Workup and management of liver transplantation in alcohol-related liver disease.

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.

Alcohol-associated liver disease.

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.

Ethanol extracts of Isochrysis zhanjiangensis alleviate acute alcoholic liver injury and modulate intestinal bacteria dysbiosis in mice.

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.

Stress mechanism involved in the progression of alcoholic liver disease and the therapeutic efficacy of nanoparticles.

Alcoholic liver disease (ALD) poses a significant threat to human health, with excessive alcohol intake disrupting the immunotolerant environment of the liver and initiating a cascade of pathological events. This progressive disease unfolds through fat deposition, proinflammatory cytokine upregulation, activation of hepatic stellate cells, and eventual development of end-stage liver disease, known as hepatocellular carcinoma (HCC). ALD is intricately intertwined with stress mechanisms such as oxidative stress mediated by reactive oxygen species, endoplasmic reticulum stress, and alcohol-induced gut dysbiosis, culminating in increased inflammation. While the initial stages of ALD can be reversible with diligent care and abstinence, further progression necessitates alternative treatment approaches. Herbal medicines have shown promise, albeit limited by their poor water solubility and subsequent lack of extensive exploration. Consequently, researchers have embarked on a quest to overcome these challenges by delving into the potential of nanoparticle-mediated therapy. Nanoparticle-based treatments are being explored for liver diseases that share similar mechanisms with alcoholic liver disease. It underscores the potential of these innovative approaches to counteract the complex pathogenesis of ALD, providing new avenues for therapeutic intervention. Nevertheless, further investigations are imperative to fully unravel the therapeutic potential and unlock the promise of nanoparticle-mediated therapy specifically tailored for ALD treatment.

Alcohol and the mechanisms of liver disease.

Alcoholic liver disease (ALD), which is a leading cause of morbidity and mortality worldwide, covers a large spectrum of liver injuries ranging from simple steatosis to steatohepatitis, advanced fibrosis, cirrhosis, and hepatocellular carcinoma. The pathogenesis of ALD includes genetic and epigenetic alterations, oxidative stress, acetaldehyde-mediated toxicity and cytokine and chemokine-induced inflammation, metabolic reprogramming, immune damage, and dysbiosis of the gut microbiota. This review discusses the progress in the pathogenesis and molecular mechanism of ALD, which could provide evidence for further research on the potential therapeutic strategies targeting these pathways.

Immune dysregulation and pathophysiology of alcohol consumption and alcoholic liver disease.

Alcoholic liver disease (ALD) is a clinical-pathologic entity caused by the chronic excessive consumption of alcohol. The disease includes a broad spectrum of anomalies at the cellular and tissual level that can cause acute-on-chronic (alcoholic hepatitis) or chronic (fibrosis, cirrhosis, hepatocellular cancer) injury, having a great impact on morbidity and mortality worldwide. Alcohol is metabolized mainly in the liver. During alcohol metabolism, toxic metabolites, such as acetaldehyde and oxygen reactive species, are produced. At the intestinal level, alcohol consumption can cause dysbiosis and alter intestinal permeability, promoting the translocation of bacterial products and causing the production of inflammatory cytokines in the liver, perpetuating local inflammation during the progression of ALD. Different study groups have reported systemic inflammatory response disturbances, but reports containing a compendium of the cytokines and cells involved in the pathophysiology of the disease, from the early stages, are difficult to find. In the present review article, the role of the inflammatory mediators involved in ALD progression are described, from risky patterns of alcohol consumption to advanced stages of the disease, with the aim of understanding the involvement of immune dysregulation in the pathophysiology of ALD.

Effect of an Integrated Transplantation Mental Health Program on Alcohol Relapse After Liver Transplantation for Severe Alcoholic Hepatitis: A Single-Center Prospective Study.

