ABSTRACT
BACKGROUND AND AIMS: Methionine adenosyltransferase alpha1 (MATα1) is responsible for the biosynthesis of S-adenosylmethionine in normal liver. Alcohol consumption enhances MATα1 interaction with peptidyl-prolyl cis-trans isomerase NIMA-interacting 1 (PIN1), which blocks MATα1 mitochondrial targeting, resulting in lower mitochondrial MATα1 content and mitochondrial dysfunction in alcohol-associated liver disease (ALD) in part through upregulation of cytochrome P450 2E1. Conversely, alcohol intake enhances SUMOylation, which enhances cytochrome P450 2E1 expression. MATα1 has potential SUMOylation sites, but whether MATα1 is regulated by SUMOylation in ALD is unknown. Here, we investigated if MATα1 is regulated by SUMOylation and, if so, how it impacts mitochondrial function in ALD. APPROACH AND RESULTS: Proteomics profiling revealed hyper-SUMOylation of MATα1, and prediction software identified lysine 48 (K48) as the potential SUMOylation site in mice (K47 in humans). Experiments with primary hepatocytes, mouse, and human livers revealed that SUMOylation of MAT1α by SUMO2 depleted mitochondrial MATα1. Furthermore, mutation of MATα1 K48 prevented ethanol-induced mitochondrial membrane depolarization, MATα1 depletion, and triglyceride accumulation. Additionally, CRISPR/CRISPR associated protein 9 gene editing of MATα1 at K48 hindered ethanol-induced MATα1-PIN1 interaction, degradation, and phosphorylation of MATα1 in vitro. In vivo, CRISPR/CRISPR associated protein 9 MATα1 K48 gene-edited mice were protected from ethanol-induced fat accumulation, liver injury, MATα1-PIN1 interaction, mitochondrial MATα1 depletion, mitochondrial dysfunction, and low S-adenosylmethionine levels. CONCLUSIONS: Taken together, our findings demonstrate an essential role for SUMOylation of MATα1 K48 for interaction with PIN1 in ALD. Preventing MATα1 K48 SUMOylation may represent a potential treatment strategy for ALD.
Subject(s)
Liver Diseases, Alcoholic , Methionine Adenosyltransferase , Sumoylation , Methionine Adenosyltransferase/metabolism , Methionine Adenosyltransferase/genetics , Animals , Mice , Liver Diseases, Alcoholic/metabolism , Liver Diseases, Alcoholic/etiology , Liver Diseases, Alcoholic/genetics , Humans , Mitochondria, Liver/metabolism , Male , Hepatocytes/metabolism , Liver/metabolismABSTRACT
Alcohol-associated liver disease poses a significant global health burden, with rising alcohol consumption and prevalence of alcohol use disorder (AUD) contributing to increased morbidity and mortality. This review examines the challenges and opportunities in the care of candidates and recipients of liver transplant (LT) with AUD. Despite advancements in posttransplant patient survival, the risk of disease recurrence and alcohol relapse remains substantial. Several challenges have been identified, including (1) rising disease burden of alcohol-associated liver disease, variable transplant practices, and systemic barriers; (2) disparities in mental health therapy access and the impact on transplant; (3) variable definitions, underdiagnosis, and stigma affecting access to care; and (4) post-LT relapse, its risk factors, and consequential harm. The review focuses on the opportunities to improve AUD care for candidates and recipients of LT through effective biochemical monitoring, behavioral and pharmacologic approaches, creating Centers of Excellence for post-LT AUD care, advocating for policy reforms, and ensuring insurance coverage for necessary services as essential steps toward improving patient outcomes. The review also highlights unmet needs, such as the scarcity of addiction specialists, and calls for further research on personalized behavioral treatments, digital health, and value-based care models to optimize AUD care in the LT setting.
