1 4108 64 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 2 6393 25 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 3 4464 29 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 4 4478 32 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 5 4326 38 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 6 5386 26 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 7 4712 33 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 8 1721 30 DYSREGULATION OF AUTOPHAGY ACTS AS A PATHOGENIC MECHANISM OF NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) INDUCED BY COMMON ENVIRONMENTAL POLLUTANTS. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) HAS BEEN THE MOST COMMON CHRONIC LIVER DISEASE IN THE WORLD, INCLUDING THE DEVELOPING COUNTRIES. NAFLD IS METABOLIC DISEASE WITH SIGNIFICANT LIPID DEPOSITION IN THE HEPATOCYTES OF THE LIVER, WHICH IS USUALLY ASSOCIATED WITH OXIDATIVE STRESS, INFLAMMATION AND FIBROGENESIS, AND INSULIN RESISTANCE. PROGRESSIVE NAFLD CAN DEVELOP INTO NON-ALCOHOLIC STEATOHEPATITIS (NASH) OR HEPATOCELLULAR CARCINOMA. THE CURRENT EVIDENCE PROPOSES THAT ENVIRONMENTAL POLLUTANTS PROMOTE DEVELOPMENT AND PROGRESSION OF NAFLD, AND AUTOPHAGY PLAYS A VITAL ROLE BUT IS MULTIFACTORIAL AFFECTED IN NAFLD. IN THIS REVIEW, WE ANALYZED ON THE REGULATIONS OF COMMON ENVIRONMENTAL POLLUTANTS ON AUTOPHAGY IN NAFLD. TO CLARIFY THE INVOLVED ROLES OF AUTOPHAGY, WE DISCUSSED THE DYSREGULATION OF AUTOPHAGY BY ENVIRONMENTAL POLLUTANTS IN ADIPOSE TISSUE AND GUT, AND THEIR INTERACTIONS WITH LIVER, AS WELL AS EPIGENETIC REGULATION ON AUTOPHAGY BY ENVIRONMENTAL POLLUTANTS. FURTHERMORE, PROTECTIVE ROLES OF POTENTIAL THERAPEUTIC TREATMENTS ON THE MULTIPLE-HITS OF AUTOPHAGY IN NAFLD WERE DESCRIPTED. 2021 9 3270 25 HEPATOCELLULAR CARCINOMA IN THE CONTEXT OF NON-ALCOHOLIC STEATOHEPATITIS (NASH): RECENT ADVANCES IN THE PATHOGENIC MECHANISMS. HEPATOCELLULAR CARCINOMA (HCC) IS THE MOST COMMON TYPE OF LIVER CANCER. HCC IS PARTICULARLY AGGRESSIVE AND IS ONE OF THE LEADING CAUSES OF CANCER MORTALITY. IN RECENT DECADES, THE EPIDEMIOLOGICAL LANDSCAPE OF HCC HAS UNDERGONE SIGNIFICANT CHANGES. WHILE CHRONIC VIRAL HEPATITIS AND EXCESSIVE ALCOHOL CONSUMPTION HAVE LONG BEEN IDENTIFIED AS THE MAIN RISK FACTORS FOR HCC, NON-ALCOHOLIC STEATOHEPATITIS (NASH), PARALLELING THE WORLDWIDE EPIDEMIC OF OBESITY AND TYPE 2 DIABETES, HAS BECOME A GROWING CAUSE OF HCC IN THE US AND EUROPE. HERE, WE REVIEW THE RECENT ADVANCES IN EPIDEMIOLOGICAL, GENETIC, EPIGENETIC AND PATHOGENIC MECHANISMS AS WELL AS EXPERIMENTAL MOUSE MODELS THAT HAVE IMPROVED THE UNDERSTANDING OF NASH PROGRESSION TOWARD HCC. WE ALSO DISCUSS THE CLINICAL MANAGEMENT OF PATIENTS WITH NASH-RELATED HCC AND POSSIBLE THERAPEUTIC APPROACHES. 