Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1308533 | ENA |
REPOSITORIES: ENA
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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:Dysregulation of lipid homeostasis is a feature of alcohol-associated liver disease (ALD). A-kinase anchoring protein 12 (AKAP12) is a scaffolding partner of the cAMP-dependent protein kinase, PKA that controls its spatiotemporal localization. Activation of PKA by cAMP inhibits lipogenesis and facilitates fatty acid oxidation (FAO). We examined how AKAP12’ could regulate alcohol-associated steatosis. Alcohol exposure reduced AKAP12’s interaction with PKA and suppressed PKA activation. Forced expression of AKAP12 overcame the suppression of PKA activity in human hepatocytes and in livers of mice exposed to alcohol. This led to a decrease in hepatic steatosis. Disrupting the scaffold of AKAP12 and PKA by CRISPR editing increased steatosis and inflammation. RNA sequencing analysis of hepatocytes from alchol fed mice and normal mice demonstrated key lipogenic and inflammatory pathways regulated by AKAP12 overexpression. RNA sequencing of total liver from mice with AKAP12-PKA binding site CRISPR editing or AKAP12 overexpression confirmed regulation of lipogenic and inflammatory pathways by AKAP12
2025-03-02 | GSE290266 | GEO
Project description:Human Yes Associated Protein (hYAP) expressing mouse liver
| PRJNA384350 | ENA
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.
2023-10-07 | GSE244240 | GEO
Project description:Alcohol-associated liver disease is accompanied by changes in the intestinal mycobiome. How fungal dysbiosis contributes to liver disease is not clear. T-helper (Th17) cells mediate immune responses against fungi, but the interleukin 17 (IL17) pathway has been associated with pathogenesis of alcohol-associated liver disease. Here, we demonstrate that Candida albicans (C. albicans)-specific Th17 cells are increased in the circulation and present in the liver of patients with alcohol-associated liver disease. Chronic ethanol administration to mice results in migration of C. albicans-reactive Th17 cells from the intestine to the liver. The antifungal agent nystatin reduced intestinal fungal overgrowth, decreased C. albicans-specific Th17 cells in the liver, and reduced features of ethanol-induced liver disease in mice. Transgenic mice that express a T-cell receptor (TCR) reactive to Candida antigens develop more severe ethanol-induced liver disease than transgene-negative littermates; disease severity was reduced by administration of an antibody against IL17 to the TCR transgenic mice. Adoptive transfer of C. albicans-reactive Th17 cells exacerbated ethanol-induced liver disease in wild-type mice. IL17 receptor A (IL17ra) signaling in Kupffer cells was required for the effects of C. albicans-reactive Th17 cells. Our findings indicate that ethanol increases C. albicans-reactive Th17 cells, which contribute to alcohol-associated liver disease.
2023-02-16 | GSE215930 | GEO
Project description:Alcohol-associated liver disease is accompanied by changes in the intestinal mycobiome. How fungal dysbiosis contributes to liver disease is not clear. T-helper (Th17) cells mediate immune responses against fungi, but the interleukin 17 (IL17) pathway has been associated with pathogenesis of alcohol-associated liver disease. Here, we demonstrate that Candida albicans (C. albicans)-specific Th17 cells are increased in the circulation and present in the liver of patients with alcohol-associated liver disease. Chronic ethanol administration to mice results in migration of C. albicans-reactive Th17 cells from the intestine to the liver. The antifungal agent nystatin reduced intestinal fungal overgrowth, decreased C. albicans-specific Th17 cells in the liver, and reduced features of ethanol-induced liver disease in mice. Transgenic mice that express a T-cell receptor (TCR) reactive to Candida antigens develop more severe ethanol-induced liver disease than transgene-negative littermates; disease severity was reduced by administration of an antibody against IL17 to the TCR transgenic mice. Adoptive transfer of C. albicans-reactive Th17 cells exacerbated ethanol-induced liver disease in wild-type mice. IL17 receptor A (IL17ra) signaling in Kupffer cells was required for the effects of C. albicans-reactive Th17 cells. Our findings indicate that ethanol increases C. albicans-reactive Th17 cells, which contribute to alcohol-associated liver disease.
2023-02-16 | GSE215929 | GEO
Project description:Hepatic NMNAT1 is require to defend against alcohol-associated fatty liver disease
| PRJNA1159526 | ENA
Project description:Human Yes Associated Protein (hYAP) expressing mouse liver (set 2)
| PRJNA384356 | ENA
Project description:Human Yes Associated Protein (hYAP) expressing mouse liver (set 1)
| PRJNA384357 | ENA