Hepatic Proteomic Changes Associated with Liver Injury Caused by Alcohol Consumption in Mice.

Alcohol-associated liver disease (ALD) is a prevalent medical problem with limited effective treatment strategies. Although many biological processes contributing to ALD have been elucidated, a complete understanding of the underlying mechanisms is still lacking. The current study employed a proteomic approach to identify hepatic changes resulting from ethanol (EtOH) consumption and the genetic ablation of the formyl peptide receptor 2 (FPR2), a G-protein coupled receptor known to regulate multiple signaling pathways and biological processes, in a mouse model of ALD.

Steroid responsiveness in alcohol-associated hepatitis is linked to glucocorticoid metabolism, mitochondrial repair, and heat shock proteins.

Background: Alcohol-associated hepatitis (AH) is one of the clinical presentations of alcohol-associated liver disease. AH has poor prognosis, and corticosteroids remain the mainstay of drug therapy. However, ~40% of patients do not respond to this treatment, and the mechanisms underlying the altered response to corticosteroids are not understood.

Hepatic Transcriptome and Its Regulation Following Soluble Epoxide Hydrolase Inhibition in Alcohol-Associated Liver Disease.

Alcohol-associated liver disease (ALD) is a serious public health problem with limited pharmacologic options. The goal of the current study was to investigate the efficacy of pharmacologic inhibition of soluble epoxide hydrolase (sEH), an enzyme involved in lipid metabolism, in experimental ALD, and to examine the underlying mechanisms. C57BL/6J male mice were subjected to acute-on-chronic ethanol (EtOH) feeding with or without the sEH inhibitor 4-[[trans-4-[[[[4-trifluoromethoxy phenyl]amino]carbonyl]-amino]cyclohexyl]oxy]-benzoic acid (TUCB).

Drinking and laboratory biomarkers, and nutritional status characterize the clinical presentation of early-stage alcohol-associated liver disease.

Chronic and heavy alcohol consumption is commonly observed in alcohol use disorder (AUD). AUD often leads to alcohol-associated organ injury, including alcohol-associated liver disease (ALD). Approximately 10-20% of patients with AUD progress to ALD.

Mice Developed Exacerbated Alcohol-Associated Liver Disease.

Alcohol-associated liver disease (ALD) is the most common chronic liver disease and carries a significant healthcare burden. ALD has no long-term treatment options aside from abstinence, and the mechanisms that contribute to its pathogenesis are not fully understood. This study aimed to investigate the role of formyl peptide receptor 2 (FPR2), a receptor for immunomodulatory signals, in the pathogenesis of ALD.

Resolvin D1 attenuated liver injury caused by chronic ethanol and acute LPS challenge in mice.

Alcohol-associated liver disease (ALD) is a major health problem with limited effective treatment options. Alcohol-associated hepatitis (AH) is a subset of severe ALD with a high rate of mortality due to infection, severe inflammation, and ultimately multi-organ failure. There is an urgent need for novel therapeutic approaches to alleviate the human suffering associated with this condition.

The environmental pollutant, polychlorinated biphenyl 126, alters liver function in a rodent model of alcohol-associated liver disease.

Background: The prevalence of alcohol-associated liver disease (ALD), a subtype of fatty liver disease (FLD), continues to rise. ALD is a major cause of preventable death. Polychlorinated biphenyl (PCB) 126 is an environmentally relevant, dioxin-like pollutant whose negative metabolic effects have been well documented.

Liver-specific drug delivery platforms: Applications for the treatment of alcohol-associated liver disease.

Alcohol-associated liver disease (ALD) is a common chronic liver disease and major contributor to liver disease-related deaths worldwide. Despite its pre-valence, there are few effective pharmacological options for the severe stages of this disease. While much pre-clinical research attention is paid to drug development in ALD, many of these experimental therapeutics have limitations such as poor pharmacokinetics, poor efficacy, or off-target side effects due to systemic administration.

Analysis of alcohol use, consumption of micronutrient and macronutrients, and liver health in the 2017-2018 National Health and Nutrition Examination Survey.