2020 10 615 29 BIOACTIVE COMPONENTS AND POSSIBLE ACTIVITIES OF MEDICINAL MUSHROOMS IN ALLEVIATING THE PATHOGENESIS OF NONALCOHOLIC FATTY LIVER DISEASE (REVIEW). NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A GLOBAL DISEASE THAT IS CLOSELY ASSOCIATED WITH OBESITY, TYPE 2 DIABETES MELLITUS, AND CARDIOVASCULAR DISEASE. EXCESSIVE FAT ACCUMULATION, FATTY DEGENERATION, AND CHRONIC INFLAMMATION OF THE LIVER ACTIVATE THE PROGRESSION OF NAFLD FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS AND FURTHER TO LIVER FIBROSIS, CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA. THE UNDERLYING MECHANISM FOR THE DEVELOPMENT AND PROGRESSION OF NAFLD IS COMPLEX AND A MULTIPLE-HIT HYPOTHESIS INCLUDING DIETARY, ENVIRONMENTAL, GENETIC, AND EPIGENETIC FACTORS HAS BEEN RAISED. INCREASED DE NOVO LIPOGENESIS, DECREASED LIPOLYSIS, AND INSULIN RESISTANCE ARE ASSOCIATED WITH THE DEVELOPMENT OF NAFLD. CURRENTLY, NO EFFECTIVE DRUG THERAPIES ARE APPROVED FOR THE TREATMENT OF NAFLD. SEVERAL MEDICINAL MUSHROOMS HAVE BEEN FOUND TO HAVE SIGNIFICANT WEIGHT CONTROL AND GUT MICROBE MODULATION ACTIVITIES AND ANTIHYPERTRIGLYCERIDEMIC, ANTIHYPERGLYCEMIC, ANTIOXIDANT, AND ANTI-INFLAMMATORY EFFECTS, WHICH MAY BE USEFUL TO PREVENT AND ATTENUATE THE DEVELOPMENT AND PROGRESSION OF NAFLD. THESE BENEFICIAL EFFECTS ARE ASSOCIATED WITH MUSHROOMS' BIOACTIVE COMPONENTS, SUCH AS POLYSACCHARIDES, DIETARY FIBERS, ANTIOXIDANTS, AND OTHER COMPOUNDS DERIVED FROM FRUITING BODIES, CULTURED MYCELIUM, AND/OR BROTH OF MEDICINAL MUSHROOMS. THIS ARTICLE PRESENTS AN OVERVIEW OF MULTIPLE ASPECTS OF NAFLD, INCLUDING THE EPIDEMIOLOGY, PATHOGENESIS, MANAGEMENT, AND TREATMENT. THE BIOACTIVE COMPONENTS AND POSSIBLE ACTIVITIES OF MEDICINAL MUSHROOMS IN ALLEVIATING THE PATHOGENESIS OF NAFLD ARE ALSO REVIEWED. 2021 11 5807 26 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 12 469 28 ARID1A LOSS DRIVES NONALCOHOLIC STEATOHEPATITIS IN MICE THROUGH EPIGENETIC DYSREGULATION OF HEPATIC LIPOGENESIS AND FATTY ACID OXIDATION. NONALCOHOLIC STEATOHEPATITIS (NASH) IS A RAPIDLY GROWING CAUSE OF CHRONIC LIVER DAMAGE, CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA. HOW FATTY LIVER PATHOGENESIS IS SUBJECT TO EPIGENETIC REGULATION IS UNKNOWN. WE HYPOTHESIZED THAT