1 6106 92 THE EMERGING ROLE OF MICRORNAS IN NAFLD: HIGHLIGHT OF MICRORNA-29A IN MODULATING OXIDATIVE STRESS, INFLAMMATION, AND BEYOND. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A COMMON CAUSE OF CHRONIC LIVER DISEASE AND RANGES FROM STEATOSIS TO STEATOHEPATITIS AND TO LIVER FIBROSIS. LIPOTOXICITY IN HEPATOCYTES, ELEVATED OXIDATIVE STRESS AND THE ACTIVATION OF PROINFLAMMATORY MEDIATORS OF KUPFFER CELLS, AND FIBROGENIC PATHWAYS OF ACTIVATED HEPATIC STELLATE CELLS CAN CONTRIBUTE TO THE DEVELOPMENT OF NAFLD. MICRORNAS (MIRS) PLAY A CRUCIAL ROLE IN THE DYSREGULATED METABOLISM AND INFLAMMATORY SIGNALING CONNECTED WITH NAFLD AND ITS PROGRESSION TOWARDS MORE SEVERE STAGES. OF NOTE, THE PROTECTIVE EFFECT OF NON-CODING MIR-29A ON LIVER DAMAGE AND ITS VERSATILE ACTION ON EPIGENETIC ACTIVITY, MITOCHONDRIAL HOMEOSTASIS AND IMMUNOMODULATION MAY IMPROVE OUR PERCEPTION OF THE PATHOGENESIS OF NAFLD. HEREIN, WE REVIEW THE BIOLOGICAL FUNCTIONS OF CRITICAL MIRS IN NAFLD, AS WELL AS HIGHLIGHT THE EMERGING ROLE OF MIR-29A IN THERAPEUTIC APPLICATION AND THE RECENT ADVANCES IN MOLECULAR MECHANISMS UNDERLYING ITS LIVER PROTECTIVE EFFECT. 2020 2 1721 37 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 3 5386 36 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 4 4326 40 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 5 4722 32 NONCODING RNAS IN NONALCOHOLIC FATTY LIVER DISEASE: POTENTIAL DIAGNOSIS AND PROGNOSIS BIOMARKERS. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS CURRENTLY THE MOST COMMON CHRONIC LIVER DISEASE WORLDWIDE IN PART DUE TO THE CONCOMITANT OBESITY PANDEMIC AND INSULIN RESISTANCE (IR). IT IS INCREASINGLY BECOMING EVIDENT THAT NAFLD IS A DISEASE AFFECTING NUMEROUS EXTRAHEPATIC VITAL ORGANS AND REGULATORY PATHWAYS. THE MOLECULAR MECHANISMS UNDERLYING THE NONALCOHOLIC STEATOSIS FORMATION ARE POORLY UNDERSTOOD, AND LITTLE INFORMATION IS AVAILABLE ON THE PATHWAYS THAT ARE RESPONSIBLE FOR THE PROGRESSIVE HEPATOCELLULAR DAMAGE THAT FOLLOWS LIPID ACCUMULATION. RECENTLY, MUCH RESEARCH HAS FOCUSED ON THE IDENTIFICATION OF THE EPIGENETIC MODIFICATIONS THAT CONTRIBUTE TO NAFLD PATHOGENESIS. NONCODING RNAS (NCRNAS) ARE ONE OF SUCH EPIGENETIC FACTORS THAT COULD BE IMPLICATED IN THE NAFLD DEVELOPMENT AND PROGRESSION. IN THIS REVIEW, WE SUMMARIZE THE CURRENT KNOWLEDGE OF THE GENETIC AND EPIGENETIC FACTORS POTENTIALLY UNDERLYING THE DISEASE. PARTICULAR EMPHASIS WILL BE PUT ON THE CONTRIBUTION OF MICRORNAS (MIRNAS), LONG NONCODING RNAS (LNCRNAS), AND CIRCULAR RNAS (CIRCRNAS) TO THE PATHOPHYSIOLOGY OF NAFLD AS WELL AS THEIR POTENTIAL USE AS THERAPEUTIC TARGETS OR AS MARKERS FOR THE PREDICTION AND THE PROGRESSION OF THE DISEASE. 