BACKGROUND: Liver transplantation (LT) for severe alcohol-associated hepatitis (AH) remains controversial due to perceived increased recidivism risk after LT because of a lack of protracted abstinence before LT. Data on risk stratification for alcohol relapse after LT are limited. We sought to evaluate the utility of having a mental health program embedded in a transplantation center in risk assessment for alcohol relapse-free patient survival after LT. METHODS: We conducted a prospective analysis of all patients with a diagnosis of severe AH hospitalized at a single transplant center from April 2015 to April 2020. After a comprehensive mental health risk stratification, patients were either waitlisted for LT or declined for waitlisting. The primary endpoint was alcohol relapse-free patient survival rate for those who received LT. The secondary endpoint compared survival rates between patients who received LT and those who did not. The median follow-up was 10 months. RESULTS: Among the 83 patients included in the study, 54 patients were waitlisted for LT (65%, group 1) and 29 were declined (35%, group 2). Patient characteristics and median Model for End-Stage Liver Disease score on presentation were comparable for both cohorts (36 in group 1, 38 in group 2; P = .8). Group 1 had significantly better Stanford Integrated Psychosocial Assessment for Transplantation total scores (median 40 vs 57; P < .01), presence of social support (100% of patients in group 1 vs 76% in group 2; P < .01), and less prevalence of active tobacco smokers (30% in group 1 vs 66% in group 2; P < .01). For those who were not waitlisted, 72.5% experienced rapid deterioration of hepatic function. Among the 54 patients waitlisted, 29 patients received LT (54%), whereas 19 died while on the waiting list (35%). One- and 3-year patient survival after LT were 92.5% and 92.5%, respectively. The overall and sustained alcohol relapse rates after LT were 10.3% and 3.5%, respectively. CONCLUSION: Severe AH is a complex medical and mental health disease and requires an intense risk assessment for recidivism after LT. Our study shows that an integrated transplantation mental health program provides an accurate risk stratification for alcohol relapse after LT, a successful intervention to mitigate recidivism risk, and optimal short-term alcohol relapse-free patient survival. Future studies should focus on enhancing the guidelines for broader application.

The effect of Lactobacillus rhamnosus B10 on alcoholic liver injury and intestinal microbiota in alcohol-induced mice model.

Lactobacillus rhamnosus B10 (L. rhamnosus B10) isolated from the baby feces was given to an alcohol mice model, aiming to investigate the effects of L. rhamnosus B10 on alcoholic liver injury by regulating intestinal microbiota. C57BL/6N mice were fed with liquid diet Lieber-DeCarli with or without 5% (v/v) ethanol for 8 weeks, and treated with L. rhamnosus B10 at the last 2 weeks. The results showed that L. rhamnosus B10 decreased the serum total cholesterol (1.48 mmol/L), triglycerides (0.97 mmol/L), alanine aminotransferase (26.4 U/L), aspartate aminotransferase (14.2 U/L), lipopolysaccharide (0.23 EU/mL), and tumor necrosis factor-α (138 pg/mL). In addition, L. rhamnosus B10 also reduced the liver triglycerides (1.02 mmol/g prot), alanine aminotransferase (17.8 mmol/g prot) and aspartate aminotransferase (12.5 mmol/g prot) in alcohol mice, thereby ameliorating alcohol-induced liver injury. The changes of intestinal microbiota composition on class, family and genus level in cecum were analyzed. The intestinal symbiotic abundance of Firmicutes was elevated while gram-negative bacteria Proteobacteria and Deferribacteres was decreased in alcohol mice treated with L. rhamnosus B10 for 2 weeks. In summary, this study provided evidence for the therapeutic effects of probiotics on alcoholic liver injury by regulating intestinal flora.

Alcoholic liver disease: a new insight into the pathogenesis of liver disease.

Excessive alcohol consumption contributes to a broad clinical spectrum of liver diseases, from simple steatosis to end-stage hepatocellular carcinoma. The liver is the primary organ that metabolizes ingested alcohol and is exquisitely sensitive to alcohol intake. Alcohol metabolism is classified into two pathways: oxidative and non-oxidative alcohol metabolism. Both oxidative and non-oxidative alcohol metabolisms and their metabolites have toxic consequences for multiple organs, including the liver, adipose tissue, intestine, and pancreas. Although many studies have focused on the effects of oxidative alcohol metabolites on liver damage, the importance of non-oxidative alcohol metabolites in cellular damage has also been discovered. Furthermore, extrahepatic alcohol effects are crucial for providing additional information necessary for the progression of alcoholic liver disease. Therefore, studying the effects of alcohol-producing metabolites and interorgan crosstalk between the liver and peripheral organs that express ethanol-metabolizing enzymes will facilitate a comprehensive understanding of the pathogenesis of alcoholic liver disease. This review focuses on alcohol-metabolite-associated hepatotoxicity due to oxidative and non-oxidative alcohol metabolites and the role of interorgan crosstalk in alcoholic liver disease pathogenesis.

Skeletal muscle satellite cell-derived mesenchymal stem cells ameliorate acute alcohol-induced liver injury.