CHROMATIN REMODELING IS IMPORTANT FOR THE PATHOGENESIS OF FATTY LIVER DISEASE. AT-RICH INTERACTIVE DOMAIN-CONTAINING PROTEIN 1A (ARID1A), A DNA-BINDING COMPONENT OF THE SWITCH/SUCROSE NONFERMENTABLE ADENOSINE TRIPHOSPHATE-DEPENDENT CHROMATIN-REMODELING COMPLEX, CONTRIBUTES TO NUCLEOSOME REPOSITIONING AND ACCESS BY TRANSCRIPTIONAL REGULATORS. LIVER-SPECIFIC DELETION OF ARID1A (ARID1A LIVER KNOCKOUT [LKO]) CAUSED THE DEVELOPMENT OF AGE-DEPENDENT FATTY LIVER DISEASE IN MICE. TRANSCRIPTOME ANALYSIS REVEALED UP-REGULATION OF LIPOGENESIS AND DOWN-REGULATION OF FATTY ACID OXIDATION GENES. AS EVIDENCE OF DIRECT REGULATION, ARID1A DEMONSTRATED DIRECT BINDING TO THE PROMOTERS OF MANY OF THESE DIFFERENTIALLY REGULATED GENES. ADDITIONALLY, ARID1A LKO MICE WERE MORE SUSCEPTIBLE TO HIGH-FAT DIET-INDUCED LIVER STEATOSIS AND FIBROSIS. WE DELETED PTEN IN COMBINATION WITH ARID1A TO SYNERGISTICALLY DRIVE FATTY LIVER PROGRESSION. INHIBITION OF LIPOGENESIS USING CAT-2003, A POTENT STEROL REGULATORY ELEMENT-BINDING PROTEIN INHIBITOR, MEDIATED IMPROVEMENTS IN MARKERS OF FATTY LIVER DISEASE PROGRESSION IN THIS ARID1A/PTEN DOUBLE KNOCKOUT MODEL. CONCLUSION: ARID1A PLAYS A ROLE IN THE EPIGENETIC REGULATION OF HEPATIC LIPID HOMEOSTASIS, AND ITS SUPPRESSION CONTRIBUTES TO FATTY LIVER PATHOGENESIS. COMBINED ARID1A AND PTEN DELETION SHOWS ACCELERATED FATTY LIVER DISEASE PROGRESSION AND IS A USEFUL MOUSE MODEL FOR STUDYING THERAPEUTIC STRATEGIES FOR NASH. 2019 13 6264 28 THE MULTIPLE-HIT PATHOGENESIS OF NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD). NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS INCREASINGLY PREVALENT AND REPRESENTS A GROWING CHALLENGE IN TERMS OF PREVENTION AND TREATMENT. DESPITE ITS HIGH PREVALENCE, ONLY A SMALL MINORITY OF AFFECTED PATIENTS DEVELOPS INFLAMMATION AND SUBSEQUENTLY FIBROSIS AND CHRONIC LIVER DISEASE, WHILE MOST OF THEM ONLY EXHIBIT SIMPLE STEATOSIS. IN THIS CONTEXT, THE FULL UNDERSTANDING OF THE MECHANISMS UNDERLYING THE DEVELOPMENT OF NAFLD AND NON-ALCOHOLIC STEATOHEPATITIS (NASH) IS OF EXTREME IMPORTANCE; DESPITE ADVANCES IN THIS FIELD, KNOWLEDGE ON THE PATHOGENESIS OF NAFLD IS STILL INCOMPLETE. THE 'TWO-HIT' HYPOTHESIS IS NOW OBSOLETE, AS IT IS INADEQUATE TO EXPLAIN THE SEVERAL MOLECULAR AND METABOLIC CHANGES THAT TAKE PLACE IN NAFLD. THE "MULTIPLE HIT" HYPOTHESIS CONSIDERS MULTIPLE INSULTS ACTING TOGETHER ON GENETICALLY PREDISPOSED SUBJECTS TO INDUCE NAFLD AND PROVIDES A MORE ACCURATE EXPLANATION OF NAFLD PATHOGENESIS. SUCH HITS INCLUDE INSULIN RESISTANCE, HORMONES SECRETED FROM THE ADIPOSE TISSUE, NUTRITIONAL FACTORS, GUT MICROBIOTA AND GENETIC AND EPIGENETIC FACTORS. IN THIS ARTICLE, WE REVIEW THE FACTORS THAT FORM THIS HYPOTHESIS. 