-lethal mechanism-based bacterial choline TMA lyase inhibitors to blunt gut microbe-dependent production of TMA in the context of chronic ethanol administration. Indices of liver injury were quantified by complementary RNA sequencing, biochemical, and histological approaches. In addition, we examined the impact of ethanol consumption and TMA lyase inhibition on gut microbiome structure via 16S rRNA sequencing. RESULTS: We show the gut microbial choline metabolite trimethylamine (TMA) is elevated in AH patients, which is correlated with reduced hepatic expression of the TMA oxygenase flavin-containing monooxygenase 3 (FMO3). Provocatively, we find that small molecule inhibition of gut microbial choline TMA lyase activity protects mice from ethanol-induced liver injury. TMA lyase inhibitor-driven improvement in ethanol-induced liver injury is associated with distinct reorganization of the gut microbiome community and host liver transcriptome. CONCLUSIONS: The microbial metabolite TMA is a biomarker of AH, and blocking TMA production from gut microbes can blunt ALD in mice.
2021-03-31 | GSE157681 | GEO
Project description:Mitochondrial dysfunction is one of many key factors in the etiology of alcoholic liver disease (ALD). Lysine acetylation is known to regulate numerous mitochondrial metabolic pathways and recent reports demonstrate that alcohol-induced protein acylation negatively impacts these processes. To identify regulatory mechanisms attributed to alcohol-induced protein post-translational modifications, we employed a model of alcohol consumption within the context of wild type (WT), sirtuin 3 knockout (SIRT3 KO), and sirtuin 5 knockout(SIRT5 KO) mice to manipulate hepatic mitochondrial protein acylation. Mitochondrial fractions were examined by label-free quantitative HPLC-MS/MS to reveal competition between lysine acetylation and succinylation. A class of proteins defined as “differential acyl switching proteins” demonstrate select sensitivity to alcohol-induced protein acylation. A number of these proteins reveal saturated lysine-site occupancy, suggesting a significant level of differential stoichiometry in the setting of ethanol consumption. We hypothesize that ethanol downregulates numerous mitochondrial metabolic pathways through differential acyl switching proteins.
2019-01-23 | PXD012089 | Pride
Project description:X-linked adrenoleukodystrophy (X-ALD) is an inherited disorder characterized by axonopathy and demyelination in the central nervous system and adrenal insufficiency. Main X-ALD phenotypes are: (i) an adult adrenomyeloneuropathy (AMN) with axonopathy in spinal cords, (ii) cerebral AMN with brain demyelination (cAMN) and (iii) a childhood variant, cALD, characterized by severe cerebral demyelination. Loss of function of the ABCD1 peroxisomal fatty acid transporter and subsequent accumulation of very-long-chain fatty acids (VLCFAs) are the common culprits to all forms of X-ALD, an aberrant microglial activation accounts for the cerebral forms. How same mutation in the ABCD1 gene can lead to clinically very distinct phenotypes and what factors account for the dissimilar clinical outcomes and prognosis of X-ALD variants remain elusive. We wonder whether epigenetics mechanisms could answer the lack of genotype-phenotype correlation. We employed Illumina state of the art technology to analyze the differential methylation of over 485,000 CpG sites throughout the entire human genome and used stringent statistical criteria to define differential methylation patterns between brains of cALD, cAMN and age-matched controls. We identified a common X-ALD methylation signature comprising the hypermethylation in genes harboring the trimethylated histone H3K27me3 mark in their promoters, the hypermethylation for genes driven the oligodendrocyte lineage, and the hypomethylation for immune-associated genes. We also examined the methylated differences between cALD and cAMN resulting with differential immune response pathways and concordance methylation levels with phenotype severity. The detected methylation differences correlated with transcriptional and translational consequences, as supported by Affymetrix expression arrays, quantitative PCR and WB changes. The reliability of these changes was further demonstrated by validating DNA methylation by an independent pyrosequencing assay. From these evidences, we propose the altered transcriptional programs in oligodendrocyte differentiation in X-ALD patients. These observations may provide new therapeutic epigenetic agents.
2019-02-01 | GSE78218 | GEO
Project description:Alcoholic liver disease (ALD) encompasses conditions ranging from simple steatosis to cirrhosis and even liver cancer. It has gained significant global attention in recent years. Despite this, effective pharmacological treatments for ALD remain elusive, and the core mechanisms underlying the disease are not yet fully comprehended. S100A16, a newly identified calcium-binding protein, is linked to lipid metabolism. Our research has discovered elevated levels of the S100A16 protein in both serum and liver tissue of ALD patients. A similar surge in hepatic S100A16 expression was noted in a Gao-binge alcohol feeding mouse model. S100a16 knockdown alleviated ethanol-induced liver injury, steatosis and inflammation. Conversely, S100a16 transgenic mice showed aggravating phenomenon. Mechanistically, we identify mesencephalic astrocyte-derived neurotrophic factor (MANF) as a regulated entity downstream of S100a16 deletion. MANF inhibited ER-stress signal transduction induced by alcohol stimulation. Meanwhile, MANF silencing suppressed the inhibition effect of S100a16 knockout on ethanol-induced lipid droplets accumulation in primary hepatocytes. Our data suggested that S100a16 deletion protects mice against alcoholic liver lipid accumulation and inflammation dependent on upregulating MANF and inhibiting ER stress. This offers a potential therapeutic avenue for ALD treatment.
2023-09-26 | GSE243683 | GEO
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:We analyzed the effect of chronic alcohol intake on the genome-wide binding activity of NF-κB during the initial response phase following partial hepatectomy. We analyzed the data in the adapted state as well as in response to partial hepatectomy, using chromatin immunoprecipitation followed by promoter microarray analysis. We found several ethanol-specific NF-κB binding target promoters in the chronic adapted state.. Partial hepatectomy induced a diet-independent shift in NF-κB binding loci relative to the transcription start sites. We employed a novel pattern count analysis to exhaustively enumerate and compare the number of promoters corresponding to the temporal binding patterns between ethanol and isocaloric pair-fed control groups. We found that NF-κB bound genes govern negative regulation of cell growth and inflammatory response immediately following hepatectomy. We, integrated the ChIP-chip results with a time series gene expression data set to identify the NF-κB promoter binding targets that showed differential gene expression changes at the baseline-adapted condition as well as after PHx. We identified a set of differential patterns of NF-κB binding that were specific to the ethanol and pair-fed control groups. We found the regulatory pathways and co-incident transcription factor binding motifs corresponding some of the key comparative-binding patterns.
2015-10-23 | GSE74273 | GEO
Project description:The pregane X receptor (PXR), a xenobiotioc-sensing nuclear receptor has been implicated in alcohol-associated liver disease (ALD). The role of PXR signaling in potentiating ethanol (EtOH)-induced hepatotoxicty in male wild-type (WT) mice was reported previously, however, how PXR signaling modulated EtOH-induced hepatotoxicty in female is still unknown. Several mRNAs that are involved in retinol and steroid hormone biosynthesis, chemical carcinogeneiss, and arachidonic acid metabolism were increased by EtOH in a PXR-dependent manner. Overall, female PXR-null mice are resistant against chronic EtOH-induced hepatotoxicity than their WT counterparts.
2023-08-09 | GSE239714 | GEO