Cultured human skeletal-muscle satellite cells have properties of mesenchymal stem cells (skeletal muscle satellite cell-derived mesenchymal stem cells, SkMSCs) and play anti-inflammatory roles by secreting prostaglandin E2 and hepatocyte growth factor (HGF). To evaluate the utility of SkMSCs in treating liver diseases, we determined whether SkMSCs could ameliorate acute liver and gut inflammation induced by binge ethanol administration. Binge drinking of ethanol led to weight loss in the body and spleen, liver inflammation and steatosis, and increased serum ALT and AST levels (markers of liver injury), along with increased IL-1ß, TNF-α, and iNOS expression levels in mice. However, levels of these binge-drinking-induced indicators were reduced by a single intraperitoneal treatment of SkMSCs. Furthermore, levels of bacteria-derived lipopolysaccharide decreased in the livers and sera of ethanol-exposed mice after SkMSC administration. SkMSCs decreased the extent of tissue inflammation and reduced villus and crypt lengths in the small intestine after alcohol binge drinking. SkMSCs also reduced the leakage of blood albumin, an indicator of leaky gut, in the stool of ethanol-exposed mice. Alcohol-induced damage to human colonic Caco-2/tc7 cells was also alleviated by HGF. Therefore, a single treatment with SkMSCs can attenuate alcoholic liver damage by reducing inflammatory responses in the liver and gut, suggesting that SkMSCs could be used in cell therapy to treat alcoholic liver diseases.

CRIg on liver macrophages clears pathobionts and protects against alcoholic liver disease.

Complement receptor of immunoglobulin superfamily (CRIg) is expressed on liver macrophages and directly binds complement component C3b or Gram-positive bacteria to mediate phagocytosis. CRIg plays important roles in several immune-mediated diseases, but it is not clear how its pathogen recognition and phagocytic functions maintain homeostasis and prevent disease. We previously associated cytolysin-positive Enterococcus faecalis with severity of alcohol-related liver disease. Here, we demonstrate that CRIg is reduced in liver tissues from patients with alcohol-related liver disease. CRIg-deficient mice developed more severe ethanol-induced liver disease than wild-type mice; disease severity was reduced with loss of toll-like receptor 2. CRIg-deficient mice were less efficient than wild-type mice at clearing Gram-positive bacteria such as Enterococcus faecalis that had translocated from gut to liver. Administration of the soluble extracellular domain CRIg-Ig protein protected mice from ethanol-induced steatohepatitis. Our findings indicate that ethanol impairs hepatic clearance of translocated pathobionts, via decreased hepatic CRIg, which facilitates progression of liver disease.

A New Perspective on Fish Oil: The Prevention of Alcoholic Liver Disease.

The mechanisms of alcoholic liver diseases (ALD) are very complex and interrelated, including abnormal lipid metabolism, oxidative stress, and gut-derived endotoxin pathway. On the other hand, fish oil is rich in n-3 polyunsaturated fatty acids (PUFAs), such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), which decrease blood triglyceride concentration in hypertriglycemia patients and show protective effects against fatty liver. However, there is limited evidence from studies of the relationship between fish oil and ALD based on the viewpoint of the intestinal integrity and microflora. Therefore, this review discusses the mechanism of amelioration for ALD by fish oil. Based on our previous studies, partial replacement of olive oil by fish oil in alcohol-containing liquid diet ameliorated the liver damage including fatty liver and inflammation in rats. Based on these results, the mechanisms of hepatoprotective effects due to fish oil substitution were discussed in three parts, such as regulating lipid metabolism, decreasing oxidative stress and maintaining intestinal health. First of all, we found that fish oil substitution increased plasma adiponectin levels, and then increasing MCAD and CPT-1 mRNA levels to accelerate fatty acid oxidation in liver, then further prevent ethanol-induced hepatosteatosis in rats with chronic alcohol-feeding. Fish oil replacement also enhanced hepatic autophagy flux, which enhanced lipid degradation, then inhibited lipid accumulation in liver. Secondly, the appreciable proportion of fish oil decreased lipid peroxidation by reducing the protein expression of cytochrome p450 2E1 in chronic alcohol-feeding rats. We also speculated that the appropriate proportion of n-6 and n-3 PUFAs is very important for preventing alcoholic liver disease. At last, substituting fish oil for olive oil normalized the intestinal permeability and fecal microbiota composition, thus providing a low plasma endotoxin level and inflammatory responses, which exert ameliorative effects on ethanol-induced liver injuries in rats.

