1 319 124 ALCOHOLIC LIVER DISEASE. ALCOHOLIC LIVER DISEASE (ALD) IS THE MOST PREVALENT TYPE OF CHRONIC LIVER DISEASE WORLDWIDE. ALD CAN PROGRESS FROM ALCOHOLIC FATTY LIVER (AFL) TO ALCOHOLIC STEATOHEPATITIS (ASH), WHICH IS CHARACTERIZED BY HEPATIC INFLAMMATION. CHRONIC ASH CAN EVENTUALLY LEAD TO FIBROSIS AND CIRRHOSIS AND IN SOME CASES HEPATOCELLULAR CANCER (HCC). IN ADDITION, SEVERE ASH (WITH OR WITHOUT CIRRHOSIS) CAN LEAD TO ALCOHOLIC HEPATITIS, WHICH IS AN ACUTE CLINICAL PRESENTATION OF ALD THAT IS ASSOCIATED WITH LIVER FAILURE AND HIGH MORTALITY. MOST INDIVIDUALS CONSUMING >40 G OF ALCOHOL PER DAY DEVELOP AFL; HOWEVER, ONLY A SUBSET OF INDIVIDUALS WILL DEVELOP MORE ADVANCED DISEASE. GENETIC, EPIGENETIC AND NON-GENETIC FACTORS MIGHT EXPLAIN THE CONSIDERABLE INTERINDIVIDUAL VARIATION IN ALD PHENOTYPE. THE PATHOGENESIS OF ALD INCLUDES HEPATIC STEATOSIS, OXIDATIVE STRESS, ACETALDEHYDE-MEDIATED TOXICITY AND CYTOKINE AND CHEMOKINE-INDUCED INFLAMMATION. DIAGNOSIS OF ALD INVOLVES ASSESSING PATIENTS FOR ALCOHOL USE DISORDER AND SIGNS OF ADVANCED LIVER DISEASE. THE DEGREE OF AFL AND LIVER FIBROSIS CAN BE DETERMINED BY ULTRASONOGRAPHY, TRANSIENT ELASTOGRAPHY, MRI, MEASUREMENT OF SERUM BIOMARKERS AND LIVER BIOPSY HISTOLOGY. ALCOHOL ABSTINENCE ACHIEVED BY PSYCHOSOMATIC INTERVENTION IS THE BEST TREATMENT FOR ALL STAGES OF ALD. IN THE CASE OF ADVANCED DISEASE SUCH AS CIRRHOSIS OR HCC, LIVER TRANSPLANTATION MAY BE REQUIRED. THUS, NEW THERAPIES ARE URGENTLY NEEDED. 2018 2 4108 28 MECHANISMS AND DISEASE CONSEQUENCES OF NONALCOHOLIC FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE LEADING CHRONIC LIVER DISEASE WORLDWIDE. ITS MORE ADVANCED SUBTYPE, NONALCOHOLIC STEATOHEPATITIS (NASH), CONNOTES PROGRESSIVE LIVER INJURY THAT CAN LEAD TO CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. HERE WE PROVIDE AN IN-DEPTH DISCUSSION OF THE UNDERLYING PATHOGENETIC MECHANISMS THAT LEAD TO PROGRESSIVE LIVER INJURY, INCLUDING THE METABOLIC ORIGINS OF NAFLD, THE EFFECT OF NAFLD ON HEPATIC GLUCOSE AND LIPID METABOLISM, BILE ACID TOXICITY, MACROPHAGE DYSFUNCTION, AND HEPATIC STELLATE CELL ACTIVATION, AND CONSIDER THE ROLE OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL FACTORS THAT PROMOTE FIBROSIS PROGRESSION AND RISK OF HEPATOCELLULAR CARCINOMA IN NASH. 2021 3 5772 52 SPECTRUM, SCREENING, AND DIAGNOSIS OF ALCOHOL-RELATED LIVER DISEASE. ALCOHOL-RELATED LIVER DISEASE (ALD) REPRESENTS ONE OF THE LEADING CAUSES OF CHRONIC LIVER DISEASE AND IS A MAJOR CAUSE OF LIVER-RELATED DEATHS WORLDWIDE. ALD ENCOMPASSES A RANGE OF DISORDERS INCLUDING SIMPLE STEATOSIS, ALCOHOLIC STEATOHEPATITIS, FIBROSIS, CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA. PATIENTS WITH UNDERLYING ALD AND CONTINUED HEAVY ALCOHOL CONSUMPTION CAN ALSO DEVELOP AN EPISODE OF ACUTE-ON-CHRONIC LIVER INJURY CALLED ALCOHOL-ASSOCIATED HEPATITIS, THE MOST SEVERE FORM OF THE DISEASE, WHICH PORTENDS A POOR PROGNOSIS. THE MOST IMPORTANT RISK FACTOR FOR THE DEVELOPMENT OF ALD IS THE AMOUNT OF ALCOHOL CONSUMED. INDIVIDUAL SUSCEPTIBILITY TO PROGRESSION TO ADVANCED FIBROSIS AMONG HEAVY DRINKERS IS LIKELY DETERMINED BY A COMBINATION OF BEHAVIORAL, ENVIRONMENTAL, GENETIC, AND EPIGENETIC FACTORS, BUT THE MECHANISMS ARE LARGELY UNKNOWN. THE ONLY EFFECTIVE THERAPY FOR ALD IS PROLONGED ALCOHOL