2016 14 6651 28 UPDATE ON GENETICS AND EPIGENETICS IN METABOLIC ASSOCIATED FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS BECOMING THE MOST FREQUENT CHRONIC LIVER DISEASE WORLDWIDE. METABOLIC (DYSFUNCTION) ASSOCIATED FATTY LIVER DISEASE (MAFLD) IS SUGGESTED TO REPLACE THE NOMENCLATURE OF NAFLD. FOR INDIVIDUALS WITH METABOLIC DYSFUNCTION, MULTIPLE NAFLD-RELATED FACTORS ALSO CONTRIBUTE TO THE DEVELOPMENT AND PROGRESSION OF MAFLD INCLUDING GENETICS AND EPIGENETICS. THE APPLICATION OF GENOME-WIDE ASSOCIATION STUDY (GWAS) AND EXOME-WIDE ASSOCIATION STUDY (EWAS) UNCOVERS SINGLE-NUCLEOTIDE POLYMORPHISMS (SNPS) IN MAFLD. IN ADDITION TO THE CLASSIC SNPS IN PNPLA3, TM6SF2, AND GCKR, SOME NEW SNPS HAVE BEEN FOUND RECENTLY TO CONTRIBUTE TO THE PATHOGENESIS OF LIVER STEATOSIS. EPIGENETIC FACTORS INVOLVING DNA METHYLATION, HISTONE MODIFICATIONS, NON-CODING RNAS REGULATIONS, AND RNA METHYLATION ALSO PLAY A CRITICAL ROLE IN MAFLD. DNA METHYLATION IS THE MOST REPORTED EPIGENETIC MODIFICATION. DEVELOPING A NON-INVASION BIOMARKER TO DISTINGUISH METABOLIC STEATOHEPATITIS (MASH) OR LIVER FIBROSIS IS ONGOING. IN THIS REVIEW, WE SUMMARIZED AND DISCUSSED THE LATEST PROGRESS IN GENETIC AND EPIGENETIC FACTORS OF NAFLD/MAFLD, IN ORDER TO PROVIDE POTENTIAL CLUES FOR MAFLD TREATMENT. 2022 15 4314 27 MICRORNAS AS CONTROLLED SYSTEMS AND CONTROLLERS IN NON-ALCOHOLIC FATTY LIVER DISEASE. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A MULTI-FACETED CONDITION INCLUDING SIMPLE STEATOSIS ALONE OR ASSOCIATED WITH INFLAMMATION AND BALLOONING (NON-ALCOHOLIC STEATOHEPATITIS) AND EVENTUALLY FIBROSIS. THE NAFLD INCIDENCE HAS INCREASED OVER THE LAST TWENTY YEARS BECOMING THE MOST FREQUENT CHRONIC LIVER DISEASE IN INDUSTRIALIZED COUNTRIES. OBESITY, VISCERAL ADIPOSITY, INSULIN RESISTANCE, AND MANY OTHER DISORDERS THAT CHARACTERIZE METABOLIC SYNDROME ARE THE MAJOR PREDISPOSING RISK FACTORS FOR NAFLD. FURTHERMORE, DIFFERENT FACTORS, INCLUDING GENETIC BACKGROUND, EPIGENETIC MECHANISMS AND ENVIRONMENTAL FACTORS, SUCH AS DIET AND PHYSICAL EXERCISE, CONTRIBUTE TO NAFLD DEVELOPMENT AND PROGRESSION. SEVERAL LINES OF EVIDENCE DEMONSTRATE THAT SPECIFIC MICRORNAS EXPRESSION PROFILES ARE STRONGLY ASSOCIATED WITH SEVERAL PATHOLOGICAL CONDITIONS INCLUDING NAFLD. IN NAFLD, MICRORNA DEREGULATION IN RESPONSE TO INTRINSIC GENETIC OR EPIGENETIC FACTORS OR ENVIRONMENTAL FACTORS CONTRIBUTES TO METABOLIC DYSFUNCTION. IN THIS REVIEW WE FOCUSED ON MICRORNAS ROLE BOTH AS CONTROLLED AND CONTROLLERS MOLECULES IN NAFLD DEVELOPMENT AND/OR THEIR EVENTUAL VALUE AS NON-INVASIVE BIOMARKERS OF DISEASE. 