Subject(s)
Alcoholism , Liver Diseases, Alcoholic , Liver Transplantation , Humans , Liver Transplantation/adverse effects , Liver Transplantation/standards , Liver Diseases, Alcoholic/surgery , Liver Diseases, Alcoholic/therapy , Liver Diseases, Alcoholic/epidemiology , Liver Diseases, Alcoholic/diagnosis , Liver Diseases, Alcoholic/etiology , Alcoholism/complications , Alcoholism/therapy , Alcoholism/epidemiology , Risk Factors , Health Services Accessibility , Recurrence , Healthcare Disparities , Prevalence , Transplant Recipients/statistics & numerical data , Alcohol Drinking/adverse effects , Alcohol Drinking/epidemiology , End Stage Liver Disease/surgery , End Stage Liver Disease/diagnosis , End Stage Liver Disease/therapy , End Stage Liver Disease/complications , End Stage Liver Disease/mortalityABSTRACT
Understanding the role of iron in ethanol-derived hepatic stress could help elucidate the efficacy of dietary or clinical interventions designed to minimize liver damage from chronic alcohol consumption. We hypothesized that normal levels of iron are involved in ethanol-derived liver damage and reduced dietary iron intake would lower the damage caused by ethanol. We used a pair-fed mouse model utilizing basal Lieber-DeCarli liquid diets for 22 weeks to test this hypothesis. In our mouse model, chronic ethanol exposure led to mild hepatic stress possibly characteristic of early-stage alcoholic liver disease, seen as increases in liver-to-body weight ratios. Dietary iron restriction caused a slight decrease in non-heme iron and ferritin (FeRL) expression while it increased transferrin receptor 1 (TfR1) expression without changing ferroportin 1 (FPN1) expression. It also elevated protein lysine acetylation to a more significant level than in ethanol-fed mice under normal dietary iron conditions. Interestingly, iron restriction led to an additional reduction in nicotinamide adenine dinucleotide (NAD+) and NADH levels. Consistent with this observation, the major mitochondrial NAD+-dependent deacetylase, NAD-dependent deacetylase sirtuin-3 (SIRT3), expression was significantly reduced causing increased protein lysine acetylation in ethanol-fed mice at normal and low-iron conditions. In addition, the detection of superoxide dismutase 1 and 2 levels (SOD1 and SOD2) and oxidative phosphorylation (OXPHOS) complex activities allowed us to evaluate the changes in antioxidant and energy metabolism regulated by ethanol consumption at normal and low-iron conditions. We observed that the ethanol-fed mice had mild liver damage associated with reduced energy and antioxidant metabolism. On the other hand, iron restriction may exacerbate certain activities of ethanol further, such as increased protein lysine acetylation and reduced antioxidant metabolism. This metabolic change may prove a barrier to the effectiveness of dietary reduction of iron intake as a preventative measure in chronic alcohol consumption.
Subject(s)
Antioxidants , Energy Metabolism , Ethanol , Animals , Mice , Acetylation/drug effects , Energy Metabolism/drug effects , Antioxidants/metabolism , Male , Iron/metabolism , Superoxide Dismutase-1/metabolism , Superoxide Dismutase-1/genetics , Superoxide Dismutase/metabolism , Lysine/metabolism , Liver/metabolism , Liver/drug effects , Receptors, Transferrin/metabolism , Sirtuin 3/metabolism , Sirtuin 3/genetics , NAD/metabolism , Ferritins/metabolism , Cation Transport Proteins/metabolism , Cation Transport Proteins/genetics , Oxidative Stress/drug effects , Mice, Inbred C57BL , Liver Diseases, Alcoholic/metabolism , Liver Diseases, Alcoholic/pathology , Liver Diseases, Alcoholic/etiologyABSTRACT
BACKGROUND: Alcoholic liver disease (ALD) is responsible for 3.3 million deaths per annum. Efficacious therapeutic modalities or drug treatments for ALD have not yet been found, so it is urgent to seek new agents for preventing ALD and its related disease. Many experiments have indicated that modulating the gut microbiota and regulating the toll-like receptor 4 (TLR4)/nuclear transcription factor-κB (NF-κB) inflammatory pathway can provide a new target for prevention and treatment of ALD. Marine microalgae have their natural metabolic pathways to synthesize various of bioactive compounds as promising candidates for hepatoprotection. In this study, we investigated ethanol extracts from Isochrysis zhanjiangensis (EEIZ) to evaluate their ability to alleviate acute alcoholic liver injury, regulate TLR4/NF-κB inflammatory pathway and modulate intestinal bacteria dysbiosis in mice for ALD treatment. RESULTS: In the acute ALD mouse model, EEIZ reduced levels of aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, triacylglyceride, total cholesterol and low-density lipoprotein, while increasing the level of high-density lipoprotein. Besides, TLR4, myeloid differentiation factor 88, NF-κB and tumor necrosis factor-α expression levels in liver tissue were effectively downregulated by EEIZ. Furthermore, treatment with EEIZ enhanced intestinal homeostasis and significantly alleviated the damage caused by alcohol. CONCLUSION: EEIZ showed effective hepatoprotective activity against alcohol-induced acute liver injury in mice as it could alleviate hepatocyte damage, suppress the TLR4/NF-κB inflammatory pathway and regulate the intestinal flora structure. EEIZ could be a good candidate for preventing acute alcoholic liver injury. © 2024 Society of Chemical Industry.