ABSTINENCE. DIAGNOSIS OF ALD INVOLVES ASSESSING PATIENTS FOR ALCOHOL USE DISORDER AND SIGNS OF ADVANCED LIVER DISEASE. IN CLINICAL PRACTICE, THE HISTOLOGICAL ASSESSMENT FOR ALD DIAGNOSIS IS UNCOMMON, AND IT IS USUALLY BASED ON THE MEDICAL HISTORY, CLINICAL MANIFESTATIONS, AND LABORATORY AND IMAGING TESTS. SEVERAL PROMISING BIOMARKERS THAT CAN HAVE BOTH DIAGNOSTIC AND PROGNOSTIC VALUE IN PATIENTS WITH ALD HAVE BEEN IDENTIFIED IN RECENT YEARS. THIS REVIEW PROVIDES AN OVERVIEW OF THE CLINICAL SPECTRUM OF ALD, THE DIAGNOSTIC APPROACH OF THE DISEASE FROM DIFFERENT PERSPECTIVES AS WELL AS CURRENT DIAGNOSTIC AND PROGNOSTIC BIOMARKERS. 2023 4 4659 42 NEW APPROACHES FOR STUDYING ALCOHOLIC LIVER DISEASE. ALCOHOLIC LIVER DISEASE (ALD) IS MAJOR CAUSE OF CHRONIC LIVER INJURY WHICH RESULTS IN LIVER FIBROSIS AND CIRRHOSIS. ACCORDING TO THE SURVEILLANCE REPORT PUBLISHED BY THE NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM, LIVER CIRRHOSIS IS THE 12TH LEADING CAUSE OF DEATH IN THE UNITED STATES WITH 48 % OF THESE DEATHS BEING ATTRIBUTED TO EXCESSIVE ALCOHOL CONSUMPTION. ALD INCLUDES A SPECTRUM OF DISORDERS FROM SIMPLE STEATOSIS TO STEATOHEPATITIS, FIBROSIS, AND HEPATOCELLULAR CARCINOMA. SEVERAL MECHANISMS PLAY A CRITICAL ROLE IN THE PATHOGENESIS OF ALD. THESE INCLUDE ETHANOL-INDUCED OXIDATIVE STRESS AND DEPLETION OF GLUTATHIONE, PATHOLOGICAL METHIONINE METABOLISM, INCREASED GUT PERMEABILITY AND RELEASE OF ENDOTOXINS INTO THE PORTAL BLOOD, RECRUITMENT AND ACTIVATION OF INFLAMMATORY CELLS INCLUDING BONE MARROW-DERIVED AND LIVER RESIDENT MACROPHAGES (KUPFFER CELLS). CHRONIC ALCOHOL CONSUMPTION RESULTS IN LIVER DAMAGE AND ACTIVATION OF HEPATIC STELLATE CELLS (HSCS) AND MYOFIBROBLASTS, LEADING TO LIVER FIBROSIS. HERE WE DISCUSS THE CURRENT VIEW ON FACTORS THAT ARE SPECIFIC FOR DIFFERENT STAGES OF ALD AND THOSE THAT REGULATE ITS PROGRESSION, INCLUDING CYTOKINES AND CHEMOKINES, ALCOHOL-RESPONSIVE INTRACELLULAR SIGNALING PATHWAYS, AND TRANSCRIPTIONAL FACTORS. WE ALSO REVIEW RECENT STUDIES DEMONSTRATING THAT ALCOHOL-MEDIATED CHANGES CAN BE REGULATED ON AN EPIGENETIC LEVEL, INCLUDING MICRORNAS. FINALLY, WE DISCUSS THE REVERSIBILITY OF LIVER FIBROSIS AND INACTIVATION OF HSCS AS A POTENTIAL STRATEGY FOR TREATING ALCOHOL-INDUCED LIVER DAMAGE. 2014 5 4464 40 MOLECULAR MECHANISMS OF NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)/NONALCOHOLIC STEATOHEPATITIS (NASH). NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE MOST COMMON CHRONIC LIVER DISEASES WORLDWIDE AND HAS GARNERED INCREASING ATTENTION IN RECENT DECADES. NAFLD IS CHARACTERIZED BY A WIDE RANGE OF LIVER CHANGES, FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS (NASH), CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA. THE PATHOGENESIS OF NAFLD/NASH IS VERY COMPLICATED AND INVOLVES LIPID ACCUMULATION, INSULIN RESISTANCE, INFLAMMATION, AND FIBROGENESIS. IN ADDITION, NAFLD IS CLOSELY ASSOCIATED WITH COMPLICATIONS SUCH AS OBESITY, DYSLIPIDEMIA, AND TYPE 2 DIABETES. IN PARTICULAR, THE CLINICAL SPECTRUM, PATHOPHYSIOLOGY, AND THERAPEUTIC OPTIONS OF NAFLD SHARE MANY THINGS IN COMMON WITH DIABETES. INSULIN RESISTANCE IS AN UNDERLYING BASIS FOR THE PATHOGENESIS OF DIABETES AND NAFLD. THIS CHAPTER FOCUSES ON THE MOLECULAR MECHANISM INVOLVED IN THE PATHOGENESIS OF INSULIN RESISTANCE, DIABETES, AND NASH/NAFLD INCLUDING THOSE THAT DRIVE DISEASE PROGRESSION SUCH AS OXIDATIVE STRESS, GENETIC AND EPIGENETIC MECHANISMS, ADIPONECTIN, CYTOKINES, AND IMMUNE CELLS. 