New advances in molecular mechanisms and emerging therapeutic targets in alcoholic liver diseases

Alcoholic liver disease is a major health problem in the United States and worldwide. Chronic alcohol consumption can cause steatosis, inflammation, fibrosis, cirrhosis and even liver cancer. Significant progress has been made to understand key events and molecular players for the onset and progression of alcoholic liver disease from both experimental and clinical alcohol studies. No successful treatments are currently available for treating alcoholic liver disease; therefore, development of novel pathophysiological-targeted therapies is urgently needed. This review summarizes the recent progress on animal models used to study alcoholic liver disease and the detrimental factors that contribute to alcoholic liver disease pathogenesis including miRNAs, S-adenosylmethionine, Zinc deficiency, cytosolic lipin-1β, IRF3-mediated apoptosis, RIP3-mediated necrosis and hepcidin. In addition, we summarize emerging adaptive protective effects induced by alcohol to attenuate alcohol-induced liver pathogenesis including FoxO3, IL-22, autophagy and nuclear lipin-1α.

Intestinal virome:An important research direction for alcoholic and nonalcoholic liver diseases

In recent years,the interaction between the gut microflora and liver diseases has attracted much attention.The intestinal microflora is composed of bacteria,archaea,fungi and viruses.There are few studies on the intestinal virome,and whether it has a causal relationship with bacterial changes in the gut is still unclear.However,it is undeniable that the intestinal virome is also a very important portion of the blueprint for the development of liver diseases and the diagnosis and therapeutic modalities in the future.

Protective mechanism of Coprinus comatus polysaccharide on acute alcoholic liver injury in mice,the metabolomics and gut microbiota investigation

Coprinus comatus polysaccharide(CCP)has significant hepatoprotective effect.To explore hepatoprotective mechanism of CCP,the study analyzed preventive effect of CCP on acute alcoholic liver injury in mice by histopathological examination and biochemical analysis.Simultaneously,hepatoprotective mechanism was also analyzed in conjunction with metabolomics and proliferation of gut microbiota.The results showed that CCP significantly decreased alanine aminotransferase(ALT),aspartate aminotransferase(AST)and triglyceride(TG)levels in serum of alcoholic liver disease(ALD)mice.Histopathological examination showed that CCP can significantly improve liver damage.Metabolomics results showed that there were significant differences in the level of metabolites in liver tissue of control group,ALD group and CCP group,including taurine,xanthosine,fumaric acid and arachidonic acid,among others.Metabolites pathways analysis showed that hepatoprotective effect of CCP was related to energy metabolism,biosynthesis of unsaturated fatty acids,amino acids metabolism and lipid metabolism.Additionally,CCP inhibited an increase in the number of Clostridium perfringens,Enterobacteriaceae and Enterococcus,and a decrease in the number of Lactobacillus and Bifidobacterium in the gut of ALD mice.All these findings suggested that CCP treatment reversed the phenotype of ethanol-induced liver injury and the associated metabolites pathways.

Significance of gut microbiota in alcoholic and non-alcoholic fatty liver diseases

Liver-gut communication is vital in fatty liver diseases,and gut microbes are the key regulators in maintaining liver homeostasis.Chronic alcohol abuse and persistent overnutrition create dysbiosis in gut ecology,which can contribute to fatty liver disease.In this review,we discuss the gut microbial compositional changes that occur in alcoholic and nonalcoholic fatty liver diseases and how this gut microbial dysbiosis and its metabolic products are involved in fatty liver disease pathophysiology.We also summarize the new approaches related to gut microbes that might help in the diagnosis and treatment of fatty liver disease.

Elafibranor:A promising treatment for alcoholic liver disease,metabolic-associated fatty liver disease,and cholestatic liver disease

Liver diseases pose a significant threat to human health.Although effective therapeutic agents exist for some liver diseases,there remains a critical need for advancements in research to address the gaps in treatment options and improve patient outcomes.This article reviews the assessment of Elafibranor's effects on liver fibrosis and intestinal barrier function in a mouse model of alcoholic liver disease(ALD),as reported by Koizumi et al in the World Journal of Gastroenterology.We summarize the impact and mechanisms of Elafibranor on ALD,metabolic-associated fatty liver disease,and cholestatic liver disease based on current research.We also explore its potential as a dual agonist of PPARα/δ,which is undergoing Phase III clinical trials for metabolic-associated steatohepatitis.Our goal is to stimulate further investigation into Elafibranor's use for preventing and treating these liver diseases and to provide insights for its clinical application.