Arbutin attenuates ethanol-induced acute hepatic injury by the modulation of oxidative stress and Nrf-2/HO-1 signaling pathway.

Alcoholic liver disease (ALD) is a pervasive ailment due to the excessive consumption of alcohol and there is no operative drug for its treatment. The current exploration was intended to examine the hepatoprotective efficacy of arbutin against ethanol-provoked liver injury in rats via the modulation of the Nrf-2/HO-1 signaling cascade. Wistar rats were challenged with the 3 g/kg/day (40% v/v) of ethanol for 4 weeks to provoke the ALD and concomitantly supplemented with 40 mg/kg of arbutin. The liver function markers enzymes, inflammatory cytokines, and oxidative stress markers levels were scrutinized by using the respective assay kits. The mRNA expression of Nrf-2/HO-1 signaling proteins was studied by reverse-transcription polymerase chain reaction. The histological alterations of liver tissues were examined. HepG2 cells were used for the in vitro studies. The levels of oxidative stress markers and liver marker enzymes were examined by using kits. Reactive oxygen species (ROS) and apoptotic cell death was detected by using fluorescent staining. There were no major differences in the body weight and liver weight of experimental animals. Arbutin treatment appreciably reduced the liver marker enzymes, upregulated superoxide dismutase, glutathione peroxidase, total antioxidant capacity, and the hydroxyl scavenging ability, and diminished the tumor necrosis factor-α and interleukin-6 levels in the serum of ethanol provoked animals. Arbutin triggered Nrf-2/HO-1 signaling cascade liver tissues of ethanol-provoked animals. Histological findings proved the preventing effects of arbutin. Arbutin did not demonstrate toxicity to the HepG2 cells. It reduced the aspartate aminotransferase and alanine aminotransferase, ROS, apoptotic cell death, lipid peroxidation and improved the antioxidants' levels in the ethanol-challenged HepG2 cells. In conclusion, our findings unveiled the hepatoprotective efficacy of arbutin against ethanol-provoked liver injury in rats. It could be a promising agent to treat alcoholic liver disease in the future.

Pathophysiological Aspects of Alcohol Metabolism in the Liver.

Alcoholic liver disease (ALD) is a globally prevalent chronic liver disease caused by chronic or binge consumption of alcohol. The liver is the major organ that metabolizes alcohol; therefore, it is particularly sensitive to alcohol intake. Metabolites and byproducts generated during alcohol metabolism cause liver damage, leading to ALD via several mechanisms, such as impairing lipid metabolism, intensifying inflammatory reactions, and inducing fibrosis. Despite the severity of ALD, the development of novel treatments has been hampered by the lack of animal models that fully mimic human ALD. To overcome the current limitations of ALD studies and therapy development, it is necessary to understand the molecular mechanisms underlying alcohol-induced liver injury. Hence, to provide insights into the progression of ALD, this review examines previous studies conducted on alcohol metabolism in the liver. There is a particular focus on the occurrence of ALD caused by hepatotoxicity originating from alcohol metabolism.

Alcohol-Related Liver Disease: Basic Mechanisms and Clinical Perspectives.

Alcohol-related liver disease (ALD) refers to the liver damage occurring due to excessive alcohol consumption and involves a broad spectrum of diseases that includes liver steatosis, steatohepatitis, hepatitis, cirrhosis, and hepatocellular carcinoma (HCC). The progression of ALD is mainly associated with the amount and duration of alcohol usage; however, it is also influenced by genetic, epigenetic, and environmental factors. The definite diagnosis of ALD is based on a liver biopsy, although several non-invasive diagnostic tools and serum biomarkers have emerging roles in the early detection of ALD. While alcohol abstinence and nutritional support remain the cornerstone of ALD treatment, growing evidence has revealed that the therapeutic agents that target oxidative stress or gut-liver axis, inflammatory response inhibition, and liver regeneration enhancement also play a role in ALD management. Furthermore, microRNAs modulation and mesenchymal stem cell-based therapy have emerging potential as ALD therapeutic options. This review summarizes the updated understanding of the pathophysiology, diagnosis, and novel therapeutic approaches for ALD.

CD39-mediated ATP-adenosine signalling promotes hepatic stellate cell activation and alcoholic liver disease.

