Mus musculus breed:C57BL/6 N
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1159526 | ENA |
REPOSITORIES: ENA
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Project description:Nicotinamide mononucleotide adenylyltransferase 1 (NMNAT1), an NAD+ synthetase in Preiss-Handler and salvage pathways, governs nuclear NAD+ homeostasis. This study investigated the role of NMNAT1 on alcohol-associated liver disease (ALD). Decreased NMNAT1 expression and activity were observed in the liver of alcohol-associated hepatitis patients and either liver or primary hepatocytes from ALD mice. F-box and WD repeat domain containing 7 (FBXW7)-regulated interferon regulatory factor 1 (IRF1) ubiquitination degradation contributed to alcohol-inhibited NMNAT1 transcriptional level. Hepatic NMNAT1 knockout aggravated alcohol-induced hepatic NAD+ decline and further hepatic steatosis and liver injury. Metabolomics and transcriptomics interaction revealed that cysteine sulfinic acid decarboxylase (CSAD)-regulated taurine pathway was involved in NMNAT1-disrupted hepatic lipid metabolism in ALD. Hepatic CSAD overexpression or taurine supply attenuated hepatic NMNAT1 knockout-aggravated ALD, respectively. Hepatic NMNAT1 loss inhibited NMN-protected ALD. Replenishing hepatic NMNAT1 reversed liver lipid accumulation in ALD mice. These findings identified NMNAT1 as a promising therapeutic target for ALD.
2025-05-25 | GSE297696 | GEO
Project description:The tumor suppressor p53 is critical for tumor suppression and other biological events. Yet, the regulatory role of p53 in alcohol-induced fatty liver remains unclear. Here, we show a role for p53 in regulating the ethanol metabolism via acetaldehyde dehydrogenase 2 (ALDH2), a key enzyme responsible for oxidization of alcohol. Through repressing ethanol oxidization, p53 suppresses intracellular levels of acetyl-CoA and histone acetylation, leading to the inhibition of the stearoyl-CoA desaturase-1 (SCD1) gene expression. Mechanistically, p53 directly binds to ALDH2 and prevents the formation of its active tetramer, and indirectly limits the production of pyruvate that promotes the activity of ALDH2. Notably, p53 deficient mice exhibit increased lipid accumulation, which can be reversed by ALDH2 depletion. Moreover, hepatic specific knockdown of SCD1 diminishes ethanol-induced fatty liver caused by p53 loss. By contrast, overexpression of SCD1 in liver promotes ethanol-induced fatty liver development in wildtype mice, while has mild effect on p53-/- or ALDH2-/- mice. Overall, our findings reveal a previously unrecognized function of p53 in alcohol-induced fatty liver, and uncover pyruvate as a natural regulator of ALDH2.
2023-02-08 | GSE222743 | GEO
Project description:To investigate the function of read-through circRNAs in liver, we obtained human NASH liver tissues and normal liver tissues patients without NAFLD undergoing surgery for hepatic hemangioma.Patients with positive hepatitis B surface antigen or anti-hepatitis C virus (HCV) antibody with detectable HCV RNA, excessive alcohol consumption (20 g/day in men or 10 g/day in women), secondary fatty liver (e.g., use of systemic steroids or tamoxifen), or malignancies before baseline were excluded. We then performed exome capture mRNA sequencing using livers from three NASH patients and three patients with hepatic hemangioma.
2022-09-08 | GSE212741 | GEO
Project description:Alcohol induced fatty liver cause a dangerous health problem and is the major cause of morbidity and mortality worldwide. Garlic (Allium sativum) is documented to possess anti-fatty liver properties. However the exact molecular mechanisms are unknown. The main aim of this experiment is to elucidate the underlying pathways through which garlic ameliorates alcohol induced fatty liver. Dially disulfide and garlic oil were the garlic compounds used in this study. Leiber DeCarli ethanol liquid diet was to induce fatty liver in C57BL/6 mice model. Also the expression impaired by alcohol induced fatty liver is another aim of this study.
2012-10-01 | GSE40334 | 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.
2014-10-07 | E-MTAB-2311 | biostudies-arrayexpress
Project description:Metabolic dysfunction-associated steatotic liver disease and its progressive and inflammatory form metabolic dysfunction-associated steatohepatitis represents a global health challenge, with limited treatment options available. In this study we identified an endogenous, understudied omega-6 fatty acid metabolite, arachidonoyl-taurine (ARA-T), capable of mitigating liver disease. ARA-T levels increased in human plasma of chronic and acute fatty liver and their abundance can be driven in humans and mice by dietary supplementation of arachidonic acid. Surprisingly, our genetic model of elevated circulating ARA-T levels prevented inflammation and hepatic steatosis by increased uptake and turnover of fatty acids in the liver. Pharmacological administration of ARA-T reduced liver weight and diet-induced hepatic lipid deposition in mice, demonstrating its potential to protect against and reverse the progression of liver disease. Thus, ARA-T may represent a way to protect against pro-inflammatory actions of omega-6 fatty acids thereby contributing to regulation of inflammation and accumulation of hepatic lipids.