Background: Alcohol use is a major global healthcare burden that contributes to numerous adverse health outcomes, including liver disease. Many factors influence individual susceptibility to alcohol-associated diseases, including nutritional factors. The objective of the current study was to examine inter-relations among alcohol, dietary micronutrients and macronutrient consumption, and liver health by analyzing data from the 2017-2018 National Health and Nutrition Examination Survey (NHANES).

Human Beta Defensin 2 Ameliorated Alcohol-Associated Liver Disease in Mice.

Alcohol-associated liver disease (ALD) is a prevalent liver disorder and significant global healthcare burden with limited effective therapeutic options. The gut-liver axis is a critical factor contributing to susceptibility to liver injury due to alcohol consumption. In the current study, we tested whether human beta defensin-2 (hBD-2), a small anti-microbial peptide, attenuates experimental chronic ALD.

Feeding mice a diet high in oxidized linoleic acid metabolites does not alter liver oxylipin concentrations.

The oxidation of dietary linoleic acid (LA) produces oxidized LA metabolites (OXLAMs) known to regulate multiple signaling pathways in vivo. Recently, we reported that feeding OXLAMs to mice resulted in liver inflammation and apoptosis. However, it is not known whether this is due to a direct effect of OXLAMs accumulating in the liver, or to their degradation into bioactive shorter chain molecules (e.

Linoleic Acid-Derived Oxylipins Differentiate Early Stage Alcoholic Hepatitis From Mild Alcohol-Associated Liver Injury.

Alcohol-associated liver disease (ALD) is a spectrum of liver disorders ranging from steatosis to steatohepatitis, fibrosis, and cirrhosis. Alcohol-associated hepatitis (AH) is an acute and often severe form of ALD with substantial morbidity and mortality. The mechanisms and mediators of ALD progression and severity are not well understood, and effective therapeutic options are limited.

Polychlorinated biphenyls altered gut microbiome in CAR and PXR knockout mice exhibiting toxicant-associated steatohepatitis.

Polychlorinated biphenyls (PCBs) are persistent organic pollutants associated with non-alcoholic fatty liver disease (NAFLD). Previously, we demonstrated that the PCB mixture, Aroclor1260, exacerbated NAFLD, reflective of toxicant-associated steatohepatitis, in diet-induced obese mice, in part through pregnane-xenobiotic receptor (PXR) and constitutive androstane receptor (CAR) activation. Recent studies have also reported PCB-induced changes in the gut microbiome that consequently impact NAFLD.

Ileum Gene Expression in Response to Acute Systemic Inflammation in Mice Chronically Fed Ethanol: Beneficial Effects of Elevated Tissue n-3 PUFAs.

Chronic alcohol consumption leads to disturbances in intestinal function which can be exacerbated by inflammation and modulated by different factors, e.g., polyunsaturated fatty acids (PUFAs).

Beneficial effects of an endogenous enrichment in n3-PUFAs on Wnt signaling are associated with attenuation of alcohol-mediated liver disease in mice.

Alcohol-associated liver disease (ALD) is a major human health issue for which there are limited treatment options. Experimental evidence suggests that nutrition plays an important role in ALD pathogenesis, and specific dietary fatty acids, for example, n6 or n3-PUFAs, may exacerbate or attenuate ALD, respectively. The purpose of the current study was to determine whether the beneficial effects of n3-PUFA enrichment in ALD were mediated, in part, by improvement in Wnt signaling.

Transcriptional signatures of the small intestinal mucosa in response to ethanol in transgenic mice rich in endogenous n3 fatty acids.

The intestine interacts with many factors, including dietary components and ethanol (EtOH), which can impact intestinal health. Previous studies showed that different types of dietary fats can modulate EtOH-induced changes in the intestine; however, mechanisms underlying these effects are not completely understood. Here, we examined intestinal transcriptional responses to EtOH in WT and transgenic fat-1 mice (which endogenously convert n6 to n3 polyunsaturated fatty acids [PUFAs]) to identify novel genes and pathways involved in EtOH-associated gut pathology and discern the impact of n3 PUFA enrichment.