2021 6 321 62 ALCOHOLIC-RELATED LIVER DISEASE: PATHOGENESIS, MANAGEMENT AND FUTURE THERAPEUTIC DEVELOPMENTS. 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. 2020 7 6726 28 VITAMIN-DEPENDENT METHIONINE METABOLISM AND ALCOHOLIC LIVER DISEASE. EMERGING EVIDENCE INDICATES THAT ETHANOL-INDUCED ALTERATIONS IN HEPATIC METHIONINE METABOLISM PLAY A CENTRAL ROLE IN THE PATHOGENESIS OF ALCOHOLIC LIVER DISEASE (ALD). BECAUSE MALNUTRITION IS A UNIVERSAL CLINICAL FINDING IN THIS DISEASE AND HEPATIC METHIONINE METABOLISM IS DEPENDENT UPON DIETARY FOLATE AND VITAMINS B-6 AND B-12, ALD CAN BE CONSIDERED AN INDUCED NUTRITIONAL DISORDER THAT IS CONDITIONED BY ALCOHOL ABUSE. THE PRESENT REVIEW DESCRIBES THE ETIOLOGIES OF THESE 3 VITAMIN DEFICIENCIES IN ALD AND HOW THEY INTERACT WITH CHRONIC ETHANOL EXPOSURE TO ALTER HEPATIC METHIONINE METABOLISM. SUBSEQUENT SECTIONS FOCUS ON MOLECULAR MECHANISMS FOR THE INTERACTIONS OF ABERRANT METHIONINE METABOLISM WITH ETHANOL IN THE PATHOGENESIS OF ALD, IN PARTICULAR THE ROLE OF S-ADENOSYLMETHIONINE (SAM) IN REGULATING THE EPIGENETIC EXPRESSIONS OF GENES RELEVANT TO PATHWAYS OF LIVER INJURY. THE REVIEW WILL CONCLUDE WITH DESCRIPTIONS OF STUDIES ON THE EFFICACY OF SAM IN THE TREATMENT OF ALD AND WITH DISCUSSION OF POTENTIALLY FRUITFUL FUTURE AVENUES OF RESEARCH. 2011 8 4199 33 METABOLIC REPROGRAMMING AND CELL FATE REGULATION IN ALCOHOLIC LIVER DISEASE. ALCOHOLIC LIVER DISEASE (ALD) SHOULD BE DEFINED AS A LIFE-STYLE METABOLIC DISEASE. ITS PATHOGENESIS IS DRIVEN BY ALTERED CELL FATE OF BOTH PARENCHYMAL AND NON-PARENCHYMAL LIVER CELL TYPES, CONTRIBUTING TO DIFFERENT PATHOLOGIC SPECTRA. A CRITICAL TURNING POINT IN PROGRESSION OF ALD IS CHRONIC ALCOHOLIC STEATOHEPATITIS (ASH) OR ALCOHOLIC NEUTROPHILIC HEPATITIS (AH), WHICH MARKEDLY PREDISPOSES PATIENTS TO MOST DEVASTATING ALD SEQUELA, CIRRHOSIS AND LIVER CANCER. RESULTS: OUR RESEARCH IDENTIFIES THE PIVOTAL ROLES OF UNIQUE METABOLIC REPROGRAMMING IN M1 ACTIVATION OF HEPATIC MACROPHAGES (HM) AND MYOFIBROBLASTIC ACTIVATION (MF) OF HEPATIC STELLATE CELLS (HSC) IN THE GENESIS OF INFLAMMATION AND FIBROSIS, THE TWO KEY HISTOLOGICAL FEATURES OF CHRONIC ASH AND NEUTROPHILIC AH. FOR M1 HM ACTIVATION, HEIGHTENED PROINFLAMMATORY IRON REDOX SIGNALING IN ENDOSOMES OR CAVEOSOMES RESULTS FROM ALTERED IRON METABOLISM AND STORAGE, PROMOTING IKK/NF-KB ACTIVATION VIA INTERACTIVE ACTIVATION OF P21RAS, TAK1, AND PI3K. FOR MF CELL FATE REGULATION OF HSC, ACTIVATION OF THE MORPHOGEN WNT PATHWAY CAUSED BY THE NUCLEAR PROTEIN NECDIN OR THE SINGLE-PASS TRANS-MEMBRANE PROTEIN DLK1, REPROGRAMS LIPID METABOLISM VIA MECP2-MEDIATED EPIGENETIC REPRESSION OF THE KEY HSC QUIESCENCE GENE PPAR-GAMMA. CONCLUSIONS: THE FINDINGS FROM THESE STUDIES RE-ENFORCE THE IMPORTANCE OF METABOLIC REPROGRAMMING IN CELL FATE REGULATION REQUIRED FOR THE PATHOGENESIS OF ALD. 2015 9 3269 37 HEPATOCELLULAR CARCINOMA IN ALCOHOLIC AND NON-ALCOHOLIC FATTY LIVER DISEASE-ONE OF A KIND OR TWO DIFFERENT ENEMIES? HEPATOCELLULAR CANCER (HCC) IS A CANCER WITH AN OVERALL POOR PROGNOSIS AND AN ALARMING GLOBALLY RISING INCIDENCE. WHILE VIRAL ETIOLOGY OF CHRONIC