2020 6 1285 35 DECIPHERING THE ROLE OF ABERRANT DNA METHYLATION IN NAFLD AND NASH. THE GLOBAL INCIDENCE OF NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS MOUNTING INCESSANTLY, AND IT IS EMERGING AS THE MOST FREQUENT CAUSE OF CHRONIC AND END STAGE LIVER DISORDERS. IT IS THE STARTING POINT FOR A RANGE OF CONDITIONS FROM SIMPLE STEATOSIS TO MORE PROGRESSIVE NONALCOHOLIC STEATOHEPATITIS (NASH) AND ASSOCIATED HEPATOCELLULAR CARCINOMA (HCC). DYSREGULATION OF INSULIN SECRETION AND DYSLIPIDEMIA DUE TO OBESITY AND OTHER LIFESTYLE VARIABLES ARE THE PRIMARY CONTRIBUTORS TO ESTABLISHMENT OF NAFLD. ONSET AND PROGRESSION OF NAFLD IS ORCHESTRATED BY AN INTERPLAY OF METABOLIC ENVIRONMENT WITH GENETIC AND EPIGENETIC FACTORS. AN INCOMPLETELY UNDERSTOOD MECHANISM OF NAFLD PROGRESSION HAS GREATLY HAMPERED THE PROGRESS IN IDENTIFICATION OF NOVEL PROGNOSTIC AND THERAPEUTIC STRATEGIES. EMERGING EVIDENCE SUGGESTS ALTERED DNA METHYLATION PATTERN AS A KEY DETERMINANT OF NAFLD PATHOGENESIS. ENVIRONMENTAL AND LIFESTYLE FACTORS CAN MANIPULATE DNA METHYLATION PATTERNS IN A REVERSIBLE MANNER, WHICH MANIFESTS AS CHANGES IN GENE EXPRESSION. IN THIS REVIEW WE ATTEMPT TO HIGHLIGHT THE IMPORTANCE OF DNA METHYLATION IN ESTABLISHMENT AND PROGRESSION OF NAFLD. DEVELOPMENT OF NOVEL DIAGNOSTIC, PROGNOSTIC AND THERAPEUTIC STRATEGIES CENTERED AROUND DNA METHYLATION SIGNATURES AND MODIFIERS HAS ALSO BEEN EXPLORED. 2022 7 4720 37 NONCODING RNAS AS ADDITIONAL MEDIATORS OF EPIGENETIC REGULATION IN NONALCOHOLIC FATTY LIVER DISEASE. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) HAS EMERGED AS THE MOST COMMON CAUSE OF CHRONIC LIVER DISORDER WORLDWIDE. IT REPRESENTS A SPECTRUM THAT INCLUDES A CONTINUUM OF DIFFERENT CLINICAL ENTITIES RANGING FROM SIMPLE STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS, WHICH CAN EVOLVE TO CIRRHOSIS AND IN SOME CASES TO HEPATOCELLULAR CARCINOMA, ULTIMATELY LEADING TO LIVER FAILURE. THE PATHOGENESIS OF NAFLD AND THE MECHANISMS UNDERLYING ITS PROGRESSION TO MORE PATHOLOGICAL STAGES ARE NOT COMPLETELY UNDERSTOOD. BESIDES GENETIC FACTORS, EVIDENCE INDICATES THAT EPIGENETIC MECHANISMS OCCURRING IN RESPONSE TO ENVIRONMENTAL STIMULI ALSO CONTRIBUTE TO THE DISEASE RISK. NONCODING RNAS (NCRNAS), INCLUDING MICRORNAS, LONG NONCODING RNAS, AND CIRCULAR RNAS, ARE ONE OF THE EPIGENETIC FACTORS THAT PLAY KEY REGULATORY ROLES IN THE DEVELOPMENT OF NAFLD. AS THE FIELD OF NCRNAS IS RAPIDLY EVOLVING, THE PRESENT REVIEW AIMS TO EXPLORE THE CURRENT STATE OF KNOWLEDGE ON THE ROLES OF THESE RNA SPECIES IN THE PATHOGENESIS OF NAFLD, HIGHLIGHT RELEVANT MECHANISMS BY WHICH SOME NCRNAS CAN MODULATE REGULATORY NETWORKS IMPLICATED IN NAFLD, AND DISCUSS KEY CHALLENGES AND FUTURE DIRECTIONS FACING CURRENT RESEARCH IN THE HOPES OF DEVELOPING NCRNAS AS NEXT-GENERATION NON-INVASIVE DIAGNOSTICS AND THERAPIES IN NAFLD AND SUBSEQUENT PROGRESSION TO HEPATOCELLULAR CARCINOMA. 