An Update on Animal Models of Alcohol-Associated Liver Disease

American Journal Of Pathology, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 1, 2025

Language: Английский

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Cell-to-cell and organ-to-organ crosstalk in the pathogenesis of alcohol-associated liver disease

eGastroenterology, Journal Year: 2024, Volume and Issue: 2(4), P. e100104 - e100104

Published: Dec. 1, 2024

Alcohol-associated liver disease (ALD) is a growing global health concern and its prevalence severity are increasing steadily. While bacterial endotoxin translocation into the portal circulation well-established key factor, recent evidence highlights critical role of sterile inflammation, triggered by diverse stimuli, in alcohol-induced injury. This review provides comprehensive analysis complex interactions within hepatic microenvironment ALD. It examines contributions both parenchymal cells, like hepatocytes, non-parenchymal such as stellate Kupffer neutrophils, sinusoidal endothelial driving progression disease. Additionally, we explored involvement mediators, including cytokines, chemokines inflammasomes, which regulate inflammatory responses promote injury fibrosis. A particular focus has been placed on extracellular vesicles (EVs) essential mediators intercellular communication beyond liver. These facilitate transfer signalling molecules, microRNAs proteins, modulate immune responses, fibrogenesis lipid metabolism, thereby influencing progression. Moreover, underscore importance organ-to-organ crosstalk, particularly gut-liver axis, where dysbiosis increased intestinal permeability lead to microbial translocation, exacerbating inflammation. The adipose-liver axis also highlighted, impact adipokines free fatty acids from adipose tissue steatosis inflammation context alcohol consumption.

Language: Английский

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Chronic alcohol consumption accelerates cardiovascular aging and decreases cardiovascular reserve capacity

GeroScience, Journal Year: 2025, Volume and Issue: unknown

Published: March 20, 2025

Abstract The pathology of cardiovascular aging is complex, involving mitochondrial dysfunction, oxidative and nitrative stress, DNA injury, impaired lipid metabolism, cell death, senescence, chronic inflammation. These processes lead to remodeling structural changes in the system, resulting a progressive decline reserve capacity health, an increased risk diseases mortality. Excessive alcohol consumption exacerbates these risks by promoting hypertension, stroke, arrhythmias, coronary artery disease, cardiomyopathy, sudden cardiac yet effects on remain unclear. Herein, we explored impact 6-month 5% Lieber-DeCarli diet young (3 months old) (24–26 Fisher F344BNF1 rats. We assessed detailed hemodynamics, function, oxidative/nitrative inflammation, myocardial fibrosis using pressure–volume isolated vascular rings, various histological, biochemical, molecular biology methods. Alcohol both rats disrupted cholesterol triglyceride leading systolic contractile function. In rats, further exacerbated diastolic dysfunction fibrosis. also apoptosis, senescence vasculature, contributing endothelial total peripheral resistance. Additionally, aging-related ventriculo-arterial uncoupling diminished efficiency, reducing capacity. conclusion, promotes diminishes already associated with aging.

Language: Английский

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Mitochondrial quality control in alcohol-associated liver disease

Hepatology Communications, Journal Year: 2024, Volume and Issue: 8(11)

Published: Oct. 24, 2024

Excessive alcohol consumption is a leading cause of alcohol-associated liver disease (ALD), significant global health concern with limited therapeutic options. Understanding the key factors contributing to ALD pathogenesis crucial for identifying potential targets. Central intricate interplay between metabolism and cellular processes, particularly involving mitochondria. Mitochondria are essential organelles in liver, critical energy production metabolic functions. However, they vulnerable alcohol-induced damage due their involvement metabolism. Alcohol disrupts mitochondrial function, impairing ATP triggering oxidative stress, which leads inflammation. Mitochondrial quality control mechanisms, including biogenesis, dynamics, mitophagy, maintaining optimal function. Chronic checkpoints, dysfunction that impairs fatty acid oxidation contributes hepatic steatosis ALD. Moreover, promotes accumulation damaged mitochondria release proinflammatory components, exacerbating Preserving presents promising approach mitigate progression. In this review, we provide comprehensive overview effects on function highlighting role pathogenesis. these mechanisms may pave way development novel interventions

Language: Английский

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Alcohol Use Disorder and the Gut–Brain Axis: A Narrative Review of the Role of Gut Microbiota and Implications for Treatment

Microorganisms, Journal Year: 2025, Volume and Issue: 13(1), P. 67 - 67

Published: Jan. 2, 2025

Alcohol use disorder (AUD) affects millions of people worldwide and can lead to deleterious physical social consequences. Recent research has highlighted not only the effect alcohol on gut microbiome, but also role microbiome gut-brain axis in development maintenance disorder. This review provides an overview reciprocal relationship between consumption including effects microbial composition, changes metabolites response consumption, how may modulate behavior. We discuss gut-mediated mechanisms neuroinflammation that contribute result from AUD, disruption intestinal barrier, toll-like receptor signaling, activation glial cells immune cells. Finally, we current evidence microbial-directed therapies for AUD implications this our understanding pathophysiology future directions.