CD39 is associated with diverse physiological and pathological processes, including cell proliferation and differentiation. Adenosine triphosphate (ATP) is hydrolysed to adenosine by different enzymes including ecto-nucleoside triphosphate diphosphohydrolase-1/ENTPD1 (CD39) and ecto-5'-nucleotidase (CD73), regulating many physiological and pathological processes in various diseases, but these changes and functions in alcoholic liver disease are generally unknown. In this study, an alcoholic liver disease model in vivo was induced by ethanol plus carbon tetrachloride(CCl4) administered to C57BL/6 mice, who were the intraperitoneally injected with the CD39 inhibitor sodium polyoxotungstate (POM1) or colchicine from the 5th week to the 8th week. Meanwhile, hepatic stellate cells were stimulated by acetaldehyde to replicate alcoholic liver fibrosis models in vitro. Exogenous ATP and POM1 were added in turn to the culture system. Pharmacological blockade of CD39 largely prevents liver damage and collagen deposition. We found that blockade or silencing of CD39 prevented acetaldehyde-induced proliferation of HSC-T6 cells and the expression of fibrogenic factors. Moreover, blockade or silencing of CD39 could block the activation of the adenosine A2A and adenosine A2B receptors and the TGF-ß/Smad3 pathway, which are essential events in HSC activation. Thus, blockade of CD39 to inhibit the transduction of ATP to adenosine may prevent HSC activation, alleviating alcoholic hepatic fibrosis. The findings from this study suggest ATP-adenosine signalling is a novel therapeutic and preventive target for alcoholic liver disease.

Arrb2 causes hepatic lipid metabolism disorder via AMPK pathway based on metabolomics in alcoholic fatty liver.

BACKGROUND AND AIMS: Alcoholic fatty liver (AFL) is an early form of alcoholic liver disease (ALD) that usually manifests as lipid synthesis abnormalities in hepatocytes. ß-arrestin2 (Arrb2) is involved in multiple biological processes. The present study aimed to explore the role of Arrb2 in the regulation of lipid metabolism in AFL and the underlying mechanism and identify potential targets for the treatment of AFL. METHODS: The expression of Arrb2 was detected in liver tissues obtained from AFL patients and Gao-binge AFL model mice. In addition, we specifically knocked down Arrb2 in AFL mouse liver in vivo and used Arrb2-siRNA or pEX3-Arrb2 to silence or overexpress Arrb2 in AML-12 cells in vitro to explore the functional role and underlying regulatory mechanism of Arrb2 in AFL. Finally, we investigated whether Arrb2 could cause changes in hepatic lipid metabolites, thereby leading to dysregulation of lipid metabolism based on liquid chromatography-mass spectrometry (LC-MS) analysis. RESULTS: Arrb2 was up-regulated in the livers of AFL patients and AFL mice. The in vivo and in vitro results confirmed that Arrb2 could induce lipid accumulation and metabolism disorders. Mechanistically, Arrb2 induced hepatic metabolism disorder via AMP-activated protein kinase (AMPK) pathway. The results of LC-MS analysis revealed that hepatic lipid metabolites with the most significant differences were primary bile acids. CONCLUSIONS: Arrb2 induces hepatic lipid metabolism disorders via AMPK pathway in AFL. On one hand, Arrb2 increases fatty acid synthesis. On the other hand, Arrb2 could increase the cholesterol synthesis, thereby leading to the up-regulation of primary bile acid levels.

Ubiquitin-specific protease 22 ameliorates chronic alcohol-associated liver disease by regulating BRD4.

Alcohol-associated liver disease (ALD) is a liver system disease caused by alcohol abuse, and it involves complex processes ranging from steatosis to fibrosis, cirrhosis and hepatocellular carcinoma. Steatosis and inflammation are the main phenomena involved in ALD. Ubiquitin-specific protease 22 (USP22) plays an important role in liver steatosis; however, its functional contribution to ALD remains unclear. USP22-silenced mice were fed a Lieber-DeCarli liquid diet. AML-12 and HEK293T cells were used to detect the interaction between USP22 and BRD4. Here, we report that hepatic USP22 expression was dramatically upregulated in mice with ALD. Inflammation and steatosis were significantly ameliorated following USP22 silencing in vivo, as indicated by decreased IL-6 and IL-1ß levels. We further showed that the overexpression of USP22 increased inflammation, while knocking down BRD4 suppressed the inflammatory response in AML-12 cells. Notably, USP22 functioned as a BRD4 deubiquitinase to facilitate BRD4 inflammatory functions. More importantly, the expression levels of USP22 and BRD4 in patients with ALD were significantly increased. In conclusion, USP22 acts a key pathogenic factor in ALD by deubiquitinating BRD4, which facilitates the inflammatory response and aggravates ALD.