LIVER DISEASE AND HCC IS DOWN-TRENDING, ALCOHOL AND EXCESS CALORIE INTAKE HAVE EMERGED AS MAJOR CULPRITS. ALCOHOL RELATED LIVER DISEASE (ALD) AND NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) SHARE SIMILAR PATHOGENETIC MECHANISM OF HEPATIC INJURY AND IN PROMOTING DEVELOPMENT OF HCC; YET SOME GENETIC AND EPIGENETIC FEATURES ARE DISTINCT AND MAY PROMISE CLINICAL UTILITY. POPULATION BASED INTERVENTION ARE URGENTLY NEEDED TO REDUCE ALCOHOL USE AND IMPROVE METABOLIC FACTORS SUCH AS OBESITY AND DIABETES. THE GOAL IS TO IDENTIFY AT-RISK PATIENTS, TO LINK THESE PATIENTS TO CARE AND TO PROVIDE EFFECTIVE MANAGEMENT OF CHRONIC LIVER DISEASE AND HCC. THIS REVIEW FOCUSES ON THE EPIDEMIOLOGY, PATHOPHYSIOLOGY INCLUDING GENETIC AND EPIGENETIC ALTERCATION AS WELL AS CLINICAL ASPECTS OF ALD AND NAFLD ASSOCIATED HCC. 2019 10 558 27 B-VITAMIN DEPENDENT METHIONINE METABOLISM AND ALCOHOLIC LIVER DISEASE. CONVINCING EVIDENCE LINKS ABERRANT B-VITAMIN DEPENDENT HEPATIC METHIONINE METABOLISM TO THE PATHOGENESIS OF ALCOHOLIC LIVER DISEASE (ALD). THIS REVIEW FOCUSES ON THE ESSENTIAL ROLES OF FOLATE AND VITAMINS B6 AND B12 IN HEPATIC METHIONINE METABOLISM, THE CAUSES OF THEIR DEFICIENCIES AMONG CHRONIC ALCOHOLIC PERSONS, AND HOW THEIR DEFICIENCIES TOGETHER WITH CHRONIC ALCOHOL EXPOSURE IMPACT ON ABERRANT METHIONINE METABOLISM IN THE PATHOGENESIS OF ALD. FOLATE IS THE DIETARY TRANSMETHYLATION DONOR FOR THE PRODUCTION OF S-ADENOSYLMETHIONINE (SAM), WHICH IS THE SUBSTRATE FOR ALL METHYLTRANSFERASES THAT REGULATE GENE EXPRESSIONS IN PATHWAYS OF LIVER INJURY, AS WELL AS A REGULATOR OF THE TRANSSULFURATION PATHWAY THAT IS ESSENTIAL FOR PRODUCTION OF GLUTATHIONE (GSH), THE PRINCIPAL ANTIOXIDANT FOR DEFENSE AGAINST OXIDATIVE LIVER INJURY. VITAMIN B12 REGULATES TRANSMETHYLATION REACTIONS FOR SAM PRODUCTION AND VITAMIN B6 REGULATES TRANSSULFURATION REACTIONS FOR GSH PRODUCTION. FOLATE DEFICIENCY ACCELERATES THE EXPERIMENTAL DEVELOPMENT OF ALD IN ETHANOL-FED ANIMALS WHILE REDUCING LIVER SAM LEVELS WITH RESULTANT ABNORMAL GENE EXPRESSION AND DECREASED PRODUCTION OF ANTIOXIDANT GSH. THROUGH ITS EFFECTS ON FOLATE METABOLISM, REDUCED SAM ALSO IMPAIRS NUCLEOTIDE BALANCE WITH RESULTANT INCREASED DNA STRAND BREAKS, OXIDATION, HEPATOCELLULAR APOPTOSIS, AND RISK OF CARCINOGENESIS. THE REVIEW ENCOMPASSES REFERENCED STUDIES ON MECHANISMS FOR PERTURBATIONS OF METHIONINE METABOLISM IN ALD, EVIDENCE FOR ALTERED GENE EXPRESSIONS AND THEIR EPIGENETIC REGULATION IN THE PATHOGENESIS OF ALD, AND CLINICAL STUDIES ON POTENTIAL PREVENTION AND TREATMENT OF ALD BY CORRECTION OF METHIONINE METABOLISM WITH SAM. 2013 11 320 46 ALCOHOLIC LIVER DISEASE: PATHOGENESIS AND NEW THERAPEUTIC TARGETS. ALCOHOLIC LIVER DISEASE (ALD) IS A MAJOR CAUSE OF CHRONIC LIVER DISEASE WORLDWIDE AND CAN LEAD TO FIBROSIS AND CIRRHOSIS. THE LATEST SURVEILLANCE REPORT PUBLISHED BY THE NATIONAL INSTITUTE ON ALCOHOL ABUSE AND ALCOHOLISM SHOWED THAT LIVER CIRRHOSIS WAS THE 12TH LEADING CAUSE OF DEATH IN THE UNITED STATES, WITH A TOTAL OF 29,925 DEATHS IN 2007, 48% OF WHICH WERE ALCOHOL RELATED. THE SPECTRUM OF ALD INCLUDES SIMPLE STEATOSIS, ALCOHOLIC HEPATITIS, FIBROSIS, CIRRHOSIS, AND SUPERIMPOSED HEPATOCELLULAR CARCINOMA. EARLY WORK ON THE PATHOGENESIS OF THE DISEASE FOCUSED ON ETHANOL METABOLISM-ASSOCIATED