Subject(s)
Haptophyta , Liver Diseases, Alcoholic , Mice , Animals , Ethanol/metabolism , Toll-Like Receptor 4/genetics , Toll-Like Receptor 4/metabolism , Toll-Like Receptor 4/therapeutic use , Haptophyta/metabolism , NF-kappa B/genetics , NF-kappa B/metabolism , Dysbiosis/drug therapy , Dysbiosis/metabolism , Liver/metabolism , Liver Diseases, Alcoholic/etiology , Bacteria/metabolism , Mice, Inbred C57BLABSTRACT
Alcohol-related liver disease (ALD) represents the most common indication for liver transplantation (LT) worldwide. Outcomes of LT for ALD are comparable with those of LT for other etiologies; however, ALD is still considered a controversial indication for LT, mainly because it is considered a self-inflicted disease with a high risk of return to alcohol use after LT. Pre-LT evaluation criteria have changed over time, with a progressive re-evaluation of the required pre-transplant duration of abstinence. Despite the fact that some transplant programs still require 6 months of abstinence in order to consider a patient suitable for LT, there is increasing evidence that a pre-transplant abstinence period of <6 months can be considered for well-selected patients. Early LT for severe alcohol-related hepatitis that has not responded to medical therapy has been shown to be an effective therapeutic option with high survival benefit when performed within strict and well-recognized criteria. However, high variability in LT access exists for these patients due to the presence of social and medical stigma. A psycho-social assessment, together with an evaluation by an addiction specialist, should be mandatory in patients with ALD who are potential candidates for LT in order to assess the risk of post-transplant return to alcohol use and to ensure good long-term outcomes. Finally, before LT, attention should be paid to the presence of other potential comorbidities (i.e., cardiovascular and neurological diseases), which could represent a potential contraindication to LT. Similarly, after LT, patients should be adequately monitored for the development of cardiovascular events and screened for "de novo" tumors, although standardized protocols for this monitoring do not exist at this time.
Subject(s)
Hepatitis, Alcoholic , Liver Diseases, Alcoholic , Liver Transplantation , Humans , Liver Diseases, Alcoholic/diagnosis , Liver Diseases, Alcoholic/etiology , Liver Diseases, Alcoholic/surgery , Alcohol Abstinence , Recurrence , Alcohol Drinking/adverse effects , Alcohol Drinking/epidemiologyABSTRACT
Alcoholic liver disease (ALD) is currently, worldwide, the second most common cause of human fatalities every year. Alcohol use disorders (AUDs) lead to 80% of hepatotoxic deaths, and about 40% of cases of cirrhosis are alcohol-related. An acceptable daily intake (ADI) of ethanol is hard to establish and studies somewhat controversially recommend a variety of dosages of ADI, whilst others regard any intake as dangerous. Steatohepatitis should be viewed as "the rate limiting step": generally, it can be overcome by abstinence, although in some patients, abstinence has little effect, with the risk of fibrosis, leading in some cases to hepatocellular carcinoma (HCC). Chronic alcoholism can also cause hypercortisolism, specifically pseudo-Cushing Syndrome, whose diagnosis is challenging. If fibrosis is spotted early, patients may be enrolled in detoxification programs to achieve abstinence. Treatment drugs include silybin, metadoxine and adenosyl methionine. Nutrition and the proper use of micronutrients are important, albeit often overlooked in ALD treatment. Other drugs, with promising antifibrotic effects, are now being studied. This review deals with the clinical and pathogenetic aspects of alcohol-related liver fibrosis and suggests possible future strategies to prevent cirrhosis.
Subject(s)
Alcoholism , Humans , Alcoholism/complications , Liver Cirrhosis/etiology , Liver Cirrhosis, Alcoholic/complications , Liver Cirrhosis, Alcoholic/etiology , Liver Diseases, Alcoholic/etiology , Liver Diseases, Alcoholic/complicationsABSTRACT
Alcohol-associated liver disease (ALD) is a major contributor to liver-related mortality globally. An increasing body of evidence underscores the pivotal role of platelets throughout the spectrum of liver injury and recovery, offering unique insights into liver homeostasis and pathobiology. Alcoholic-associated steatohepatitis is characterized by the infiltration of hepatic neutrophils. Recent studies have highlighted the extensive distance neutrophils travel through sinusoids to reach the liver injury site, relying on a platelet-paved endothelium for efficient crawling. The adherence of platelets to neutrophils is crucial for accurate migration from circulation to the inflammatory site. A gradual decline in platelet levels leads to diminished neutrophil recruitment. Platelets exhibit the ability to activate neutrophils. Platelet activation is heightened upon the release of platelet granule contents, which synergistically activate neutrophils through their respective receptors. The sequence culminates in the formation of platelet-neutrophil complexes and the release of neutrophil extracellular traps intensifies liver damage, fosters inflammatory immune responses, and triggers hepatotoxic processes. Neutrophil infiltration is a hallmark of alcohol-associated steatohepatitis, and the roles of neutrophils in ALD pathogenesis have been studied extensively, however, the involvement of platelets in ALD has received little attention. The current review consolidates recent findings on the intricate and diverse roles of platelets and neutrophils in liver pathophysiology and in ALD. Potential therapeutic strategies are highlighted, focusing on targeting platelet-neutrophil interactions and activation in ALD. The anticipation is that innovative methods for manipulating platelet and neutrophil functions will open promising avenues for future ALD therapy.