Mechanisms of Environmental Contributions to Fatty Liver Disease.

Purpose: Fatty liver disease (FLD) affects over 25% of the global population and may lead to liver-related mortality due to cirrhosis and liver cancer. FLD caused by occupational and environmental chemical exposures is termed "toxicant-associated steatohepatitis" (TASH). The current review addresses the scientific progress made in the mechanistic understanding of TASH since its initial description in 2010.

Mechanisms, biomarkers and targets for therapy in alcohol-associated liver injury: From Genetics to nutrition: Summary of the ISBRA 2018 symposium.

The symposium "Mechanisms, Biomarkers and Targets for Therapy in Alcohol-associated Liver Injury: From Genetics to Nutrition" was held at the 19th Congress of International Society for Biomedical Research on Alcoholism on September 13th, 2018 in Kyoto, Japan. The goal of the symposium was to discuss the importance of genetics and nutrition in alcoholic liver disease (ALD) development from mechanistic and therapeutic perspectives. The following is a summary of this session addressing the gene polymorphisms in ALD, the role of zinc in gut-liver axis perturbations associated with ALD, highlighting the importance of dietary fat in ALD pathogenesis, the hepatic n6 and n3 PUFA oxylipin pattern associated with ethanol-induced liver injury, and finally deliberating on new biomarkers for alcoholic hepatitis and their implications for diagnosis and therapy.

Ethanol and unsaturated dietary fat induce unique patterns of hepatic ω-6 and ω-3 PUFA oxylipins in a mouse model of alcoholic liver disease.

Alcoholic liver disease (ALD), a significant health problem, progresses through the course of several pathologies including steatosis, steatohepatitis, fibrosis, and cirrhosis. There are no effective FDA-approved medications to prevent or treat any stages of ALD, and the mechanisms involved in ALD pathogenesis are not well understood. Bioactive lipid metabolites play a crucial role in numerous pathological conditions, as well as in the induction and resolution of inflammation.

Oxidized linoleic acid metabolites induce liver mitochondrial dysfunction, apoptosis, and NLRP3 activation in mice.

Circulating oxidized linoleic acid (LA) metabolites (OXLAMs) are increased in patients with nonalcoholic steatohepatitis (NASH) and their levels correlate with disease severity. However, the mechanisms by which OXLAMs contribute to NASH development are incompletely understood. We tested the hypothesis that LA or OXLAMs provided directly through the diet are involved in the development of hepatic injury.

Effects of diets enriched in linoleic acid and its peroxidation products on brain fatty acids, oxylipins, and aldehydes in mice.

Background: Linoleic acid (LA) is abundant in modern industrialized diets. Oxidized LA metabolites (OXLAMs) and reactive aldehydes, such as 4-hydroxy-2-nonenal (4-HNE), are present in heated vegetable oils and can be endogenously synthesized following consumption of dietary LA. OXLAMs have been implicated in cerebellar degeneration in chicks; 4-HNE is linked to neurodegenerative conditions in mammals.

Role of Nutrition in Alcoholic Liver Disease: Summary of the Symposium at the ESBRA 2017 Congress.

The symposium, "Role of Nutrition in Alcoholic Liver Disease", was held at the European Society for Biomedical Research on Alcoholism Congress on 9 October 2017 in Crete, Greece. The goal of the symposium was to highlight recent advances and developments in the field of alcohol and nutrition. The symposium was focused on experimental and clinical aspects in relation to the role of different types of dietary nutrients and malnutrition in the pathogenesis of alcoholic liver disease (ALD).

Rodent Models of Alcoholic Liver Disease: Role of Binge Ethanol Administration.

Both chronic and acute (binge) alcohol drinking are important health and economic concerns worldwide and prominent risk factors for the development of alcoholic liver disease (ALD). There are no FDA-approved medications to prevent or to treat any stage of ALD. Therefore, discovery of novel therapeutic strategies remains a critical need for patients with ALD.