2014 16 1348 26 DETERMINANTS OF FIBROSIS PROGRESSION AND REGRESSION IN NASH. CIRRHOSIS HAS BECOME THE MAJOR LIVER-RELATED CLINICAL ENDPOINT IN NON-ALCOHOLIC STEATOHEPATITIS (NASH). HOWEVER, PROGRESSION TO CIRRHOSIS IS LESS PREDICTABLE IN NASH THAN IN OTHER CHRONIC LIVER DISEASES. THIS IS DUE TO THE COMPLEX AND MULTIFACTORIAL AETIOLOGY OF NASH, WHICH IS DETERMINED BY LIFESTYLE AND NUTRITION, MULTIPLE GENETIC AND EPIGENETIC FACTORS, AND A PROMINENT ROLE OF HEPATIC AND EXTRAHEPATIC COMORBIDITIES. THUS, MODEST CHANGES IN THESE COFACTORS CAN ALSO INDUCE FIBROSIS REGRESSION, AT LEAST IN PATIENTS WITH PRECIRRHOTIC LIVER DISEASE. FIBROGENESIS IN NASH CORRELATES WITH, BUT IS INDIRECTLY COUPLED TO, CLASSICAL INFLAMMATION, SINCE FIBROSIS PROGRESSION IS DRIVEN BY REPETITIVE PERIODS OF REPAIR. WHILE HEPATOCYTE LIPOAPOPTOSIS IS A KEY DRIVING FORCE OF FIBROSIS PROGRESSION, ACTIVATED HEPATIC STELLATE CELLS, MYOFIBROBLASTS, CHOLANGIOCYTES, MACROPHAGES AND COMPONENTS OF THE PATHOLOGICAL EXTRACELLULAR MATRIX ARE MAJOR FIBROGENIC EFFECTORS AND THUS PHARMACOLOGICAL TARGETS FOR THERAPIES AIMED AT INHIBITION OF FIBROSIS PROGRESSION OR INDUCTION OF FIBROSIS REVERSAL. THE ADVENT OF NOVEL, HIGHLY SENSITIVE AND SPECIFIC SERUM BIOMARKERS AND IMAGING METHODS TO ASSESS THE DYNAMICS OF LIVER FIBROSIS IN NASH WILL IMPROVE DETECTION, STRATIFICATION AND FOLLOW-UP OF PATIENTS WITH PROGRESSIVE NASH . THESE NON-INVASIVE TOOLS WILL ALSO PROMOTE THE CLINICAL DEVELOPMENT OF ANTIFIBROTIC DRUGS, BY PERMITTING THE DESIGN OF LEAN PROOF-OF-CONCEPT STUDIES, AND ENABLING DEVELOPMENT OF A PERSONALISED ANTIFIBROTIC THERAPY FOR PATIENTS WITH RAPID FIBROSIS PROGRESSION OR ADVANCED DISEASE. 2018 17 4884 28 OVERVIEW OF THE PATHOGENESIS, GENETIC, AND NON-INVASIVE CLINICAL, BIOCHEMICAL, AND SCORING METHODS IN THE ASSESSMENT OF NAFLD. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST PREVALENT CHRONIC LIVER DISEASE WORLDWIDE. IT REPRESENTS A RANGE OF DISORDERS, INCLUDING SIMPLE STEATOSIS, NONALCOHOLIC STEATOHEPATITIS (NASH), AND LIVER CIRRHOSIS, AND ITS PREVALENCE CONTINUES TO RISE. IN SOME CASES, HEPATOCELLULAR CARCINOMA (HCC) MAY DEVELOP. THE DEVELOP;MENT OF NON-INVASIVE DIAGNOSTIC AND SCREENING TOOLS IS NEEDED, IN ORDER TO REDUCE THE FREQUENCY OF LIVER BIOPSIES. THE MOST PROMISING METHODS ARE THOSE ABLE TO EXCLUDE ADVANCED FIBROSIS AND QUANTIFY STEATOSIS. IN THIS STUDY, NEW PERSPECTIVE MARKERS FOR INFLAMMATION, OXIDATIVE STRESS, APOPTOSIS, AND FIBROGENESIS; EMERGING SCORING MODELS FOR DETECTING HEPATIC STEATOSIS AND FIBROSIS; AND NEW GENETIC, EPIGENETIC, AND MULTIOMIC STUDIES ARE DISCUSSED. AS ISOLATED BIOCHEMICAL PARAMETERS ARE NOT SPECIFIC OR SENSITIVE ENOUGH TO PREDICT THE PRESENCE OF NASH AND FIBROSIS, THERE IS A TENDENCY TO USE VARIOUS MARKERS AND COMBINE THEM INTO MATHEMATICAL ALGORITHMS. SEVERAL PREDICTIVE MODELS AND SCORING SYSTEMS HAVE BEEN DEVELOPED. CURRENT DATA SUGGESTS THAT PANELS OF MARKERS (NAFLD FIBROSIS SCORE, FIB-4 SCORE, BARD SCORE, AND OTHERS) ARE USEFUL DIAGNOSTIC MODALITIES TO MINIMIZE THE NUMBER OF LIVER BIOPSIES. THE REVIEW UNVEILS PATHOPHYSIOLOGICAL ASPECTS RELATED TO NEW TRENDS IN CURRENT NON-INVASIVE BIOCHEMICAL, GENETIC, AND SCORING METHODS, AND PROVIDES INSIGHT INTO THEIR DIAGNOSTIC ACCURACIES AND SUITABILITY IN CLINICAL PRACTICE. 2019 18 1666 30 DOWNREGULATION OF MICRORNA-145A-5P PROMOTES STEATOSIS-TO-NASH PROGRESSION THROUGH UPREGULATION OF NR4A2. BACKGROUND & AIMS: THE MOLECULAR MECHANISMS UNDERLYING THE PROGRESSION OF SIMPLE STEATOSIS TO NON-ALCOHOLIC STEATOHEPATITIS (NASH) REMAIN INCOMPLETELY UNDERSTOOD, THOUGH THE POTENTIAL ROLE OF EPIGENETIC REGULATION BY MICRORNA (MIRNAS) IS AN AREA OF INCREASING INTEREST. IN THE PRESENT STUDY, WE AIMED TO INVESTIGATE THE ROLE AND MECHANISM OF MIRNAS DURING STEATOSIS-TO-NASH PROGRESSION. METHODS: MIR-145A-5P WAS IDENTIFIED AS AN IMPORTANT CHECKPOINT IN STEATOSIS-TO-NASH PROGRESSION. IN VIVO LOSS-OF-FUNCTION AND GAIN-OF-FUNCTION STUDIES WERE PERFORMED TO EXPLORE THE ROLE OF MIR-145A-5P AND NR4A2 IN NASH PROGRESSION. RNA-SEQUENCING AND BIOINFORMATIC ANALYSIS WERE USED TO INVESTIGATE THE TARGETS OF MIR-145A-5P. RESULTS: SUPPRESSION OF MIR-145A-5P IN THE LIVER AGGRAVATED LIPID ACCUMULATION AND ACTIVATED HEPATIC INFLAMMATION, LIVER INJURY AND FIBROSIS IN STEATOTIC MICE, WHEREAS ITS RESTORATION MARKEDLY ATTENUATED DIET-INDUCED NASH PATHOGENESIS. MECHANISTICALLY, MIR-145A-5P WAS ABLE TO DOWNREGULATE THE NUCLEAR RECEPTOR NR4A2 AND THUS INHIBIT THE EXPRESSION OF NASH-ASSOCIATED GENES. SIMILARLY, NR4A2 OVEREXPRESSION PROMOTED STEATOSIS-TO-NASH PROGRESSION WHILE LIVER-SPECIFIC NR4A2 KNOCKOUT MICE WERE PROTECTED FROM DIET-INDUCED NASH. THIS ROLE OF THE MIR-145A-5P/NR4A2 