Peroxisome proliferator-activated receptor agonists:A new hope towards the management of alcoholic liver disease

In this editorial,we examine a paper by Koizumi et al,on the role of peroxisome proliferator-activated receptor(PPAR)agonists in alcoholic liver disease(ALD).The study determined whether elafibranor protected the intestinal barrier and reduced liver fibrosis in a mouse model of ALD.The study also underlines the role of PPARs in intestinal barrier function and lipid homeostasis,which are both affected by ALD.Effective therapies are necessary for ALD because it is a critical health issue that affects people worldwide.This editorial analyzes the possibility of PPAR agonists as treatments for ALD.As key factors of inflammation and metabolism,PPARs offer multiple methods for managing the complex etiology of ALD.We assess the abilities of PPARα,PPARγ,and PPARβ/δagonists to prevent steatosis,inflammation,and fibrosis due to liver diseases.Recent research carried out in preclinical and clinical settings has shown that PPAR agonists can reduce the severity of liver disease.This editorial discusses the data analyzed and the obstacles,advantages,and mechanisms of action of PPAR agonists for ALD.Further research is needed to understand the efficacy,safety,and mechanisms of PPAR agonists for treating ALD.

Small-molecule chemical probes for the potential therapeutic targets in alcoholic liver diseases

Alcoholic liver disease(ALD)encompasses a range of conditions resulting from prolonged and excessive alcohol consumption,causing liver damage such as alcoholic fatty liver,inflammation,fibrosis,and cirrhosis.Alcohol consumption contributes to millions of deaths each year.So far,the effective treatments for ALD are limited.To date,the most effective treatment for ALD is still prevention by avoiding excessive alcohol consumption,and only few specialized medicines are in the market for the treatment of patients suffering from ALD.Small molecules targeting various pathways implicated in ALD pathogenesis can potentially be used for effective therapeutics development.In this review,we provide a concise overview of the latest research findings on potential therapeutic targets,specifically emphasizing small-molecule interventions for the treatment and prevention of ALD.

Pathogenesis of alcoholic liver disease:Role of oxidative metabolism

Alcohol consumption is a predominant etiological factor in the pathogenesis of chronic liver diseases, resulting in fatty liver, alcoholic hepatitis, fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). Although the pathogenesis of alcoholic liver disease (ALD) involves complex and still unclear biological processes, the oxidative metabolites of ethanol such as acetaldehyde and reactive oxygen species (ROS) play a preeminent role in the clinical and pathological spectrum of ALD. Ethanol oxidative metabolism influences intracellular signaling pathways and deranges the transcriptional control of several genes, leading to fat accumulation, fibrogenesis and activation of innate and adaptive immunity. Acetaldehyde is known to be toxic to the liver and alters lipid homeostasis, decreasing peroxisome proliferator-activated receptors and increasing sterol regulatory element binding protein activity via an AMP-activated protein kinase (AMPK)-dependent mechanism. AMPK activation by ROS modulates autophagy, which has an important role in removing lipid droplets. Acetaldehyde and aldehydes generated from lipid peroxidation induce collagen synthesis by their ability to form protein adducts that activate transforming-growth-factor-β-dependent and independent profibrogenic pathways in activated hepatic stellate cells (HSCs). Furthermore, activation of innate and adaptive immunity in response to ethanol metabolism plays a key role in the development and progression of ALD. Acetaldehyde alters the intestinal barrier and promote lipopolysaccharide (LPS) translocation by disrupting tight and adherent junctions in human colonic mucosa. Acetaldehyde and LPS induce Kupffer cells to release ROS and proinflammatory cytokines and chemokines that contribute to neutrophils infiltration. In addition, alcohol consumption inhibits natural killer cells that are cytotoxic to HSCs and thus have an important antifibrotic function in the liver. Ethanol metabolism may also interfere with cell-mediated adaptive immunity by impairing proteasome function in macrophages and dendritic cells, and consequently alters allogenic antigen presentation. Finally, acetaldehyde and ROS have a role in alcohol-related carcinogenesis because they can form DNA adducts that are prone to mutagenesis, and they interfere with methylation, synthesis and repair of DNA, thereby increasing HCC susceptibility.