Subject(s)
Blood Platelets , Liver Diseases, Alcoholic , Neutrophils , Humans , Neutrophils/immunology , Neutrophils/metabolism , Neutrophils/pathology , Blood Platelets/metabolism , Blood Platelets/pathology , Liver Diseases, Alcoholic/pathology , Liver Diseases, Alcoholic/immunology , Liver Diseases, Alcoholic/metabolism , Liver Diseases, Alcoholic/etiology , Animals , Neutrophil Infiltration , Liver/pathology , Liver/immunology , Liver/metabolism , Cell Communication , Platelet ActivationABSTRACT
BACKGROUND: APOH plays an essential role in lipid metabolism and the transport of lipids in the circulation. Previous studies have shown that APOH deficiency causes fatty liver and gut microbiota dysbiosis in mouse models. However, the role and potential mechanisms of APOH deficiency in the pathogenesis of alcoholic liver disease remain unclear. METHODS: C57BL/6 WT and ApoH-/- mice were used to construct the binge-on-chronic alcohol feeding model. Mouse liver transcriptome, targeted bile acid metabolome, and 16S gut bacterial taxa were assayed and analyzed. Open-source human liver transcriptome dataset was analyzed. RESULTS: ApoH-/- mice fed with alcohol showed severe hepatic steatosis. Liver RNAseq and RT-qPCR data indicated that APOH deficiency predominantly impacts hepatic lipid metabolism by disrupting de novo lipogenesis, cholesterol processing, and bile acid metabolism. A targeted bile acid metabolomics assay indicated significant changes in bile acid composition, including increased percentages of TCA in the liver and DCA in the gut of alcohol-fed ApoH-/- mice. The concentrations of CA, NorCA, and HCA in the liver were higher in ApoH-/- mice on an ethanol diet compared to the control mice (p < 0.05). Additionally, APOH deficiency altered the composition of gut flora, which correlated with changes in the liver bile acid composition in the ethanol-feeding mouse model. Finally, open-source transcript-level data from human ALD livers highlighted a remarkable link between APOH downregulation and steatohepatitis, as well as bile acid metabolism. CONCLUSION: APOH deficiency aggravates alcohol induced hepatic steatosis through the disruption of gut microbiota homeostasis and bile acid metabolism in mice.
Subject(s)
Bile Acids and Salts , Dysbiosis , Gastrointestinal Microbiome , Lipid Metabolism , Liver Diseases, Alcoholic , Animals , Humans , Male , Mice , Bile Acids and Salts/metabolism , Disease Models, Animal , Dysbiosis/metabolism , Dysbiosis/microbiology , Dysbiosis/chemically induced , Liver/metabolism , Liver/pathology , Liver Diseases, Alcoholic/metabolism , Liver Diseases, Alcoholic/microbiology , Liver Diseases, Alcoholic/pathology , Liver Diseases, Alcoholic/genetics , Liver Diseases, Alcoholic/etiology , Mice, Inbred C57BL , Mice, KnockoutABSTRACT
BACKGROUND: Environmental pollutants, including polychlorinated biphenyls (PCBs) have been implicated in the pathogenesis of liver disease. Our group recently demonstrated that PCB126 promoted steatosis, hepatomegaly, and modulated intermediary metabolism in a rodent model of alcohol-associated liver disease (ALD). OBJECTIVE: To better understand how PCB126 promoted ALD in our previous model, the current study adopts multiple omics approaches to elucidate potential mechanistic hypotheses. METHODS: Briefly, male C57BL/6J mice were exposed to 0.2mg/kg polychlorinated biphenyl (PCB) 126 or corn oil vehicle prior to ethanol (EtOH) or control diet feeding in the chronic-binge alcohol feeding model. Liver tissues were collected and prepared for mRNA sequencing, phosphoproteomics, and inductively coupled plasma mass spectrometry for metals quantification. RESULTS: Principal component analysis showed that PCB126 uniquely modified the transcriptome in EtOH-fed mice. EtOH feeding alone resulted in >4,000 differentially expressed genes (DEGs), and PCB126 exposure resulted in more DEGs in the EtOH-fed group (907 DEGs) in comparison with the pair-fed group (503 DEGs). Top 20 significant gene ontology (GO) biological processes included "peptidyl tyrosine modifications," whereas top 25 significantly decreasing GO molecular functions included "metal/ion/zinc binding." Quantitative, label-free phosphoproteomics and western blot analysis revealed no major significant PCB126 effects on total phosphorylated tyrosine residues in EtOH-fed mice. Quantified hepatic essential metal levels were primarily significantly lower in EtOH-fed mice. PCB126-exposed mice had significantly lower magnesium, cobalt, and zinc levels in EtOH-fed mice. DISCUSSION: Previous work has demonstrated that PCB126 is a modifying factor in metabolic dysfunction-associated steatotic liver disease (MASLD), and our current work suggests that pollutants also modify ALD. PCB126 may, in part, be contributing to the malnutrition aspect of ALD, where metal deficiency is known to contribute and worsen prognosis. https://doi.org/10.1289/EHP14132.