REGULATORY AXIS WAS ALSO CONFIRMED IN PRIMARY HUMAN HEPATOCYTES. FURTHERMORE, THE EXPRESSION OF MIR-145A-5P WAS REDUCED AND THE EXPRESSION OF NR4A2 WAS INCREASED IN THE LIVERS OF PATIENTS WITH NASH, WHILE THEIR EXPRESSION LEVELS SIGNIFICANTLY NEGATIVELY AND POSITIVELY CORRELATED WITH FEATURES OF LIVER PATHOLOGY, RESPECTIVELY. CONCLUSIONS: OUR FINDINGS HIGHLIGHT THE ROLE OF THE MIR-145A-5P/NR4A2 REGULATORY AXIS IN STEATOSIS-TO-NASH PROGRESSION, SUGGESTING THAT EITHER SUPPLEMENTATION OF MIR-145A-5P OR PHARMACOLOGICAL INHIBITION OF NR4A2 IN HEPATOCYTES MAY PROVIDE A PROMISING THERAPEUTIC APPROACH FOR THE TREATMENT OF NASH. IMPACT AND IMPLICATIONS: NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A DYNAMIC SPECTRUM OF CHRONIC LIVER DISEASES RANGING FROM SIMPLE STEATOSIS TO NON-ALCOHOLIC STEATOHEPATITIS (NASH). UNFORTUNATELY, THERE ARE CURRENTLY NO APPROVED DRUGS FOR NASH. OUR CURRENT STUDY IDENTIFIED MIR-145A-5P AS A NOVEL REGULATOR THAT INHIBITS STEATOSIS-TO-NASH PROGRESSION. WE FOUND THAT MIR-145A-5P WAS ABLE TO DOWNREGULATE THE NUCLEAR RECEPTOR NR4A2 TO SUPPRESS THE EXPRESSION OF NASH-ASSOCIATED GENES. THE DIFFERENTIAL EXPRESSION OF MIR-145A-5P AND NR4A2 WAS FURTHER CONFIRMED IN PATIENTS WITH NASH, RAISING THE POSSIBILITY THAT SUPPLEMENTATION OF MIR-145A-5P OR SUPPRESSION OF NR4A2 IN HEPATOCYTES MIGHT PROVIDE NOVEL STRATEGIES FOR TREATING NASH. 2023 19 5234 28 PROFILE ANALYSIS AND FUNCTIONAL MODELING IDENTIFY CIRCULAR RNAS IN NONALCOHOLIC FATTY LIVER DISEASE AS REGULATORS OF HEPATIC LIPID METABOLISM. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE LEADING CAUSE OF CHRONIC LIVER DISEASE, ASSOCIATED WITH AN OUTCOME OF HEPATIC FIBROSIS/CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. HOWEVER, LIMITED EXPLORATION OF THE UNDERLYING MECHANISMS HINDERS ITS PREVENTION AND TREATMENT. TO INVESTIGATE THE MECHANISMS OF EPIGENETIC REGULATION IN NAFLD, THE EXPRESSION PROFILE OF CIRCULAR RNA (CIRCRNA) OF RODENTS IN WHICH NAFLD WAS INDUCED BY A HIGH-FAT, HIGH-CHOLESTEROL (HFHC) DIET WAS STUDIED. MODELING OF THE CIRCRNA-MICRORNA (MIRNA) -MRNA REGULATORY NETWORK REVEALED THE FUNCTIONAL CHARACTERISTICS OF NAFLD-SPECIFIC CIRCRNAS. THE TARGETS AND EFFECTS IN THE LIVER OF SUCH NAFLD-SPECIFIC CIRCRNAS WERE FURTHER ASSESSED. OUR RESULTS UNCOVERED THAT THE DOWNREGULATION OF 28 ANNOTATED CIRCRNAS CHARACTERIZES HFHC DIET-INDUCED NAFLD. AMONG THE DOWNREGULATED CIRCRNAS, LONG INTERGENIC NON-PROTEIN CODING RNA, P53 INDUCED TRANSCRIPT (LNCPINT) -DERIVED