2022 8 4369 37 MIRNAS AND NAFLD: FROM PATHOPHYSIOLOGY TO THERAPY. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ASSOCIATED WITH A THOROUGH REPROGRAMMING OF HEPATIC METABOLISM. EPIGENETIC MECHANISMS, IN PARTICULAR THOSE ASSOCIATED WITH DEREGULATION OF THE EXPRESSIONS AND ACTIVITIES OF MICRORNAS (MIRNAS), PLAY A MAJOR ROLE IN METABOLIC DISORDERS ASSOCIATED WITH NAFLD AND THEIR PROGRESSION TOWARDS MORE SEVERE STAGES OF THE DISEASE. IN THIS REVIEW, WE DISCUSS THE RECENT PROGRESS ADDRESSING THE ROLE OF THE MANY FACETS OF COMPLEX MIRNA REGULATORY NETWORKS IN THE DEVELOPMENT AND PROGRESSION OF NAFLD. THE BASIC CONCEPTS AND MECHANISMS OF MIRNA-MEDIATED GENE REGULATION AS WELL AS THE VARIOUS SETBACKS ENCOUNTERED IN BASIC AND TRANSLATIONAL RESEARCH IN THIS FIELD ARE DEBATED. MIRNAS IDENTIFIED SO FAR, WHOSE EXPRESSIONS/ACTIVITIES ARE DEREGULATED IN NAFLD, AND WHICH CONTRIBUTE TO THE OUTCOMES OF THIS PATHOLOGY ARE FURTHER REVIEWED. FINALLY, THE POTENTIAL THERAPEUTIC USAGES IN A SHORT TO MEDIUM TERM OF MIRNA-BASED STRATEGIES IN NAFLD, IN PARTICULAR TO IDENTIFY NON-INVASIVE BIOMARKERS, OR TO DESIGN PHARMACOLOGICAL ANALOGUES/INHIBITORS HAVING A BROAD RANGE OF ACTIONS ON HEPATIC METABOLISM, ARE HIGHLIGHTED. 2019 9 4314 31 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 10 2502 26 EPIGENETICS AND LIVER FIBROSIS. LIVER FIBROSIS ARISES BECAUSE PROLONGED INJURY COMBINED WITH EXCESSIVE SCAR DEPOSITION WITHIN HEPATIC PARENCHYMA ARISING FROM OVERACTIVE WOUND HEALING RESPONSE MEDIATED BY ACTIVATED MYOFIBROBLASTS. FIBROSIS IS THE COMMON END POINT FOR ANY TYPE OF CHRONIC LIVER INJURY INCLUDING ALCOHOLIC LIVER DISEASE, NONALCOHOLIC FATTY LIVER DISEASE, VIRAL HEPATITIS, AND CHOLESTATIC LIVER DISEASES. ALTHOUGH GENETIC INFLUENCES ARE IMPORTANT, IT IS EPIGENETIC MECHANISMS THAT HAVE BEEN SHOWN TO ORCHESTRATE MANY ASPECTS OF FIBROGENESIS IN THE LIVER. NEW DISCOVERIES IN THE FIELD ARE LEADING TOWARD THE DEVELOPMENT OF EPIGENETIC BIOMARKERS AND TARGETED THERAPIES. THIS REVIEW CONSIDERS EPIGENETIC MECHANISMS AS WELL AS RECENT ADVANCES IN EPIGENETIC PROGRAMMING IN THE CONTEXT OF HEPATIC FIBROSIS. 