Effect of depletion of S100A16 on gene expression during lipid accumulation of primary hepatocytes
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE243683 | GEO | 2023/09/26
REPOSITORIES: GEO
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Project description:Alcohol’s impairment of both hepatic lipid metabolism and insulin resistance (IR) are key drivers of alcoholic steatosis, the initial stage of alcoholic liver disease (ALD). Pharmacologic reduction of lipotoxic ceramide prevents alcoholic steatosis and glucose intolerance in mice, but potential off-target effects limit its strategic utility. Here, we employed a hepatic-specific acid-ceramidase (ASAH) overexpression model to reduce hepatic ceramides in a Lieber-DeCarli model of experimental alcoholic steatosis. We examined effects of alcohol on hepatic lipid metabolism, body composition, energy homeostasis and insulin sensitivity as measured by hyperinsulinemic-euglycemic clamp. Our results demonstrate that hepatic ceramide reduction ameliorates the effects of alcohol on hepatic lipid droplet accumulation by promoting VLDL secretion and lipophagy, the latter of which involves ceramide cross-talk between the lysosomal and lipid droplet compartments. We additionally demonstrate that hepatic ceramide reduction prevents alcohol’s inhibition of hepatic insulin signaling. These effects on the liver are associated with a reduction in oxidative stress markers and are relevant to humans, as we observe peri-lipid droplet ASAH expression in human ALD. Together, our results suggest a potential role for hepatic ceramide inhibition in preventing ALD.
2020-07-08 | GSE139015 | GEO
Project description:Alcoholic liver diseases (ALDs) encompass a broad spectrum of clinical features of alcoholic fatty liver, alcoholic steatohepatitis and cirrhosis, and increased risk of hepatocellular carcinoma. While the toxic effects of alcohol likely result from complex interactions between genes and the environment, the molecular mechanisms of alcohol-induced liver damage remains undefined. Thus, a better understanding of the mechanisms regulating hepatic cell injury may lead to more effective therapeutic approaches for ALD. Here we compared the miRNA expression profile from tissues from control mice and mice receiving intragastric ethanol feeding. Four microarray hybridization studies were performed on three different pairs of liver-derived RNA from intragastric ethanol feeding and normal mice. The miRNAs differentially overexpressed in livers from ethanol fed mice.
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Project description:Alcoholic liver disease, which varies in severity from mild steatosis to cirrhosis and hepatitis, is one of the most prevalent chronic liver diseases worldwide. Excessive alcohol consumption remains the leading cause of ALD and alcohol-related complications and deaths. However, no medications have been developed to treat this disease and its pathogenesis remains elusive. Here, to understand alcohol-induced AhR activation in more detail, transcriptomic data was conducted using livers from mice subjected to either control or Lieber-DeCarli alcohol diets.
2022-09-06 | GSE179398 | GEO
Project description:Liver fibrosis has been implicated in the pathogenesis of various liver disease. Thus far, there is still no effective intervention means for this process. Recently, we have demonstrated that S100A16 participated in liver lipid accumulation and renal fibrosis. Therefore, we hypothesized that S100A16 took a critical role in liver fibrosis. S100a16 transgenic and knockdown mice were generated and stimulated with carbon tetrachloride, bile duct ligation and methionine choline deficiency diet. Alterations of gene expression in hepatic stellate cells from wild type and S100a16+/- mice were investigated by transcriptome sequencing. S100A16 expression levels in liver tissue of patients and rodent models of liver fibrosis were markedly increased. S100a16 transgenic mice showed spontaneous liver fibrosis after normal feeding for 6 months. On the contrary, silencing of S100a16 exhibited obvious protective effect against liver fibrosis caused by different stimulations. Meanwhile, results showed that deletion of S100a16 significantly inhibited hepatic stellate cells (HSCs) activation cultured in fetal bovine serum contained medium. RNA sequencing results revealed that mechanistically, C-X-C motif chemokine receptor 4 (Cxcr4) participated in the process of S100a16 in liver fibrosis. Knockdown of S100a16 inhibited Cxcr4 expression through augmenting P53 expression. SDF-1α/CXCR4-dependent extracellular signal-regulated kinase 1/2 and Akt phosphorylation mediated the effects of S100a16 on α-smooth muscle actin expression and HSCs activation. These data indicate that S100a16 deficiency prevents liver fibrosis by inhibiting Cxcr4 expression. Targeting S100A16 may provide insights into the pathogenesis of liver fibrosis and pave the way for developing strategies for liver fibrosis-related diseases prevention and treatment.
2022-03-25 | GSE199294 | 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:Chronic alcohol abuse has a detrimental effect on the brain and liver. There is no effective treatment for these patients and the mechanism underlying alcohol addiction and consequent alcohol-induced damage of the liver/brain axis remains unresolved. We compared experimental models of alcoholic liver disease (ALD) and alcohol dependence in mice and demonstrated that genetic ablation of IL17 Receptor A (IL17ra-/-), or pharmacological blockade of IL17 signaling effectively suppressed the increased voluntary alcohol drinking in alcohol-dependent mice, and blocked alcohol-induced hepatocellular and neurological damage. The level of circulating IL17A positively correlated with the alcohol use in excessive drinkers, and was further increased in patients with ALD as compared to healthy individuals. Our data suggest that IL17A is a common mediator of excessive alcohol consumption and alcohol-induced liver/brain injury, and targeting IL17A may provide a novel strategy for treatment of alcohol-induced pathology.