Subject(s)
Environmental Pollutants , Fatty Liver , Liver Diseases, Alcoholic , Polychlorinated Biphenyls , Male , Mice , Animals , Multiomics , Mice, Inbred C57BL , Ethanol/toxicity , Ethanol/metabolism , Liver/metabolism , Polychlorinated Biphenyls/toxicity , Polychlorinated Biphenyls/metabolism , Liver Diseases, Alcoholic/etiology , Liver Diseases, Alcoholic/metabolism , Liver Diseases, Alcoholic/pathology , Environmental Pollutants/toxicity , Environmental Pollutants/metabolism , Zinc/metabolism , Tyrosine/metabolismABSTRACT
Alcohol-associated liver disease (ALD) is a major cause of chronic liver disease worldwide, and comprises a spectrum of several different disorders, including simple steatosis, steatohepatitis, cirrhosis, and superimposed hepatocellular carcinoma. Although tremendous progress has been made in the field of ALD over the last 20 years, the pathogenesis of ALD remains obscure, and there are currently no FDA-approved drugs for the treatment of ALD. In this Review, we discuss new insights into the pathogenesis and therapeutic targets of ALD, utilizing the study of multiomics and other cutting-edge approaches. The potential translation of these studies into clinical practice and therapy is deliberated. We also discuss preclinical models of ALD, interplay of ALD and metabolic dysfunction, alcohol-associated liver cancer, the heterogeneity of ALD, and some potential translational research prospects for ALD.
Subject(s)
Carcinoma, Hepatocellular , Fatty Liver , Liver Diseases, Alcoholic , Liver Neoplasms , Humans , Liver Diseases, Alcoholic/drug therapy , Liver Diseases, Alcoholic/etiology , Liver Diseases, Alcoholic/pathology , Ethanol , Fatty Liver/metabolism , Liver Cirrhosis/pathology , Carcinoma, Hepatocellular/etiology , Carcinoma, Hepatocellular/metabolism , Liver Neoplasms/etiology , Liver Neoplasms/metabolism , Liver/metabolismABSTRACT
It is elusive why some heavy drinkers progress to severe alcohol-related liver disease (ALD) while others do not. This study aimed to investigate if the association between alcohol consumption and severe ALD is modified by diet. This prospective study included 303,269 UK Biobank participants. Alcohol consumption and diet were self-reported. The diet score was created from 4 items selected using LASSO. Cox proportional hazard model showed that the diet score was monotonically associated with severe ALD risk, adjusted for sociodemographics, lifestyle factors, and alcohol consumption. Relative excess risk due to interaction analysis indicated that having a higher ALD diet score and a higher alcohol consumption simultaneously confers to 2.44 times (95% CI: 1.06-3.83) higher risk than the sum of excess risk of each factor. In this work, we show that people who have a poor diet might be more susceptible to severe ALD due to alcohol consumption.