OXIDATIVE STRESS AND GLUTATHIONE DEPLETION, ABNORMAL METHIONINE METABOLISM, MALNUTRITION, AND PRODUCTION OF ENDOTOXINS THAT ACTIVATE KUPFFER CELLS. WE REVIEW FINDINGS FROM RECENT STUDIES THAT HAVE CHARACTERIZED SPECIFIC INTRACELLULAR SIGNALING PATHWAYS, TRANSCRIPTIONAL FACTORS, ASPECTS OF INNATE IMMUNITY, CHEMOKINES, EPIGENETIC FEATURES, MICRORNAS, AND STEM CELLS THAT ARE ASSOCIATED WITH ALD, IMPROVING OUR UNDERSTANDING OF ITS PATHOGENESIS. DESPITE THIS PROGRESS, NO TARGETED THERAPIES ARE AVAILABLE. THE CORNERSTONE OF TREATMENT FOR ALCOHOLIC HEPATITIS REMAINS AS IT WAS 40 YEARS AGO: ABSTINENCE, NUTRITIONAL SUPPORT, AND CORTICOSTEROIDS. THERE IS AN URGENT NEED TO DEVELOP NEW PATHOPHYSIOLOGY-ORIENTED THERAPIES. RECENT TRANSLATIONAL STUDIES OF HUMAN SAMPLES AND ANIMAL MODELS HAVE IDENTIFIED PROMISING THERAPEUTIC TARGETS. 2011 12 4709 40 NON-ALCOHOLIC FATTY LIVER DISEASE AND ALCOHOL-RELATED LIVER DISEASE: TWO INTERTWINED ENTITIES. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST COMMON CAUSE OF CHRONIC LIVER DISEASE WORLDWIDE, WITH A PREVALENCE OF 25-30%. SINCE ITS FIRST DESCRIPTION IN 1980, NAFLD HAS BEEN CONCEIVED AS A DIFFERENT ENTITY FROM ALCOHOL-RELATED FATTY LIVER DISEASE (ALD), DESPITE THAT, BOTH DISEASES HAVE AN OVERLAP IN THE PATHOPHYSIOLOGY, SHARE GENETIC-EPIGENETIC FACTORS, AND FREQUENTLY COEXIST. BOTH ENTITIES ARE CHARACTERIZED BY A BROAD SPECTRUM OF HISTOLOGICAL FEATURES RANGING FROM ISOLATED STEATOSIS TO STEATOHEPATITIS AND CIRRHOSIS. DISTINCTION BETWEEN NAFLD AND ALD IS BASED ON THE AMOUNT OF CONSUMED ALCOHOL, WHICH HAS BEEN ARBITRARILY ESTABLISHED. IN THIS CONTEXT, A PROPOSAL OF POSITIVE CRITERIA FOR NAFLD DIAGNOSIS NOT CONSIDERING EXCLUSION OF ALCOHOL CONSUMPTION AS A PREREQUISITE CRITERION FOR DIAGNOSIS HAD EMERGED, RECOGNIZING THE POSSIBILITY OF A DUAL ETIOLOGY OF FATTY LIVER IN SOME INDIVIDUALS. THE IMPACT OF MODERATE ALCOHOL USE ON THE SEVERITY OF NAFLD IS ILL-DEFINED. SOME STUDIES SUGGEST PROTECTIVE EFFECTS IN MODERATE DOSES, BUT CURRENT EVIDENCE SHOWS THAT THERE IS NO SAFE THRESHOLD FOR ALCOHOL CONSUMPTION FOR NAFLD. IN FACT, GIVEN THE SYNERGISTIC EFFECT BETWEEN ALCOHOL CONSUMPTION, OBESITY, AND METABOLIC DYSFUNCTION, IT IS LIKELY THAT ALCOHOL USE SERVES AS A SIGNIFICANT RISK FACTOR FOR THE PROGRESSION OF LIVER DISEASE IN NAFLD AND METABOLIC SYNDROME. THIS ALSO AFFECTS THE INCIDENCE OF HEPATOCELLULAR CARCINOMA. IN THIS REVIEW, WE SUMMARIZE THE OVERLAPPING PATHOPHYSIOLOGY OF NAFLD AND ALD, THE CURRENT DATA ON ALCOHOL CONSUMPTION IN PATIENTS WITH NAFLD, AND THE EFFECTS OF METABOLIC DYSFUNCTION AND OVERWEIGHT IN ALD. 2020 13 4326 44 MICRORNAS IN THE PATHOGENESIS OF NONALCOHOLIC FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), OR, MORE ACCURATELY, METABOLIC ASSOCIATED FATTY LIVER DISEASE, ACCOUNTS FOR A LARGE PROPORTION OF CHRONIC LIVER DISORDERS WORLDWIDE AND IS CLOSELY ASSOCIATED WITH OTHER CONDITIONS SUCH AS CARDIOVASCULAR DISEASE, OBESITY, AND TYPE 2 DIABETES MELLITUS. NAFLD RANGES FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS (NASH) AND CAN PROGRESS TO CIRRHOSIS AND, EVENTUALLY, ALSO HEPATOCELLULAR CARCINOMA. THE MORBIDITY AND MORTALITY ASSOCIATED WITH NAFLD ARE INCREASING RAPIDLY YEAR ON YEAR. CONSEQUENTLY, THERE IS AN URGENT NEED TO UNDERSTAND THE ETIOLOGY AND PATHOGENESIS OF NAFLD AND