Language: Английский

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Peripheral alcohol metabolism dictates ethanol consumption and drinking microstructure in mice

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 13, 2025

Abstract Background Ethanol metabolism is intimately linked with the physiological and behavioral aspects of ethanol consumption. mainly oxidized by alcohol dehydrogenase (ADH) to acetaldehyde further acetate via aldehyde dehydrogenases (ALDHs). Understanding how its metabolites work together initiate drive continued consumption crucial for identifying interventions use disorder (AUD). Therefore, goal our study was determine ADH1, which peripherally-expressed metabolizes >90% ingested ethanol, modulates metabolite distribution downstream behaviors. Methods in drinking-in-the-dark (DID) two-bottle choice (2BC) drinking paradigms, concentrations, lickometry were assessed after ADH1 inhibition and/or Adh1 -knockout ( KO) mice. Results We found that KO mice both sexes exhibited decreased preference compared wild-type (WT) DID 2BC. inhibitor fomepizole (4-MP) also significantly normal sweetened studies. Measurement revealed increased at 1h but not 15 min, peripheral slightly time points, ethanol-induced increases abolished administration controls. Similarly, accumulation as a function 2-fold higher or 4-MP treated then used this perturbation affects microstructure. consume most their first 30 min like WT display altered temporal shifts behaviors do form bout structures, resulting lower Conclusions Our demonstrates ADH1-mediated key determinant consumption, highlighting fundamental knowledge gap around

Language: Английский

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Peripheral alcohol metabolism dictates ethanol consumption and drinking microstructure in mice

Alcohol Clinical and Experimental Research, Journal Year: 2025, Volume and Issue: unknown

Published: March 21, 2025

Ethanol metabolism is intimately linked with the physiological and behavioral aspects of ethanol consumption. mainly oxidized by alcohol dehydrogenase (ADH) to acetaldehyde further acetate via aldehyde dehydrogenases (ALDHs). Understanding how its metabolites work together initiate drive continued consumption crucial for identifying interventions use disorder (AUD). Therefore, goal our study was determine ADH1, which peripherally expressed metabolizes >90% ingested ethanol, modulates metabolite distribution downstream behaviors. in drinking-in-the-dark (DID) two-bottle choice (2BC) drinking paradigms, concentrations, lickometry were assessed after ADH1 inhibition and/or Adh1-knockout (Adh1 KO) mice. We found that Adh1 KO mice both sexes exhibited decreased preference compared wild-type (WT) DID 2BC. inhibitor fomepizole (4-MP) also significantly normal sweetened studies. Measurement revealed increased at 1 h but not 15 min, peripheral slightly timepoints, ethanol-induced increases abolished administration controls. Similarly, accumulation as a function 2-fold higher or 4-MP-treated then used this perturbation affects microstructure. consume most their first 30 like WT mice, display altered temporal shifts behaviors do form bout structures, resulting lower Our demonstrates ADH1-mediated key determinant consumption, highlighting fundamental knowledge gap regarding

Language: Английский

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Alcohol-Metabolizing Enzymes, Liver Diseases and Cancer

Seminars in Liver Disease, Journal Year: 2025, Volume and Issue: unknown

Published: March 29, 2025

Alcohol is generally believed to be metabolized in the liver by alcohol dehydrogenase (ADH), aldehyde (ALDH), and a much lesser extent cytochrome P450 2E1 (CYP2E1) other enzymes. Recent studies suggest that gut also play important roles promotion of metabolism. ADH, ALDH, CYP2E1 have several polymorphisms markedly impact These alcohol-metabolizing enzymes not only affect alcohol-associated disease (ALD), but may modulate pathogenesis diseases cancer absence consumption. In this review, we discuss metabolism ALD, metabolic dysfunction–associated steatotic disease, dysfunction alcohol–associated viral hepatitis, cancer. We how endogenous ethanol production, affects Directions for future research on are elaborated.

Language: Английский

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Opposite regulation of intestinal and intrahepatic CD8⁺T cells controls alcohol-associated liver disease progression

Gut, Journal Year: 2025, Volume and Issue: unknown, P. gutjnl - 334412

Published: April 8, 2025

Background Gut-liver crosstalk plays an important role in alcohol-associated liver disease (ALD) pathogenesis; but underlying mechanisms remain obscure. Objective We examined the regulation of intestinal and intrahepatic CD8 + T lymphocytes their contribution to ALD. Design ALD patients were recruited for evaluation cells. Single-cell RNA sequencing (scRNA seq) was performed analyse peripheral cells Wildtype, CD8-specific Bcl2 transgenic ( Cd8 Bcl-2 ), −/− mice subjected chronic-plus-binge ethanol feeding. Results In patients, duodenal selectively reduced negatively correlated with injury bacterial translocation markers, while markedly increased. ScRNA seq analysis patient livers revealed several populations expressing activation survival genes (eg, ). Transcriptomics functional studies a key prosurvival BCL2 this opposite Mechanistically, feeding specifically duodenum where levels are high. Inducing reversed ethanol-induced loss cells, improved gut barrier function ameliorated ALD, deficiency linked enhanced neutrophil macrophage infiltration liver, exacerbating mice. Conclusions is associated elevation which aggravates ameliorates respectively. Restoration functions may represent novel therapeutic strategy patients.

Language: Английский

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An update on IL-22 therapies in alcohol-associated liver disease and beyond

American Journal Of Pathology, Journal Year: 2025, Volume and Issue: unknown

Published: April 1, 2025

Language: Английский

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