Subject(s)
Alcohol Drinking , Diet , Liver Diseases, Alcoholic , Humans , Alcohol Drinking/adverse effects , Alcohol Drinking/epidemiology , Male , Female , Middle Aged , Liver Diseases, Alcoholic/epidemiology , Liver Diseases, Alcoholic/etiology , Prospective Studies , Diet/adverse effects , Incidence , United Kingdom/epidemiology , Proportional Hazards Models , Aged , Adult , Risk FactorsABSTRACT
BACKGROUND: Chronic excessive use of alcohol is an important risk factor for several health and social conditions. METHODS: A cross-sectional survey, in a sample representative of the Brazilian population,was conducted to evaluate the frequency of consumption of alcoholic beverages and behaviors concerning liver diseases. Participants were prospectively interviewed using a questionnaire regarding alcohol consumption and actions toward liver health. The study accepted at most one sampling error of ±2 percentage points and considered a 95% confidence interval. RESULTS: One thousand nine hundred ninety-five subjects (1.048 women, mean age 44 years) from all Brazilian regions were interviewed. Most of the Brazilian subjects believe that alcohol abuse (63-87%) is the leading cause of cirrhosis and liver cancer, however, most responders (56%) had never been screened to assess liver damage related to alcohol consumption. A total of 55% of Brazilians drink alcoholic beverages. Among Brazilians who drink alcoholic beverages, 44% consume three or more drinks at a time, 11% consume more than 10 doses a day. Among those who consume 1 to 2 drinks a day, women (42%) consume more than men (32%) and more than the national average (37%). CONCLUSION: There is a high frequency of alcohol consumption, especially among young people, and individuals from lower social classes, with frequent consumption among women. Despite the knowledge of its adverse impact on liver health, less than half of the Brazilians have been evaluated at least once for liver disease. Education and prevention strategies need to be implemented to reduce theharmful use of alcohol.
Subject(s)
Alcohol Drinking , Socioeconomic Factors , Humans , Female , Male , Brazil/epidemiology , Adult , Alcohol Drinking/epidemiology , Alcohol Drinking/adverse effects , Cross-Sectional Studies , Middle Aged , Young Adult , Risk Factors , Liver Diseases, Alcoholic/epidemiology , Liver Diseases, Alcoholic/etiology , Prospective Studies , Surveys and Questionnaires , Aged , AdolescentABSTRACT
BACKGROUND & AIMS: Excessive alcohol consumption can lead to alcohol-associated liver disease, a spectrum of conditions ranging from steatosis to fibrosis and cirrhosis. Bile acids regulate metabolic pathways by binding to cellular and nuclear receptors, and they also interact with the gut microbiome to control microbial overgrowth. Fibroblast growth factor 19 (FGF-19) is an ileum-derived hormone induced and released in response to bile acid activation of the nuclear receptor farnesoid X receptor. FGF-19 signaling is dysregulated with ethanol consumption and is increased in patients with alcoholic hepatitis. Here, we examined the effects of FGF-19 in a mouse model of chronic + binge ethanol feeding. METHODS: After injection of adeno-associated virus-green fluorescent protein or AAV-FGF-19, female C57BL/6J mice were pair-fed a Lieber DeCarli liquid diet (5% v/v) or control diet for 10 days and were given a bolus gavage of 5% ethanol or maltose control to represent a binge drinking episode. Tissues were collected for analysis 9 hours after the binge. RESULTS: Chronic + binge ethanol feeding induced steatosis regardless of FGF-19 expression. Interestingly, FGF-19 and ethanol resulted in significantly increased liver inflammation, as measured by Il6, Tgfß, and Tnfα, compared with ethanol alone. Both ethanol and FGF-19 decreased bile acid synthesis, and FGF-19 significantly reduced secondary bile acids, leading to overgrowth of specific pathogenic bacteria including Enterococcus faecalis, Escherichia coli, and Clostridium perfringens. CONCLUSIONS: Dysregulation of FGF-19 and consequent changes in bile acid synthesis and composition during alcohol consumption may be a contributing factor to alcohol-induced liver disease and dysbiosis.