2017 11 5012 27 PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AS A TARGET AND REGULATOR OF EPIGENETIC MECHANISMS IN NONALCOHOLIC FATTY LIVER DISEASE. PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (PPARGAMMA) BELONGS TO THE SUPERFAMILY OF NUCLEAR RECEPTORS THAT CONTROL THE TRANSCRIPTION OF MULTIPLE GENES. ALTHOUGH IT IS FOUND IN MANY CELLS AND TISSUES, PPARGAMMA IS MOSTLY EXPRESSED IN THE LIVER AND ADIPOSE TISSUE. PRECLINICAL AND CLINICAL STUDIES SHOW THAT PPARGAMMA TARGETS SEVERAL GENES IMPLICATED IN VARIOUS FORMS OF CHRONIC LIVER DISEASE, INCLUDING NONALCOHOLIC FATTY LIVER DISEASE (NAFLD). CLINICAL TRIALS ARE CURRENTLY UNDERWAY TO INVESTIGATE THE BENEFICIAL EFFECTS OF PPARGAMMA AGONISTS ON NAFLD/NONALCOHOLIC STEATOHEPATITIS. UNDERSTANDING PPARGAMMA REGULATORS MAY THEREFORE AID IN UNRAVELING THE MECHANISMS GOVERNING THE DEVELOPMENT AND PROGRESSION OF NAFLD. RECENT ADVANCES IN HIGH-THROUGHPUT BIOLOGY AND GENOME SEQUENCING HAVE GREATLY FACILITATED THE IDENTIFICATION OF EPIGENETIC MODIFIERS, INCLUDING DNA METHYLATION, HISTONE MODIFIERS, AND NON-CODING RNAS AS KEY FACTORS THAT REGULATE PPARGAMMA IN NAFLD. IN CONTRAST, LITTLE IS STILL KNOWN ABOUT THE PARTICULAR MOLECULAR MECHANISMS UNDERLYING THE INTRICATE RELATIONSHIPS BETWEEN THESE EVENTS. THE PAPER THAT FOLLOWS OUTLINES OUR CURRENT UNDERSTANDING OF THE CROSSTALK BETWEEN PPARGAMMA AND EPIGENETIC REGULATORS IN NAFLD. ADVANCES IN THIS FIELD ARE LIKELY TO AID IN THE DEVELOPMENT OF EARLY NONINVASIVE DIAGNOSTICS AND FUTURE NAFLD TREATMENT STRATEGIES BASED ON PPARGAMMA EPIGENETIC CIRCUIT MODIFICATION. 2023 12 2323 23 EPIGENETIC REGULATION OF HEPATIC STELLATE CELL ACTIVATION AND MACROPHAGE IN CHRONIC LIVER INFLAMMATION. CHRONIC LIVER INFLAMMATION IS A COMPLEX PATHOLOGICAL PROCESS UNDER DIFFERENT STRESS CONDITIONS, AND THE ROLES OF STELLATE CELLS AND MACROPHAGES IN CHRONIC LIVER INFLAMMATION HAVE BEEN WIDELY REPORTED. MODERATE LIVER INFLAMMATION CAN PROTECT THE LIVER FROM DAMAGE AND FACILITATE THE RECOVERY OF LIVER INJURY. HOWEVER, AN INFLAMMATORY RESPONSE THAT IS TOO INTENSE CAN RESULT IN MASSIVE DEATH OF HEPATOCYTES, WHICH LEADS TO IRREVERSIBLE DAMAGE TO THE LIVER PARENCHYMA. EPIGENETIC REGULATION PLAYS A KEY PART IN LIVER INFLAMMATION. THIS STUDY REVIEWS THE REGULATION OF EPIGENETICS ON STELLATE CELLS AND MACROPHAGES TO EXPLORE THE NEW MECHANISMS OF EPIGENETICS ON LIVER INFLAMMATION AND PROVIDE NEW IDEAS FOR THE TREATMENT OF LIVER DISEASE. 2021 13 4659 45 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 14 1491 34 DNA HYDROXYMETHYLATION AT THE INTERFACE OF THE ENVIRONMENT AND NONALCOHOLIC FATTY LIVER DISEASE. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE MOST PREVALENT FORMS OF CHRONIC LIVER DISORDERS AMONG ADULTS, CHILDREN, AND ADOLESCENTS, AND A GROWING EPIDEMIC, WORLDWIDE. NOTWITHSTANDING THE KNOWN SUSCEPTIBILITY FACTORS FOR NAFLD, I.E., OBESITY AND METABOLIC SYNDROME, THE EXACT CAUSE(S) OF THIS DISEASE AND THE UNDERLYING MECHANISMS OF ITS INITIATION AND PROGRESSION ARE NOT FULLY ELUCIDATED. NAFLD IS A MULTI-FACETED DISEASE WITH METABOLIC, GENETIC, EPIGENETIC, AND ENVIRONMENTAL DETERMINANTS. ACCUMULATING EVIDENCE SHOWS THAT EXPOSURE TO ENVIRONMENTAL TOXICANTS CONTRIBUTES TO THE DEVELOPMENT OF NAFLD BY PROMOTING MITOCHONDRIAL DYSFUNCTION AND GENERATING REACTIVE OXYGEN SPECIES IN THE LIVER. IMBALANCES IN THE REDOX STATE OF THE CELLS ARE KNOWN TO CAUSE ALTERATIONS IN THE PATTERNS OF 5-HYDROXYMETHYLCYTOSINE (5HMC), THE OXIDATIVE PRODUCT OF 5-METHYLCYTOSINE (5MC), THEREBY INFLUENCING GENE REGULATION. THE 5HMC-MEDIATED DEREGULATION OF GENES INVOLVED IN HEPATIC METABOLISM IS AN EMERGING AREA OF RESEARCH IN NAFLD. THIS REVIEW SUMMARIZES OUR CURRENT KNOWLEDGE ON THE INTERACTIVE ROLE OF XENOBIOTIC EXPOSURE AND DNA HYDROXYMETHYLATION IN THE PATHOGENESIS OF FATTY LIVER DISEASE. INCREASING THE MECHANISTIC KNOWLEDGE OF NAFLD INITIATION AND PROGRESSION IS CRUCIAL FOR THE DEVELOPMENT OF NEW AND EFFECTIVE STRATEGIES FOR PREVENTION AND TREATMENT OF THIS DISEASE. 2019 15 6372 31 THE ROLE OF MIR-29A IN THE REGULATION, FUNCTION, AND SIGNALING OF LIVER FIBROSIS. BOTH FIBROSIS AND CIRRHOSIS OF THE LIVER ARE THE END RESULTS OF MOST KINDS OF CHRONIC LIVER DAMAGE AND REPRESENT A COMMON BUT DIFFICULT CLINICAL CHALLENGE THROUGHOUT THE WORLD. THE INHIBITION OF THE FIBROGENIC, PROLIFERATIVE, AND MIGRATORY EFFECTS OF HEPATIC STELLATE CELLS (HSCS) HAS BECOME AN EXPERIMENTAL THERAPY FOR PREVENTING AND EVEN REVERSING HEPATIC FIBROSIS. FURTHERMORE, A COMPLETE UNDERSTANDING OF THE FUNCTION OF NON-CODING RNA-MEDIATED EPIGENETIC MECHANISMS IN HSC ACTIVATION MAY IMPROVE OUR PERCEPTION OF LIVER FIBROSIS PATHOGENESIS. THIS REVIEW FOCUSES ON THE EVOLVING VIEW OF THE MOLECULAR MECHANISMS BY WHICH HSC ACTIVATION BY MIR-29A SIGNALING MAY MODERATE THE PROFIBROGENIC PHENOTYPE OF THESE CELLS, THUS SUPPORTING THE USE OF MIR-29A AGONISTS AS A POTENTIAL THERAPY FOR TREATING LIVER FIBROSIS IN THE FUTURE. 2018 16 4712 29 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 17 1128 33 COMPREHENSIVE ANALYSIS OF EPIGENETIC AND EPITRANSCRIPTOMIC GENES' EXPRESSION IN HUMAN NAFLD. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A MULTIFACTORIAL CONDITION WITH A COMPLEX ETIOLOGY. ITS INCIDENCE IS INCREASING GLOBALLY IN PARALLEL WITH THE OBESITY EPIDEMIC, AND IT IS NOW CONSIDERED THE MOST COMMON LIVER DISEASE IN WESTERN COUNTRIES. THE PRECISE MECHANISMS UNDERLYING THE DEVELOPMENT AND PROGRESSION OF NAFLD ARE COMPLEX AND STILL POORLY UNDERSTOOD. THE DYSREGULATION OF EPIGENETIC AND EPITRANSCRIPTOMIC MECHANISMS IS INCREASINGLY RECOGNIZED TO PLAY PATHOGENIC ROLES IN