Gut microbiota in alcoholic liver disease: Pathogenetic role and therapeutic perspectives

Alcoholic liver disease(ALD) is the commonest cause of cirrhosis in many Western countries and it has a high rate of morbidity and mortality. The pathogenesis is characterized by complex interactions between metabolic intermediates of alcohol. Bacterial intestinal flora is itself responsible for production of endogenous ethanol through the fermentation of carbohydrates. The intestinal metabolism of alcohol produces a high concentration of toxic acetaldehyde that modifies gut permeability and microbiota equilibrium. Furthermore it causes direct hepatocyte damage. In patients who consume alcohol over a long period, there is a modification of gut microbiota and, in particular, an increment of Gram negative bacteria. This causes endotoxemia and hyperactivation of the immune system. Endotoxin is a constituent of Gram negative bacteria cell walls. Two types of receptors, cluster of differentiation 14 and Toll-like receptors-4, present on Kupffer cells, recognize endotoxins. Several studies have demonstrated the importance of gut-liver axis and new treatments have been studied in recent years to reduce progression of ALD modifying gut microbiota. It has focused attention on antibiotics, prebiotics, probiotics and synbiotics.

Ethanol induced mitochondria injury and permeability transition pore opening: Role of mitochondria in alcoholic liver disease

AIM: To observe changes of mitochondria and investigate the effect of ethanol on mitochondrial perme- ability transition pore (PTP), mitochondrial membrane potential (MMP, ΔΨm) and intracellular calcium concentration in hepatocytes by establishing an animal model of alcoholic liver disease (ALD). METHODS: Fourty adult male Wistar rats were randomly divided into two groups, the model group (20) was administered alcohol intragastrically plus an Oliver oil diet to establish an ALD model, and the control group (20) was given an equal amount of normal saline. The ultramicrostructural changes of mitochondria were observed under electron microscopy. Mitochondria of liver was extracted, and patency of PTP, mitochondrial membrane potential (ΔΨm), mitochondrial mass and intracellular calcium concentration of isolated hepacytes were detected by flow cytometry using rhodamine123 (Rh123), Nonyl-Acridine Orange and calcium fluorescent probe Fluo-3/AM, respectively. RESULTS: Membrane and cristae were broken or disappeared in mitochondria in different shapes under electron microscopy. Some mitochondria showed U shape or megamitochondrion. In the model group, liver mitochondria PTP was broken, and mitochondria swelled, the absorbance at 450 nm, A540 decreased (0.0136 ± 0.0025 vs 0.0321 ± 0.0013, model vs control, P < 0.01); mitochondria transmembrane potential (239.4638 ± 12.7263 vs 377.5850 ± 16.8119, P < 0.01) was lowered; mitochondrial mass (17.4350 ± 1.9880 vs 31.6738 ± 3.4930, P < 0.01); and [Ca2+]i was increased in liver cells (7.0020 ± 0.5008 vs 10.2050 ± 0.4701, P < 0.01).CONCLUSION: Chronic alcohol intake might lead to broken mitochondria PTP, decreased mitochondria membrane potential and injury, and elevated intracellular Ca2+ production. Ethanol-induced chondriosome injury may be an important mechanism of alcoholic diseases.

Diagnosis of alcoholic liver disease

Alcohol is a hepatotoxin that is commonly consumed worldwide and is associated with a spectrum of liver injury including simple steatosis or fatty liver, alcoholic hepatitis, fibrosis, and cirrhosis. Alcoholic liver disease(ALD) is a general term used to refer to this spectrum of alcohol-related liver injuries. Excessive or harmful alcohol use is ranked as one of the top five risk factors for death and disability globally and results in 2.5 million deaths and 69.4 million annual disability adjusted life years. All patients who present with clinical features of hepatitis or chronic liver disease or who have elevated serum elevated transaminase levels should be screened for an alcohol use disorder. The diagnosis of ALD can generally be made based on history, clinical and laboratory findings. However, the diagnosis of ALD can be clinically challenging as there is no single diagnostic test that confirms the diagnosis and patients may not be forthcoming about their degree of alcohol consumption. In addition, clinical findings may be absent or minimal in early ALD characterized by hepatic steatosis. Typical laboratory findings in ALD include transaminase levels with aspartate aminotransferase greater than alanine aminotransferase as well as increased mean cor-puscular volume, gamma-glutamyltranspeptidase, and IgA to IgG ratio. In unclear cases, the diagnosis can be supported by imaging and liver biopsy. The histological features of ALD can ultimately define the diagnosis according to the typical presence and distribution of hepatic steatosis, inflammation, and Mallory-Denk bodies. Because of the potential reversible nature of ALD with sobriety, regular screening of the general population and early diagnosis are essential.