IDENTIFY EFFECTIVE THERAPEUTIC TARGETS. MICRORNAS (MIRNAS), IMPORTANT EPIGENETIC FACTORS, HAVE RECENTLY BEEN PROPOSED TO PARTICIPATE IN NAFLD PATHOGENESIS. HERE, WE REVIEW THE ROLES OF MIRNAS IN LIPID METABOLISM, INFLAMMATION, APOPTOSIS, FIBROSIS, HEPATIC STELLATE CELL ACTIVATION, INSULIN RESISTANCE, AND OXIDATIVE STRESS, KEY FACTORS THAT CONTRIBUTE TO THE OCCURRENCE AND PROGRESSION OF NAFLD. ADDITIONALLY, WE SUMMARIZE THE ROLE OF MIRNA-ENRICHED EXTRACELLULAR VESICLES IN NAFLD. THESE MIRNAS MAY COMPRISE SUITABLE THERAPEUTIC TARGETS FOR THE TREATMENT OF THIS CONDITION. 2021 14 6393 31 THE ROLE OF THE HISTONE METHYLTRANSFERASE EZH2 IN LIVER INFLAMMATION AND FIBROSIS IN STAM NASH MICE. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A LEADING FORM OF CHRONIC LIVER DISEASE, WITH FEW BIOMARKERS AND TREATMENT OPTIONS CURRENTLY AVAILABLE. NON-ALCOHOLIC STEATOHEPATITIS (NASH), A PROGRESSIVE DISEASE OF NAFLD, MAY LEAD TO FIBROSIS, CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA. EPIGENETIC MODIFICATION CAN CONTRIBUTE TO THE PROGRESSION OF NAFLD CAUSING NON-ALCOHOLIC STEATOHEPATITIS (NASH), IN WHICH THE EXACT ROLE OF EPIGENETICS REMAINS POORLY UNDERSTOOD. TO IDENTIFY POTENTIAL THERAPEUTICS FOR NASH, WE TESTED SMALL-MOLECULE INHIBITORS OF THE EPIGENETIC TARGET HISTONE METHYLTRANSFERASE EZH2, TAZEMETOSTAT (EPZ-6438), AND UNC1999 IN STAM NASH MICE. THE RESULTS DEMONSTRATE THAT TREATMENT WITH EZH2 INHIBITORS DECREASED SERUM TNF-ALPHA IN NASH. IN THIS STUDY, WE INVESTIGATED THAT INHIBITION OF EZH2 REDUCED MRNA EXPRESSION OF INFLAMMATORY CYTOKINES AND FIBROSIS MARKERS IN NASH MICE. IN CONCLUSION, THESE RESULTS SUGGEST THAT EZH2 MAY PRESENT A PROMISING THERAPEUTIC TARGET IN THE TREATMENT OF NASH. 2020 15 4478 27 MOLECULAR PATHOGENESIS OF NONALCOHOLIC STEATOHEPATITIS- (NASH-) RELATED HEPATOCELLULAR CARCINOMA. THE PROPORTION OF OBESE OR DIABETIC POPULATION HAS BEEN ANTICIPATED TO INCREASE IN THE UPCOMING DECADES, WHICH RISES THE PREVALENCE OF NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) AND ITS PROGRESSION TO NONALCOHOLIC STEATOHEPATITIS (NASH). RECENT EVIDENCE INDICATES THAT NASH IS THE MAIN CAUSE OF CHRONIC LIVER DISEASES AND IT IS AN IMPORTANT RISK FACTOR FOR DEVELOPMENT OF HEPATOCELLULAR CARCINOMA (HCC). ALTHOUGH THE LITERATURE ADDRESSING NASH-HCC IS GROWING RAPIDLY, LIMITED DATA IS AVAILABLE ABOUT THE ETIOLOGY OF NASH-RELATED HCC. EXPERIMENTAL STUDIES ON THE MOLECULAR MECHANISM OF HCC DEVELOPMENT IN NASH REVEAL THAT THE CARCINOGENESIS IS RELEVANT TO COMPLEX CHANGES IN SIGNALING PATHWAYS THAT MEDIATE CELL PROLIFERATION AND ENERGY METABOLISM. GENETIC OR EPIGENETIC MODIFICATIONS AND ALTERATIONS IN METABOLIC, IMMUNOLOGIC, AND ENDOCRINE PATHWAYS HAVE BEEN SHOWN TO BE CLOSELY RELATED TO INFLAMMATION, LIVER INJURY, AND FIBROSIS IN NASH ALONG WITH ITS SUBSEQUENT PROGRESSION TO HCC. IN THIS REVIEW, WE PROVIDE AN OVERVIEW ON THE CURRENT KNOWLEDGE OF NASH-RELATED HCC DEVELOPMENT AND EMPHASIZE MOLECULAR SIGNALING PATHWAYS REGARDING THEIR MECHANISM OF ACTION IN NASH-DERIVED HCC. 2018 16 3680 28 INFLAMMATION IN ALCOHOLIC LIVER DISEASE. FRANK BURR MALLORY'S LANDMARK OBSERVATION IN 1911 ON THE HISTOPATHOLOGY OF ALCOHOLIC LIVER DISEASE (ALD) WAS THE FIRST IDENTIFICATION OF A LINK BETWEEN INFLAMMATION AND ALD. IN THIS REVIEW, WE SUMMARIZE RECENT