CIRCRNAS (CIRC_0001452, CIRC_0001453, AND CIRC_0001454) TARGETED BOTH MIR-466I-3P AND MIR-669C-3P. THEIR DEFICIENCY IN NAFLD ABROGATED THE CIRCRNA-BASED INHIBITORY EFFECT ON BOTH MIRNAS, WHICH FURTHER INACTIVATED THE AMPK SIGNALING PATHWAY VIA AMPK-ALPHA1 SUPPRESSION. INHIBITION OF THE AMPK SIGNALING PATHWAY PROMOTES HEPATIC STEATOSIS, DEPENDING ON THE TRANSCRIPTIONAL AND TRANSLATIONAL UPREGULATION OF LIPOGENIC GENES, SUCH AS THOSE ENCODING STEROL REGULATORY ELEMENT-BINDING PROTEIN 1 (SREBP1) AND FATTY ACID SYNTHASE (FASN) IN HEPATOCYTES. THE LEVELS OF LNCPINT-DERIVED CIRCRNAS DISPLAYED A NEGATIVE ASSOCIATION WITH HEPATIC TRIGLYCERIDE (TG) CONCENTRATION. THESE FINDINGS SUGGEST THAT LOSS OF LNCPINT-DERIVED CIRCRNAS MAY UNDERLIE NAFLD VIA MIR-466I-3P- AND MIR-669C-3P-DEPENDENT INACTIVATION OF THE AMPK SIGNALING PATHWAY. 2022 20 2287 29 EPIGENETIC REGULATION IN LEAN NONALCOHOLIC FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), THE MOST PROMINENT CAUSE OF CHRONIC LIVER DISEASE WORLDWIDE, IS A RAPIDLY GROWING EPIDEMIC. IT CONSISTS OF A WIDE RANGE OF LIVER DISEASES, FROM STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS, AND PREDISPOSES PATIENTS TO LIVER FIBROSIS, CIRRHOSIS, AND EVEN HEPATOCELLULAR CARCINOMA. NAFLD IS STRONGLY CORRELATED WITH OBESITY; HOWEVER, IT HAS BEEN EXTENSIVELY REPORTED AMONG LEAN/NONOBESE INDIVIDUALS IN RECENT YEARS. ALTHOUGH LEAN PATIENTS DEMONSTRATE A LOWER PREVALENCE OF DIABETES MELLITUS, CENTRAL OBESITY, DYSLIPIDEMIA, HYPERTENSION, AND METABOLIC SYNDROME, A PERCENTAGE OF THESE PATIENTS MAY DEVELOP STEATOHEPATITIS, ADVANCED LIVER FIBROSIS, AND CARDIOVASCULAR DISEASE, AND HAVE INCREASED ALL-CAUSE MORTALITY. THE PATHOPHYSIOLOGICAL MECHANISMS OF LEAN NAFLD REMAIN VAGUE. STUDIES HAVE REPORTED THAT LEAN NAFLD DEMONSTRATES A CLOSE ASSOCIATION WITH ENVIRONMENTAL FACTORS, GENETIC PREDISPOSITION, AND EPIGENETIC MODIFICATIONS. IN THIS REVIEW, WE AIM TO DISCUSS AND SUMMARIZE THE EPIGENETIC MECHANISMS INVOLVED IN LEAN NAFLD AND TO INTRODUCE THE INTERACTION BETWEEN EPIGENETIC PATTERNS AND GENETIC OR NON GENETIC FACTORS. SEVERAL EPIGENETIC MECHANISMS HAVE BEEN IMPLICATED IN THE REGULATION OF LEAN NAFLD. THESE INCLUDE DNA METHYLATION, HISTONE MODIFICATIONS, AND NONCODING-RNA-MEDIATED GENE REGULATION. EPIGENETICS IS AN AREA OF SPECIAL INTEREST IN THE SETTING OF LEAN NAFLD AS IT COULD PROVIDE NEW INSIGHTS INTO THE THERAPEUTIC OPTIONS AND NONINVASIVE BIOMARKERS THAT TARGET THIS UNDER-RECOGNIZED AND CHALLENGING DISORDER. 2023