MULTIPLE CONDITIONS, INCLUDING CHRONIC LIVER DISEASES. HERE, WE HAVE PERFORMED A COMPREHENSIVE ANALYSIS OF THE EXPRESSION OF EPIGENETIC AND EPITRANSCRIPTOMIC GENES IN A TOTAL OF 903 LIVER TISSUE SAMPLES CORRESPONDING TO PATIENTS WITH NORMAL LIVER, OBESE PATIENTS, AND PATIENTS WITH NON-ALCOHOLIC FATTY LIVER (NAFL) AND NON-ALCOHOLIC STEATOHEPATITIS (NASH), ADVANCING STAGES IN NAFLD PROGRESSION. WE INTEGRATED TEN TRANSCRIPTOMIC DATASETS IN AN UNBIASED MANNER, ENABLING THEIR ROBUST ANALYSIS AND COMPARISON. WE DESCRIBE THE COMPLETE LANDSCAPE OF EPIGENETIC AND EPITRANSCRIPTOMIC GENES' EXPRESSION ALONG THE COURSE OF THE DISEASE. WE IDENTIFY SIGNATURES OF GENES SIGNIFICANTLY DYSREGULATED IN ASSOCIATION WITH DISEASE PROGRESSION, PARTICULARLY WITH LIVER FIBROSIS DEVELOPMENT. MOST OF THESE EPIGENETIC AND EPITRANSCRIPTOMIC EFFECTORS HAVE NOT BEEN PREVIOUSLY DESCRIBED IN HUMAN NAFLD, AND THEIR ALTERED EXPRESSION MAY HAVE PATHOGENIC IMPLICATIONS. WE ALSO PERFORMED A COMPREHENSIVE ANALYSIS OF THE EXPRESSION OF ENZYMES INVOLVED IN THE METABOLISM OF THE SUBSTRATES AND COFACTORS OF EPIGENETIC AND EPITRANSCRIPTOMIC EFFECTORS. THIS STUDY PROVIDES NOVEL INFORMATION ON NAFLD PATHOGENESIS AND MAY ALSO GUIDE THE IDENTIFICATION OF DRUG TARGETS TO TREAT THIS CONDITION AND ITS PROGRESSION TOWARDS HEPATOCELLULAR CARCINOMA. 2023 18 1233 31 CROSSTALK BETWEEN KIDNEY AND LIVER IN NON-ALCOHOLIC FATTY LIVER DISEASE: MECHANISMS AND THERAPEUTIC APPROACHES. LIVER AND KIDNEY ARE VITAL ORGANS THAT MAINTAIN HOMEOSTASIS AND INJURY TO EITHER OF THEM TRIGGERS PATHOGENIC PATHWAYS AFFECTING THE OTHER. FOR EXAMPLE, NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) PROMOTES THE PROGRESSION OF CHRONIC KIDNEY DISEASE (CKD), VICE VERSA ACUTE KIDNEY INJURY (AKI) ENDORSES THE INDUCTION AND PROGRESSION OF LIVER DYSFUNCTION. PROGRESS IN CLINICAL AND BASIC RESEARCH SUGGEST A ROLE OF EXCESSIVE FRUCTOSE INTAKE, INSULIN RESISTANCE, INFLAMMATORY CYTOKINES PRODUCTION, ACTIVATION OF THE RENIN-ANGIOTENSIN SYSTEM, REDOX IMBALANCE, AND THEIR IMPACT ON EPIGENETIC REGULATION OF GENE EXPRESSION IN THIS CONTEXT. RECENT DEVELOPMENTS IN EXPERIMENTAL AND CLINICAL RESEARCH HAVE IDENTIFIED SEVERAL BIOCHEMICAL AND MOLECULAR PATHWAYS FOR AKI-LIVER INTERACTION, INCLUDING ALTERED LIVER ENZYMES PROFILE, METABOLIC ACIDOSIS, OXIDATIVE STRESS, ACTIVATION OF INFLAMMATORY AND REGULATED CELL DEATH PATHWAYS. THIS REVIEW FOCUSES ON THE CURRENT PRECLINICAL AND CLINICAL FINDINGS ON KIDNEY-LIVER CROSSTALK IN NAFLD-CKD AND AKI-LIVER DYSFUNCTION SETTINGS AND HIGHLIGHTS POTENTIAL MOLECULAR MECHANISMS AND THERAPEUTIC TARGETS. 