2026-05-12 | GSE292568 | GEO
Project description:Post-translational acetylation of proteins at lysine side chains by the central metabolite acetyl-CoA, is a crucial regulator of proteostasis. Ethanol metabolism in the liver induces protein acetylation and disrupts hepatic substrate metabolism. While acetylation can influence gene transcription, enzyme activity, and stability of proteins, the role of ethanol-induced acetylation in hepatic metabolism is still unclear. We used a 2H2O-based metabolic labeling approach to investigate the impact of ethanol-induced acetylation on liver metabolism in a murine model of chronic ethanol-induced liver injury. Mice were fed an ethanol containing diet for 25 days; liver proteins and acetylation patterns were monitored during the final 21 days of 2H2O labeling. The proteome, acetylome, and targeted metabolic profiling were conducted to evaluate ethanol-induced alterations in hepatic metabolism. Ethanol consumption induced hepatic steatosis, inflammation, and oxidative stress. It led to reduced turnover of mitochondrial proteins and increased turnover of cytosolic stress response proteins and metabolic enzymes. Ethanol elevated acetylation levels of mitochondrial metabolic enzymes and nuclear histones, with no significant changes in the cytosol. Acetylation stabilized mitochondrial proteins but destabilized histones. Ethanol-induced reduced mitochondrial protein turnover, linked to increased acetylation, led to hepatic protein accumulation. Impaired proteasomal and lysosomal degradation contributed to alcohol-induced hepatic proteopathy. These changes were associated with altered levels of acyl-CoAs and acyl-carnitines, amino acids, and tricarboxylic acid (TCA) cycle intermediates, reflecting impaired fatty acid oxidation, nitrogen disposal and citric acid cycle activities. In conclusion, ethanol-induced alterations in acetylome dynamics could modify hepatic substrate metabolism and contribute to liver injury in alcohol-associated liver disease through acetylation-dependent epigenetic changes and the regulation of metabolic enzymes.
2025-08-04 | PXD055349 | Pride
Project description:Background & Aims: Alcohol-associated liver disease (ALD) heavily contributes to global alcohol related mortality. Alcohol can synergize with other causes of liver disease such as metabolic syndrome induced by western diet (high fat, high fructose, high cholesterol). However, the role of individual western diet components in ALD development is not fully understood. We aimed to study the role of cholesterol in alcohol pathogenesis. Previous studies have shown that hepatic cholesterol metabolism is dysregulated with alcohol use resulting in altered lipoprotein levels. We aimed to study the role of cholesterol in ALD development using a mouse model. Approach and results: 8-week-old male mice were fed ad libitum with low fat high cholesterol diet (Research Diets, cat# D24120501, 1% cholesterol) in combination with 20% EtOH in the drinking water for 10 weeks. Compared to high-cholesterol diet alone, alcohol treated mice showed elevated levels of serum ALT and AST, INR/PT, increased liver inflammation, fibrosis, ductular reaction and signs of liver failure such as reduced HNF4α and albumin production. To assess the mechanism of alcohol-induced pathology, we performed spatial transcriptomic analysis using 5k gene Xenium panel (10x Genomics). We found that the liver adapted to high cholesterol diet by increasing cholesterol metabolism in hepatocytes. In contrast, alcohol impaired liver adaptation to high cholesterol diet by reducing cholesterol metabolism, HDL production, and hepatic cholesterol secretion, thus driving inflammation and fibrosis. Hepatocyte specific Kdm5b knockout mice were partially protected from alcohol effects by restoring cholesterol secretion in part through an upregulation of Abcg8. Accordingly, these mice were protected against alcohol-induced fibrosis development and inflammation. Conclusion: In summary, alcohol impairs liver adaptation to high cholesterol diet. Increasing liver cholesterol secretion by KDM5B inhibition protects liver from ALD development.
2026-05-04 | GSE329229 | GEO
Project description:Alcohol induced fatty liver cause a dangerous health problem and is the major cause of morbidity and mortality worldwide. Garlic (Allium sativum) is documented to possess anti-fatty liver properties. However the exact molecular mechanisms are unknown. The main aim of this experiment is to elucidate the underlying pathways through which garlic ameliorates alcohol induced fatty liver. Dially disulfide and garlic oil were the garlic compounds used in this study. Leiber DeCarli ethanol liquid diet was to induce fatty liver in C57BL/6 mice model. Also the expression impaired by alcohol induced fatty liver is another aim of this study. Leiber-Decarli ethanol diet was used to induce fatty liver in male C57BL/6 mice (n=12). For control, Lieber-DeCarli liquid control diet was fed to mice (n=4). The control mice were pair-fed to the ethanol mice. After adaptation, the ethanol fed mice were divided into three groups viz. alcohol (n=4), dially disulfide [DADS] (n=4) and garlic oil [GO] (n=4). The study started with the administration of DADS (15 mg/kg bw) or GO (50 mg/kg bw) mixed in 0.1 ml olive oil through gavage. For the control and alcohol groups, same amount of olive oil (0.1 ml) was gavaged. The mice were gavaged daily for 4 weeks. The mice were euthanized by CO2 and blood was collected by cardiac puncture. Liver, kidney, spleen, lungs and hearts were collected and their weights recorded. A portion of liver was snap frozen in liquid nitrogen (200 mg) for RNA extraction.
2012-10-01 | E-GEOD-40334 | biostudies-arrayexpress
Project description:Obesity is tightly associated with an increased risk of nonalcoholic fatty liver disease (NAFLD). However, the molecular mechanisms of obesity-induced fatty liver remain largely unknown.In order to identify genes that are potentially involved in dysfunctional hepatic lipid homeostasis in obesity, we performed a clustering analysis of Affymetrix arrays,which revealed that a number of mRNAs were dys-regulated in the livers of mice fed a high-fat diet (HFD), compared with mice fed a normal chow diet (ND). To identify genes that are potentially involved in dysfunctional hepatic lipid homeostasis in obesity, male C57BL/6 mice aged 8 weeks were fed a normal diet (ND) or high-fat-diet (HFD) containing 60 Kcal% of fat for 12 weeks. Then mice were sacrificed and total RNAs were isoloated from hepatic tissues. Affymetrix array hybridisation and scanning were performed using Mouse Genome 430 2.0 chips.Total RNA samples obtained from six mice per group (ND and HFD) and pooled by each of the two were used for microarray analysis.
2014-05-09 | E-GEOD-57425 | biostudies-arrayexpress