ADVANCES REGARDING THE ORIGINS AND ROLES OF VARIOUS INFLAMMATORY COMPONENTS IN ALD. METABOLISM OF ETHANOL GENERATES A NUMBER OF METABOLITES, INCLUDING ACETATE, REACTIVE OXYGEN SPECIES, ACETALDEHYDE, AND EPIGENETIC CHANGES, THAT CAN INDUCE INFLAMMATORY RESPONSES. ALCOHOL AND ITS METABOLITES CAN ALSO INITIATE AND AGGRAVATE INFLAMMATORY CONDITIONS BY PROMOTING GUT LEAKINESS OF MICROBIAL PRODUCTS, BY SENSITIZING IMMUNE CELLS TO STIMULATION, AND BY ACTIVATING INNATE IMMUNE PATHWAYS, SUCH AS COMPLEMENT. CHRONIC ALCOHOL CONSUMPTION ALSO SENSITIZES NONIMMUNE CELLS, E.G., HEPATOCYTES, TO INFLAMMATORY SIGNALS AND IMPAIRS THEIR ABILITY TO RESPOND TO PROTECTIVE SIGNALS. BASED ON THESE ADVANCES, A NUMBER OF INFLAMMATORY TARGETS HAVE BEEN IDENTIFIED WITH POTENTIAL FOR THERAPEUTIC INTERVENTION IN ALD, PRESENTING NEW OPPORTUNITIES AND CHALLENGES FOR TRANSLATIONAL RESEARCH. 2012 17 4712 32 NON-ALCOHOLIC FATTY LIVER DISEASE: METABOLIC, GENETIC, EPIGENETIC AND ENVIRONMENTAL RISK FACTORS. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE MOST FREQUENT CAUSES OF CHRONIC LIVER DISEASE IN THE WESTERN WORLD, PROBABLY DUE TO THE GROWING PREVALENCE OF OBESITY, METABOLIC DISEASES, AND EXPOSURE TO SOME ENVIRONMENTAL AGENTS. IN CERTAIN PATIENTS, SIMPLE HEPATIC STEATOSIS CAN PROGRESS TO NON-ALCOHOLIC STEATOHEPATITIS (NASH), WHICH CAN SOMETIMES LEAD TO LIVER CIRRHOSIS AND ITS COMPLICATIONS INCLUDING HEPATOCELLULAR CARCINOMA. UNDERSTANDING THE MECHANISMS THAT CAUSE THE PROGRESSION OF NAFLD TO NASH IS CRUCIAL TO BE ABLE TO CONTROL THE ADVANCEMENT OF THE DISEASE. THE MAIN HYPOTHESIS CONSIDERS THAT IT IS DUE TO MULTIPLE FACTORS THAT ACT TOGETHER ON GENETICALLY PREDISPOSED SUBJECTS TO SUFFER FROM NAFLD INCLUDING INSULIN RESISTANCE, NUTRITIONAL FACTORS, GUT MICROBIOTA, AND GENETIC AND EPIGENETIC FACTORS. IN THIS ARTICLE, WE WILL DISCUSS THE EPIDEMIOLOGY OF NAFLD, AND WE OVERVIEW SEVERAL TOPICS THAT INFLUENCE THE DEVELOPMENT OF THE DISEASE FROM SIMPLE STEATOSIS TO LIVER CIRRHOSIS AND ITS POSSIBLE COMPLICATIONS. 2021 18 6339 37 THE ROLE OF EPIGENETIC CHANGES IN THE PROGRESSION OF ALCOHOLIC STEATOHEPATITIS. ALCOHOLIC STEATOHEPATITIS (ASH) IS A PROGRESSION HEPATITIS WITH SEVERE FATTY LIVER AND ITS MORTALITY RATE FOR 30-DAYS IN PATIENTS ARE OVER 30%. ADDITIONALLY, ASH IS WELL KNOWN FOR ONE-FIFTH ALL ALCOHOLIC RELATED LIVER DISEASES IN THE WORLD. EXCESSIVE CHRONIC ALCOHOL CONSUMPTION IS ONE OF THE MOST COMMON CAUSES OF THE PROGRESSION OF ASH AND IS ASSOCIATED WITH POOR PROGNOSIS AND LIVER FAILURE. ALCOHOL ABUSE DYSREGULATES THE LIPID HOMEOSTASIS AND CAUSES OXIDATIVE STRESS AND INFLAMMATION IN THE LIVER. CONSEQUENTLY, METABOLIC PATHWAYS STIMULATING HEPATIC ACCUMULATION OF EXCESSIVE LIPID DROPLETS ARE INDUCED. RECENTLY, MANY STUDIES HAVE INDICATED A LINK BETWEEN ASH AND EPIGENETIC CHANGES, SHOWING DIFFERENTIAL EXPRESSION OF ALCOHOL-INDUCED EPIGENETIC GENES IN THE LIVER. HOWEVER, THE SPECIFIC MECHANISMS UNDERLYING THE PATHOGENESIS OF ASH REMAIN ELUSIVE. THUS, WE HERE SUMMARIZE THE CURRENT KNOWLEDGE ABOUT THE ROLES OF EPIGENETICS IN LIPOGENESIS, INFLAMMATION, AND APOPTOSIS IN THE CONTEXT OF ASH PATHOPHYSIOLOGY. ESPECIALLY, WE HIGHLIGHT THE LATEST FINDINGS ON THE ROLES OF SIRTUINS, A CONSERVED FAMILY OF CLASS-III HISTONE DEACETYLASES, IN ASH. ADDITIONALLY, WE DISCUSS THE INVOLVEMENT OF DNA METHYLATION, HISTONE MODIFICATIONS, AND MIRNAS IN ASH AS WELL AS THE ONGOING EFFORTS FOR THE CLINICAL TRANSLATION OF THE FINDINGS IN ASH-RELATED EPIGENETIC CHANGES. 