Alcohol-induced Hsp90 acetylation is a novel driver of liver sinusoidal endothelial dysfunction and alcohol-related liver disease.

BACKGROUND & AIMS: Liver sinusoidal endothelial cell (LSEC) dysfunction has been reported in alcohol-related liver disease, yet it is not known whether LSECs metabolize alcohol. Thus, we investigated this, as well as the mechanisms of alcohol-induced LSEC dysfunction and a potential therapeutic approach for alcohol-induced liver injury. METHODS: Primary human, rat and mouse LSECs were used. Histone deacetylase 6 (HDAC6) was overexpressed specifically in liver ECs via adeno-associated virus (AAV)-mediated gene delivery to decrease heat shock protein 90 (Hsp90) acetylation in ethanol-fed mice. RESULTS: LSECs expressed CYP2E1 and alcohol dehydrogenase 1 (ADH1) and metabolized alcohol. Ethanol induced CYP2E1 in LSECs, but not ADH1. Alcohol metabolism by CYP2E1 increased Hsp90 acetylation and decreased its interaction with endothelial nitric oxide synthase (eNOS) leading to a decrease in nitric oxide (NO) production. A non-acetylation mutant of Hsp90 increased its interaction with eNOS and NO production, whereas a hyperacetylation mutant decreased NO production. These results indicate that Hsp90 acetylation is responsible for decreases in its interaction with eNOS and eNOS-derived NO production. AAV8-driven HDAC6 overexpression specifically in liver ECs deacetylated Hsp90, restored Hsp90's interaction with eNOS and ameliorated alcohol-induced liver injury in mice. CONCLUSION: Restoring LSEC function is important for ameliorating alcohol-induced liver injury. To this end, blocking acetylation of Hsp90 specifically in LSECs via AAV-mediated gene delivery has the potential to be a new therapeutic strategy. LAY SUMMARY: Alcohol metabolism in liver sinusoidal endothelial cells (LSECs) and the mechanism of alcohol-induced LSEC dysfunction are largely unknown. Herein, we demonstrate that LSECs can metabolize alcohol. We also uncover a mechanism by which alcohol induces LSEC dysfunction and liver injury, and we identify a potential therapeutic strategy to prevent this.

Mulberry leaves extract ameliorates alcohol-induced liver damages through reduction of acetaldehyde toxicity and inhibition of apoptosis caused by oxidative stress signals.

Mulberry leaves (Morus alba L.), which are traditional Chinese herbs, exert several biological functions, such as antioxidant, anti-inflammation, antidiabetic, and antitumor. Alcohol intake increases inflammation and oxidative stress, and this increase causes liver injury and leads to liver steatosis, cirrhosis, and hepatocellular carcinoma, which are major health problems worldwide. Previous report indicated that mulberry leaf extract (MLE) exited hepatoprotection effects against chronic alcohol-induced liver damages. In this present study, we investigated the effects of MLE on acute alcohol and liver injury induced by its metabolized compound called acetaldehyde (ACE) by using in vivo and in vitro models. Administration of MLE reversed acute alcohol-induced liver damages, increased acetaldehyde (ACE) level, and decreased aldehyde dehydrogenase activity in a dose-dependent manner. Acute alcohol exposure-induced leukocyte infiltration and pro-inflammation factors, including cyclooxygenase-2 (COX-2), tumor necrosis factor-α (TNF-α), and interleukin-6 (IL-6), were blocked by MLE in proportion to MLE concentration. MLE prevented alcohol-induced liver apoptosis via enhanced caveolin-1 expression and attenuated EGFR/STAT3/iNOS pathway using immunohistochemical analysis. ACE induced proteins, such as iNOS, COX-2, TNF-α, and IL-6, and inhibited superoxide dismutase expression, whereas co-treated with MLE reversed these proteins expression. MLE also recovered alcohol-induced apoptosis in cultured Hep G2 cells. Overall, our findings indicated that MLE ameliorated acute alcohol-induced liver damages by reducing ACE toxicity and inhibiting apoptosis caused by oxidative stress signals. Our results implied that MLE might be a potential agent for treating alcohol liver disease.