Subject(s)
Bile Acids and Salts , Disease Models, Animal , Dysbiosis , Ethanol , Fibroblast Growth Factors , Liver Diseases, Alcoholic , Animals , Fibroblast Growth Factors/metabolism , Bile Acids and Salts/metabolism , Dysbiosis/microbiology , Dysbiosis/pathology , Dysbiosis/chemically induced , Mice , Female , Liver Diseases, Alcoholic/pathology , Liver Diseases, Alcoholic/metabolism , Liver Diseases, Alcoholic/microbiology , Liver Diseases, Alcoholic/etiology , Ethanol/adverse effects , Ethanol/toxicity , Gastrointestinal Microbiome/drug effects , Mice, Inbred C57BL , Liver/metabolism , Liver/pathology , Binge Drinking/complications , Binge Drinking/pathology , Binge Drinking/metabolism , HumansABSTRACT
BACKGROUND: Alcohol-associated liver disease (ALD) is a leading cause of liver-related morbidity and mortality, but there are no therapeutic targets and modalities to prevent ALD-related liver fibrosis. Peroxisome proliferator activated receptor (PPAR) α and δ play a key role in lipid metabolism and intestinal barrier homeostasis, which are major contributors to the pathological progression of ALD. Meanwhile, elafibranor (EFN), which is a dual PPARα and PPARδ agonist, has reached a phase III clinical trial for the treatment of metabolic dysfunction-associated steatotic liver disease and primary biliary cholangitis. However, the benefits of EFN for ALD treatment is unknown. AIM: To evaluate the inhibitory effects of EFN on liver fibrosis and gut-intestinal barrier dysfunction in an ALD mouse model. METHODS: ALD-related liver fibrosis was induced in female C57BL/6J mice by feeding a 2.5% ethanol (EtOH)-containing Lieber-DeCarli liquid diet and intraperitoneally injecting carbon tetrachloride thrice weekly (1 mL/kg) for 8 weeks. EFN (3 and 10 mg/kg/day) was orally administered during the experimental period. Histological and molecular analyses were performed to assess the effect of EFN on steatohepatitis, fibrosis, and intestinal barrier integrity. The EFN effects on HepG2 lipotoxicity and Caco-2 barrier function were evaluated by cell-based assays. RESULTS: The hepatic steatosis, apoptosis, and fibrosis in the ALD mice model were significantly attenuated by EFN treatment. EFN promoted lipolysis and ß-oxidation and enhanced autophagic and antioxidant capacities in EtOH-stimulated HepG2 cells, primarily through PPARα activation. Moreover, EFN inhibited the Kupffer cell-mediated inflammatory response, with blunted hepatic exposure to lipopolysaccharide (LPS) and toll like receptor 4 (TLR4)/nuclear factor kappa B (NF-κB) signaling. EFN improved intestinal hyperpermeability by restoring tight junction proteins and autophagy and by inhibiting apoptosis and proinflammatory responses. The protective effect on intestinal barrier function in the EtOH-stimulated Caco-2 cells was predominantly mediated by PPARδ activation. CONCLUSION: EFN reduced ALD-related fibrosis by inhibiting lipid accumulation and apoptosis, enhancing hepatocyte autophagic and antioxidant capacities, and suppressing LPS/TLR4/NF-κB-mediated inflammatory responses by restoring intestinal barrier function.
Subject(s)
Chalcones , Disease Models, Animal , Intestinal Mucosa , Liver Cirrhosis , Liver Diseases, Alcoholic , Mice, Inbred C57BL , PPAR alpha , Animals , Mice , Humans , Female , Liver Diseases, Alcoholic/pathology , Liver Diseases, Alcoholic/metabolism , Liver Diseases, Alcoholic/prevention & control , Liver Diseases, Alcoholic/etiology , Liver Diseases, Alcoholic/drug therapy , PPAR alpha/metabolism , PPAR alpha/agonists , Chalcones/pharmacology , Liver Cirrhosis/pathology , Liver Cirrhosis/chemically induced , Liver Cirrhosis/metabolism , Liver Cirrhosis/drug therapy , Liver Cirrhosis/prevention & control , Intestinal Mucosa/drug effects , Intestinal Mucosa/pathology , Intestinal Mucosa/metabolism , Caco-2 Cells , Liver/pathology , Liver/drug effects , Liver/metabolism , Ethanol/toxicity , Apoptosis/drug effects , Lipid Metabolism/drug effects , PPAR delta/agonists , PPAR delta/metabolism , Signal Transduction/drug effects , Oxidative Stress/drug effects , PropionatesSubject(s)
HMGB1 Protein , Liver Diseases, Alcoholic , Oxidation-Reduction , HMGB1 Protein/metabolism , Humans , Liver Diseases, Alcoholic/pathology , Liver Diseases, Alcoholic/metabolism , Liver Diseases, Alcoholic/immunology , Liver Diseases, Alcoholic/etiology , Animals , Inflammation/pathology , MiceABSTRACT
La enfermedad por hígado graso no alcohólico es la primera causa de hepatopatía en los países occidentales. La fase inicial de la enfermedad se caracteriza por esteatosis hepática, que puede evolucionar a esteatohepatitis no alcohólica y finalmente a cirrosis. La principal causa de mortalidad en estos pacientes es la enfermedad cardiovascular, seguida del cáncer y de la propia hepatopatía
Non-alcoholic fatty liver disease is the first cause of liver disease in western countries. The initial phase of the disease is characterised by liver steatosis, which may progress to non-alcoholic steatohepatitis and finally to cirrhosis. The main cause of mortality in these patients is cardiovascular disease, followed by cancer and the liver disease itself