2021 19 5807 35 STRATEGIES, MODELS AND BIOMARKERS IN EXPERIMENTAL NON-ALCOHOLIC FATTY LIVER DISEASE RESEARCH. NON-ALCOHOLIC FATTY LIVER DISEASE ENCOMPASSES A SPECTRUM OF LIVER DISEASES, INCLUDING SIMPLE STEATOSIS, STEATOHEPATITIS, LIVER FIBROSIS AND CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. NON-ALCOHOLIC FATTY LIVER DISEASE IS CURRENTLY THE MOST DOMINANT CHRONIC LIVER DISEASE IN WESTERN COUNTRIES DUE TO THE FACT THAT HEPATIC STEATOSIS IS ASSOCIATED WITH INSULIN RESISTANCE, TYPE 2 DIABETES MELLITUS, OBESITY, METABOLIC SYNDROME AND DRUG-INDUCED INJURY. A VARIETY OF CHEMICALS, MAINLY DRUGS, AND DIETS IS KNOWN TO CAUSE HEPATIC STEATOSIS IN HUMANS AND RODENTS. EXPERIMENTAL NON-ALCOHOLIC FATTY LIVER DISEASE MODELS RELY ON THE APPLICATION OF A DIET OR THE ADMINISTRATION OF DRUGS TO LABORATORY ANIMALS OR THE EXPOSURE OF HEPATIC CELL LINES TO THESE DRUGS. MORE RECENTLY, GENETICALLY MODIFIED RODENTS OR ZEBRAFISH HAVE BEEN INTRODUCED AS NON-ALCOHOLIC FATTY LIVER DISEASE MODELS. CONSIDERABLE INTEREST NOW LIES IN THE DISCOVERY AND DEVELOPMENT OF NOVEL NON-INVASIVE BIOMARKERS OF NON-ALCOHOLIC FATTY LIVER DISEASE, WITH SPECIFIC FOCUS ON HEPATIC STEATOSIS. EXPERIMENTAL DIAGNOSTIC BIOMARKERS OF NON-ALCOHOLIC FATTY LIVER DISEASE, SUCH AS (EPI)GENETIC PARAMETERS AND '-OMICS'-BASED READ-OUTS ARE STILL IN THEIR INFANCY, BUT SHOW GREAT PROMISE. IN THIS PAPER, THE ARRAY OF TOOLS AND MODELS FOR THE STUDY OF LIVER STEATOSIS IS DISCUSSED. FURTHERMORE, THE CURRENT STATE-OF-ART REGARDING EXPERIMENTAL BIOMARKERS SUCH AS EPIGENETIC, GENETIC, TRANSCRIPTOMIC, PROTEOMIC AND METABONOMIC BIOMARKERS WILL BE REVIEWED. 2015 20 5386 43 REDOX HOMEOSTASIS AND EPIGENETICS IN NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD). NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD), AN ACCUMULATION OF INTRA-HEPATIC TRIGLYCERIDES THAT IS OFTEN CONSIDERED THE HEPATIC MANIFESTATION OF INSULIN RESISTANCE, IS THE MOST COMMON CAUSE OF CHRONIC LIVER DISEASE IN THE WESTERN COUNTRIES WITH UP TO ONE THIRD OF THE POPULATION AFFECTED. NAFLD IS A SPECTRUM OF DISTURBANCES THAT ENCOMPASSES VARIOUS DEGREES OF LIVER DAMAGE RANGING FROM SIMPLE STEATOSIS TO NON-ALCOHOLIC STEATOHEPATITIS (NASH). NASH IS CHARACTERIZED BY HEPATOCELLULAR INJURY/INFLAMMATION WITH OR WITHOUT FIBROSIS. THE INDIVIDUALS WITH NAFLD DEVELOP NASH IN 10% OF THE CASES, AND ARE ALSO AT RISK OF DEVELOPING HEPATOCELLULAR CARCINOMA (HCC). EPIGENETIC MECHANISMS OF NUCLEAR CHROMATIN REMODELING, SUCH AS DNA METHYLATION, POST-TRANSLATIONAL MODIFICATIONS OF HISTONES, AND INCORPORATION OF HISTONE VARIANTS INTO THE CHROMATIN ARE INCREASINGLY RECOGNIZED AS CRUCIAL FACTORS IN THE PATHOPHYSIOLOGY OF NAFLD. NAFLD IS OFTEN ACCOMPANIED BY OXIDATIVE STRESS: REACTIVE OXYGEN SPECIES (ROS) ARE IMPLICATED IN ALTERED REDUCTION/OXIDATION (REDOX) REACTIONS THAT ATTACK CELLULAR MACROMOLECULES AND ARE DETECTED IN THE LIVER OF PATIENTS AND ANIMAL MODELS OF NAFLD. IN THIS REVIEW, WE SUMMARIZE RECENT KNOWLEDGE ADVANCEMENTS IN THE HEPATIC EPIGENETIC AND REDOX MECHANISMS, AND THEIR POSSIBLE LINKS, INVOLVED IN THE PATHOGENESIS AND TREATMENT OF NAFLD. 2013