Alcoholic liver disease and hepatitis C:A frequently underestimated combination

Alcoholic liver disease(ALD) and hepatitis C virus(HCV) infection represent, either alone or in combination, more than two thirds of all patients with liver disease in the Western world.This review discusses the epidemiology and combined impact of ALD and HCV on the progres sion of liver disease.ALD and HCV affect the progres sion of liver disease to liver cirrhosis and hepatocellular carcinoma(HCC) in a synergistic manner.Thus, the risk for HCC increases f ive times with a daily alcohol con sumption of 80 g;in the presence of HCV it is increased 20fold, and a combination of both risk factors leads to a more than 100fold risk for HCC development.Alcohol consumption also decreases the response to interferon treatment which is probably due to a lack of compliance than a direct effect on HCV replication.Several molecu lar mechanisms are discussed that could explain the synergistic interaction of alcohol and HCV on disease progression.They include modulation of the immune response and apoptosis, increased oxidative stress via induction of CYP2E1 and the hepatic accumulation of iron.Thus, both HCV and alcohol independently cause hepatic iron accumulation in > 50% of patients probably due to suppression of the liversecreted systemic iron hormone hepcidin.A better understanding of hepcidin regulation could help in developing novel therapeutic approaches to treat the chronic disease in the future.For now, it can be generally concluded that HCVinfect ed patients should abstain from alcohol and alcoholicsshould be encouraged to participate in detoxification programs.

Alcohol metabolites and lipopolysaccharide: Roles in the development and/or progression of alcoholic liver disease

The onset of alcoholic liver disease (ALD) is initiated by different cell types in the liver and a number of different factors including: products derived from ethanol-induced inflammation, ethanol metabolites, and the indirect reactions from those metabolites. Ethanol oxidation results in the production of metabolites that have been shown to bind and form protein adducts, and to increase inflammatory, fibrotic and cirrhotic responses. Lipopolysaccharide (LPS) has many deleterious effects and plays a significant role in a number of disease processes by increasing inflammatory cytokine release. In ALD, LPS is thought to be derived from a breakdown in the intestinal wall enabling LPS from resident gut bacterial cell walls to leak into the blood stream. The ability of adducts and LPS to independently stimulate the various cells of the liver provides for a two-hit mechanism by which various biological responses are induced and result in liver injury. Therefore, the purpose of this article is to evaluate the effects of a two-hit combination of ethanol metabolites and LPS on the cells of the liver to increase inflamma-tion and fi brosis, and play a role in the development and/or progression of ALD.

Hepatic stellate cells and innate immunity in alcoholic liver disease

Constant alcohol consumption is a major cause of chronic liver disease, and there has been a growing concern regarding the increased mortality rates worldwide. Alcoholic liver diseases (ALDs) range from mild to more severe conditions, such as steatosis, steatohepatitis, fibrosis, cirrhosis, and hepatocellular carcinoma. The liver is enriched with innate immune cells (e.g. natural killer cells and Kupffer cells) and hepatic stellate cells (HSCs), and interestingly, emerging evidence suggests that innate immunity contributes to the development of ALDs (e.g. steatohepatitis and liver fibrosis). Indeed, HSCs play a crucial role in alcoholic steatosis via production of endocannabinoid and retinol metabolites. This review describes the roles of the innate immunity and HSCs in the pathogenesis of ALDs, and suggests therapeutic targets and strategies to assist in the reduction of ALD.