Subject(s)
Humans , Fatty Liver/epidemiology , Non-alcoholic Fatty Liver Disease/epidemiology , Risk Factors , Liver Diseases, Alcoholic/etiology , Natural History , Fatty Liver/mortalityABSTRACT
Alcohol-related liver disease (ALD) is the most frequent cause of advanced chronic liver disease worldwide. Excessive and prolonged alcohol use leads to ALD, which ranges from early forms such as alcoholic fatty liver (AFL) and alcoholic steatohepatitis (ASH), through progressive fibrosis to cirrhosis and the development of hepatocellular cancer (HCC). In addition, patients with underlying ALD and continuous alcohol use can develop alcoholic hepatitis (AH), which presents a rapid progression of liver failure and has a high short-term mortality. Genetic, environmental and epigenetic factors influence the progression of ALD to more severe forms. The pathogenesis of ALD is complex and involves multiple pathways. Recent translational studies have demonstrated a key role of the gut-liver axis and innate immunity in hepatocellular damage and fibrosis. In severe forms, hepatocellular de-differentiation and systemic inflammation contribute to liver failure and multiorgan failure. Alcohol abstinence is the cornerstone of therapy for ALD and the prevention of its complications, but the efficacy and accessibility of psycho-familial-social interventions is still poor and effective public health policies to limit problematic alcohol use need to be implemented. Prednisolone is the only current option for AH, with a transient beneficial effect over placebo. For patients with decompensated ALD-cirrhosis and/or development of HCC, liver transplantation (LT) may be required. In recent years, early LT is being increasingly offered to carefully selected AH patients, with excellent long-term survival. New trials of AH treatments are currently ongoing, and translational studies in human samples are paving the way to new promising targeted therapies
No disponible
Subject(s)
Humans , Liver Diseases, Alcoholic/etiology , Liver Diseases, Alcoholic/therapy , Disease Management , Medical Illustration , Disease Progression , Liver Diseases, Alcoholic/metabolismABSTRACT
Estudo transversal e descritivo, desenvolvido em unidade neonatal de um hospital público de ensino do estado de São Paulo, Brasil, em que se objetivou verificar a percepção das mães quanto aos filhos recém-nascidos hospitalizados. A amostra foi constituída por 100 mulheres, questionadas, por meio do Inventário de Percepção Neonatal de Broussard, sobre quanta dificuldade esperavam que os bebês da unidade, em geral, apresentassem para comportamentos como: chorar; alimentar; regurgitar ou vomitar; evacuar; dormir e estabelecer uma rotina. Em seguida, as mesmas perguntas foram repetidas sobre o próprio filho. Noventa mães consideraram os filhos com menos dificuldades que os outros bebês da unidade. As mulheres mais jovens e as mães de bebês com maiores pesos tenderam a considerar seus filhos com mais dificuldade. O Inventário é de fácil aplicação e pode ser útil no processo de avaliação da interação mãe-filho, embora seu resultado não possa ser considerado de forma isolada.
Cross-sectional descriptive study conducted in the neonatal unit of a public teaching hospital in the state of São Paulo, Brazil, which aimed to determine the perceptions of mothers about their newborns hospitalized children. The sample consisted of 100 women questioned, through the Neonatal Perception Inventory Broussard, about how much trouble was expected to be presented by babies of the general unit, on behaviors such as crying; feeding; regurgitate or vomit; evacuate; sleep and have a routine. Then, the same questions were repeated about their own babies. Ninety mothers considered their children with fewer difficulties than other babies at the unit. Younger women and mothers of infants with higher weights tended to consider their children with more difficulty. The Inventory is easy to apply and may be useful in the evaluation of mother-child interaction, although its result cannot be considered in isolation.
Estudio descriptivo transversal realizado en la unidad neonatal de un hospital público de enseñanza en el estado de São Paulo, Brasil, que tuve como objetivo determinar las percepciones de las madres con respecto a sus hijos recién nacidos hospitalizados. La muestra consistió en 100 mujeres a quien, a través del Inventario de Percepción Neonatal Broussard, se preguntó por la cantidad de problemas esperaban que los bebés de la unidad general presentasen respecto a comportamientos como el llanto; alimentos; regurgitar o vomitar; evacuar; dormir y establecer una rutina. Entonces, las mismas preguntas se repitieron a respecto de su propio hijo. Noventa madres consideraran a sus hijos con menos dificultad que los otros bebés en la unidad. Las mujeres más jóvenes y las madres de los recién nacidos con pesos mayores tendían a ver a sus hijos con más dificultades. El inventario es fácil de aplicar y puede ser útil en la evaluación del proceso de interacción madre-hijo, aunque sus resultados no pueden ser considerados aisladamente.