2020-04-07 | GSE137228 | GEO
Project description:Background and Aim: The worldwide prevalence of alcoholic liver disease (ALD) due to escalating alcohol consumption has presented an unprecedented pressure on human health. A few studies have determined long non-coding RNAs (lncRNAs) involved in the pathogenesis of liver diseases. However, the roles of lncRNAs in ALD development is still poorly understood. Methods: An ALD mouse model was established and confirmed. Expression profiles of lncRNAs were obtained by whole transcriptome sequencing. The altered lncRNAs in ALD mice were further verified by qRT-PCR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to enrich the functions of these lncRNAs. In combination with miRNA and mRNA profiles, we constructed concise endogenous RNA (ceRNA) networks. The function of the most up/downregulated lnRNA signaling was further verified and investigated in both ALD model and AML-12 cells. Results: Totally, five downregulated lncRNAs were obtained and verified in ALD mice. The GO term and KEGG pathway analyses revealed that the identified lncRNAs were associated with alcohol-induced hepatic oxidative damage, cellular inflammation, and lipid metabolism. Integration the differentially modulated miRNAs and mRNAs with ceRNA network analysis, we constructed five ceRNA networks and screened out 30 miRNAs and 25 mRNAs that may participate in ALD. Further, we verified and investigate the function of the most downregulated lnc_1700023H06Rik. Depletion lnc_1700023H06Rik reduced genes related to lipid metabolism, especially mRNA Acat2 (ENSMUST00000159697) and Pgrmc2 (ENSMUST00000058578) in both ALD mice and AML12 cell. Knocking down lnc_1700023H06Rik induced triglyceride accumulation and LDH leakage in AML12 cells, consisting with that in alcohol-treated cells, confirming the potential pathological role of lnc_1700023H06Rik in ALD. Conclusion: The five remarkably downregulated lncRNAs in an ALD mouse model were identified as novel biomarkers, highlighting the key role of lncRNAs in the development of ALD. The effect of lnc_1700023H06Rik was further verified.
2021-08-18 | GSE179648 | GEO
Project description:Background and Aim: The worldwide prevalence of alcoholic liver disease (ALD) due to escalating alcohol consumption has presented an unprecedented pressure on human health. A few studies have determined long non-coding RNAs (lncRNAs) involved in the pathogenesis of liver diseases. However, the roles of lncRNAs in ALD development is still poorly understood. Methods: An ALD mouse model was established and confirmed. Expression profiles of lncRNAs were obtained by whole transcriptome sequencing. The altered lncRNAs in ALD mice were further verified by qRT-PCR. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were used to enrich the functions of these lncRNAs. In combination with miRNA and mRNA profiles, we constructed concise endogenous RNA (ceRNA) networks. The function of the most up/downregulated lnRNA signaling was further verified and investigated in both ALD model and AML-12 cells. Results: Totally, five downregulated lncRNAs were obtained and verified in ALD mice. The GO term and KEGG pathway analyses revealed that the identified lncRNAs were associated with alcohol-induced hepatic oxidative damage, cellular inflammation, and lipid metabolism. Integration the differentially modulated miRNAs and mRNAs with ceRNA network analysis, we constructed five ceRNA networks and screened out 30 miRNAs and 25 mRNAs that may participate in ALD. Further, we verified and investigate the function of the most downregulated lnc_1700023H06Rik. Depletion lnc_1700023H06Rik reduced genes related to lipid metabolism, especially mRNA Acat2 (ENSMUST00000159697) and Pgrmc2 (ENSMUST00000058578) in both ALD mice and AML12 cell. Knocking down lnc_1700023H06Rik induced triglyceride accumulation and LDH leakage in AML12 cells, consisting with that in alcohol-treated cells, confirming the potential pathological role of lnc_1700023H06Rik in ALD. Conclusion: The five remarkably downregulated lncRNAs in an ALD mouse model were identified as novel biomarkers, highlighting the key role of lncRNAs in the development of ALD. The effect of lnc_1700023H06Rik was further verified.
2021-08-18 | GSE175804 | 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:Alcoholic liver disease (ALD) is a leading cause of cirrhosis in the United States, which is characterized by extensive deposition of extracellular matrix proteins (ECM) and formation of a fibrous scar. Hepatic Stellate Cells (HSCs) are the major source of Collagen Type I producing myofibroblasts in ALD fibrosis. However, the mechanism of alcohol-induced activation of human and mouse HSCs is not fully understood. We compared the gene expression profiles of primary cultured human HSCs (hHSCs) isolated from patients with ALD (n=3) or without underlying liver disease (n=4) using RNA-Seq analysis. Furthermore, the gene expression profile of ALD hHSCs was compared to that of alcohol-activated mHSCs (isolated from intragastric (IG) alcohol-fed mice), or carbon-tetrachloride (CCl4)-activated mouse HSCs (mHSCs). Comparative transcriptome analysis revealed that ALD hHSCs, and alcohol- and CCl4-activated mHSCs share the expression of common HSC activation (Col1a1, Acta1, PAI-1, TIMP1, LOXL2), indicating that a common mechanism underlies activation of human and mouse HSCs. Furthermore, alcohol-activated mHSCs most closely recapitulate the gene expression profile of ALD hHSCs. We identified the genes that are similarly and uniquely upregulated in primary cultured alcohol-activated hHSCs and freshly isolated mHSCs, which include CSF1R, PLEK, LAPTM5, CD74, CD53, MMP9, CD14, CTSS, TYROBP, ITGB2, and other genes (compared to CCl4-activated mHSCs). We identified genes in alcohol-activated mHSCs from IG alcohol-fed mice that are largely consistent with the gene expression profile of primary cultured hHSCs from ALD patients. These genes are unique to alcohol-induced HSC activation in two species, and therefore, may become new targets or readout for anti-fibrotic therapy in experimental models of ALD.
2020-04-10 | GSE141100 | GEO