Role of mitochondria in alcoholic liver disease

Alcohol abuse is the leading cause of liver related morbidity and mortality.Chronic or binge alcohol drinking causes hepatic steatosis which can develop to steatohepatitis,cirrhosis and ultimately hepatocellular carcinoma.The pathogenesis of alcoholic liver disease(ALD)is poorly characterized,however several recent studies point to a major role of mitochondria in this process.Mitochondria play a crucial role in cellular energy metabolism and in reactive species formation.Alcohol treatment causes mitochondrial DNA damage,lipid accumulation and oxidative stress.Studies in both animal models and in humans showed that alcohol administration causes changes in the mitochondrial morphology and function suggesting a role of these changes in the pathogenesis of ALD.We review recent findings on mechanisms by which alcohol negatively impacts mitochondrial biogenesis and function and we will discuss the specific intracellular pathways affected by alcohol consumption.Interestingly,recent findings indicate that a large number of mitochondrial proteins are acetylated and that mitochondrial proteins acetylation and sirtuins are modulated by alcohol.Un-derstanding the mechanisms behind alcohol mediated impaired mitochondrial biogenesis and function may help identify potential therapeutic targets for treating ALD in humans.

Non-invasive diagnosis of alcoholic liver disease

Alcoholic liver disease(ALD)is the most common liver disease in the Western world.For many reasons,it isunderestimated and underdiagnosed.An early diagnosis is absolutely essential since it(1)helps to identify patients at genetic risk for ALD;(2)can trigger efficient abstinence namely in non-addicted patients;and(3)initiate screening programs to prevent life-threateningcomplications such as bleeding from varices,spontaneous bacterial peritonitis or hepatocellular cancer.The two major end points of ALD are alcoholic liver cirrhosis and the rare and clinically-defined alcoholic hepatitis(AH).The prediction and early diagnosis of both entities is still insufficiently solved and usually relies on acombination of laboratory,clinical and imaging findings.It is not widely conceived that conventional screeningtools for ALD such as ultrasound imaging or routine laboratory testing can easily overlook ca.40%of manifest alcoholic liver cirrhosis.Non-invasive methods such as transient elastography(Fibroscan),acoustic radiation force impulse imaging or shear wave elastography have significantly improved the early diagnosis of alcoholiccirrhosis.Present algorithms allow either the exclusion or the exact definition of advanced fibrosis stages in ca.95%of patients.The correct interpretation of liver stiffness requires a timely abdominal ultrasound and actual transaminase levels.Other non-invasive methods such as controlled attenuation parameter,serum levels of M30 or M65,susceptometry or breath tests are under current evaluation to assess the degree of steatosis,apoptosis and iron overload in these patients.Liver biopsy still remains an important option to rule out comorbidities and to confirm the prognosis namely for patients with AH.

Therapy for alcoholic liver disease

Alcoholism results in about 2.5 million deaths annually worldwide, representing 4% of all mortality. Although alcoholism is associated with more than 60 diseases, most mortality from alcoholism results from alcoholic liver disease (ALD). ALD includes alcoholic steatosis, alcoholic hepatitis, and alcoholic cirrhosis, in order of increasing severity. Important scoring systems of ALD severity include: Child-Pugh, a semi-quantitative scoring system useful to roughly characterize clinical severity; model for end-stage liver disease, a quantitative, objective scoring system used for prognostication and prioritization for liver transplantation; and discriminant function, used to determine whether to administer corticosteroids for alcoholic hepatitis. Abstinence is the cornerstone of ALD therapy. Psychotherapies, including twelve-step facilitation therapy, cognitive-behavioral therapy, and motivational enhancement therapy, help support abstinence. Disulfiram decreases alcohol consumption by causing unpleasant sensations after drinking alcohol from accumulation of acetaldehyde in serum, but disulfiram can be hepatotoxic. Adjunctive pharmacotherapies to reduce alcohol consumption include naltrexone, acamprosate, and baclofen. Nutritional therapy helps reverse muscle wasting, weight loss, vitamin deficiencies, and trace element deficiencies associated with ALD. Although reduced protein intake was previously recommended for advanced ALD to prevent hepatic encephalopathy, a diet containing 1.2-1.5 g of protein/kg per day is currently recommended to prevent muscle wasting. Corticosteroids are first-line therapy for severe alcoholic hepatitis (discriminant function &#x02265; 32), but proof of their efficacy in decreasing mortality remains elusive. Pentoxifylline is an alternative therapy. Complications of advanced ALD include ascites, spontaneous bacterial peritonitis, esophageal variceal bleeding, hepatic encephalopathy, hepatorenal syndrome, hepatopulmonary syndrome, and portopulmonary hypertension. Alcoholic cirrhotics have increased risk of developing hepatomas. Liver transplantation is the ultimate therapy for severe ALD, but generally requires 6 mo of proven abstinence for eligibility. Alcoholic cirrhotics who maintain abstinence generally have a relatively favorable prognosis after liver transplantation.

Alcoholic disease: Liver and beyond

The harmful use of alcohol is a worldwide problem. It has been estimated that alcohol abuse represents the world&#x02019;s third largest risk factor for disease and disability; it is a causal factor of 60 types of diseases and injuries and a concurrent cause of at least 200 others. Liver is the main organ responsible for metabolizing ethanol, thus it has been considered for long time the major victim of the harmful use of alcohol. Ethanol and its bioactive products, acetaldehyde-acetate, fatty acid ethanol esters, ethanol-protein adducts, have been regarded as hepatotoxins that directly and indirectly exert their toxic effect on the liver. A similar mechanism has been postulated for the alcohol-related pancreatic damage. Alcohol and its metabolites directly injure acinar cells and elicit stellate cells to produce and deposit extracellular matrix thus triggering the &#x0201c;necrosis-fibrosis&#x0201d; sequence that finally leads to atrophy and fibrosis, morphological hallmarks of alcoholic chronic pancreatitis. Even if less attention has been paid to the upper and lower gastrointestinal tract, ethanol produces harmful effects by inducing: (1) direct damaging of the mucosa of the esophagus and stomach; (2) modification of the sphincterial pressure and impairment of motility; and (3) alteration of gastric acid output. In the intestine, ethanol can damage the intestinal mucosa directly or indirectly by altering the resident microflora and impairing the mucosal immune system. Notably, disruption of the intestinal mucosal barrier of the small and large intestine contribute to liver damage. This review summarizes the most clinically relevant alcohol-related diseases of the digestive tract focusing on the pathogenic mechanisms by which ethanol damages liver, pancreas and gastrointestinal tract.

Hyperhomocysteinemia, endoplasmic reticulum stress, and alcoholic liver injury

Deficiencies in vitamins or other factors(B6,B12,folic acid, betaine)and genetic disorders for the metabolism of the non-protein amino acid-homocysteine(Hcy)lead to hyperhomocysteinemia(HHcy).HHcy is an integral component of several disorders including cardiovascular disease,neurodegeneration,diabetes and alcoholic liver disease.HHcy unleashes mediators of inflammation such as NFκB,IL-1β,IL-6,and IL-8,increases production of intracellular superoxide anion causing oxidative stress and reducing intracellular level of nitric oxide(NO),and induces endoplasrnic reticulum(ER)stress which can explain many processes of Hcy-promoted cell injury such as apoptosis, fat accumulation,and inflammation.Animal models have played an important role in determining the biological effects of HHcy.ER stress may also be involved in other liver diseases such as α_1-antitrypsin(α_1-AT)deficiency and hepatitis C and/or B virus infection.Future research should evaluate the possible potentiative effects of alcohol and hepatic virus infection on ER stress-induced liver injury,study potentially beneficial effects of lowering Hcy and preventing ER stress in alcoholic humans,and examine polymorphisrn of Hcy metabolizing enzymes as potential risk-factors for the development of HHcy and liver disease.

Clinical differences between alcoholic liver disease and nonalcoholic fatty liver disease

Alcoholic liver disease(ALD)and nonalcoholic fatty liver disease(NAFLD)are serious health problems worldwide.These two diseases have similar pathological spectra,ranging from simple hepatic steatosis to steatohepatitis,liver cirrhosis,and hepatocellular carcinoma.Although most subjects with excessive alcohol or food intake experience simple hepatic steatosis,a small percentage of individuals will develop progressive liver disease.Notably,both ALD and NAFLD are frequently accompanied by extrahepatic complications,including cardiovascular disease and malignancy.The survival of patients with ALD and NAFLD depends on various disease-associated conditions.This review delineates the clinical characteristics and outcomes of patients with ALD and NAFLD by comparing their epidemiology,the factors associated with disease susceptibility and progression,and the predictors and characteristics of outcomes.A comprehensive understanding of the characteristics and outcomes of ALD and NAFLD is imperative in the management of these chronic liver diseases.