2022 19 394 30 AN UPDATE IN EPIGENETICS IN METABOLIC-ASSOCIATED FATTY LIVER DISEASE. METABOLIC-ASSOCIATED FATTY LIVER DISEASE (MAFLD) IS CHARACTERIZED BY HEPATIC STEATOSIS ACCOMPANIED BY ONE OF THREE FEATURES: OVERWEIGHT OR OBESITY, T2DM, OR LEAN OR NORMAL WEIGHT WITH EVIDENCE OF METABOLIC DYSREGULATION. IT IS DISTINGUISHED BY EXCESSIVE FAT ACCUMULATION IN HEPATOCYTES, AND A DECREASE IN THE LIVER'S ABILITY TO OXIDIZE FATS, THE ACCUMULATION OF ECTOPIC FAT, AND THE ACTIVATION OF PROINFLAMMATORY PATHWAYS. CHRONIC DAMAGE WILL KEEP THIS PATHOPHYSIOLOGIC CYCLE ACTIVE CAUSING PROGRESSION FROM HEPATIC STEATOSIS TO CIRRHOSIS AND EVENTUALLY, HEPATOCARCINOMA. EPIGENETICS AFFECTING GENE EXPRESSION WITHOUT ALTERING DNA SEQUENCE ALLOWS US TO STUDY MAFLD PATHOPHYSIOLOGY FROM A DIFFERENT PERSPECTIVE, IN WHICH DNA METHYLATION PROCESSES, HISTONE MODIFICATIONS, AND MIRNAS EXPRESSION HAVE BEEN CLOSELY ASSOCIATED WITH MAFLD PROGRESSION. HOWEVER, THESE CONSIDERATIONS ALSO FACED US WITH THE CIRCUMSTANCE THAT MODIFYING THOSE EPIGENETICS PATTERNS MIGHT LEAD TO MAFLD REGRESSION. CURRENTLY, EPIGENETICS IS AN AREA OF GREAT INTEREST BECAUSE IT COULD PROVIDE NEW INSIGHTS IN THERAPEUTIC TARGETS AND NON-INVASIVE BIOMARKERS. THIS REVIEW COMPRISES AN UPDATE ON THE ROLE OF EPIGENETIC PATTERNS, AS WELL AS INNOVATIVE THERAPEUTIC TARGETS AND BIOMARKERS IN MAFLD. 2021 20 5150 32 PPARALPHA IN THE EPIGENETIC DRIVER SEAT OF NAFLD: NEW THERAPEUTIC OPPORTUNITIES FOR EPIGENETIC DRUGS? NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A GROWING EPIDEMIC AND THE MOST COMMON CAUSE OF CHRONIC LIVER DISEASE WORLDWIDE. IT CONSISTS OF A SPECTRUM OF LIVER DISORDERS RANGING FROM SIMPLE STEATOSIS TO NASH WHICH PREDISPOSES PATIENTS TO FURTHER FIBROSIS, CIRRHOSIS AND EVEN HEPATOCARCINOMA. DESPITE MUCH RESEARCH, AN APPROVED TREATMENT IS STILL LACKING. FINDING NEW THERAPEUTIC TARGETS HAS THEREFORE BEEN A MAIN PRIORITY. KNOWN AS A MAIN REGULATOR OF THE LIPID METABOLISM AND HIGHLY EXPRESSED IN THE LIVER, THE NUCLEAR RECEPTOR PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-ALPHA (PPARALPHA) HAS BEEN IDENTIFIED AS AN ATTRACTIVE THERAPEUTIC TARGET. SINCE ITS EXPRESSION IS SILENCED BY DNA HYPERMETHYLATION IN NAFLD PATIENTS, MANY RESEARCH STRATEGIES HAVE AIMED TO RESTORE THE EXPRESSION OF PPARALPHA AND ITS TARGET GENES INVOLVED IN LIPID METABOLISM. ALTHOUGH PREVIOUSLY TESTED PPARALPHA AGONISTS DID NOT AMELIORATE THE DISEASE, CURRENT RESEARCH HAS SHOWN THAT PPARALPHA ALSO INTERACTS AND REGULATES EPIGENETIC DNMT1, JMJD3, TET AND SIRT1 ENZYMES. MOREOVER, THERE IS A GROWING BODY OF EVIDENCE SUGGESTING THE ORCHESTRATING ROLE OF EPIGENETICS IN THE DEVELOPMENT AND PROGRESSION OF NAFLD. THEREFORE, CURRENT THERAPEUTIC STRATEGIES ARE SHIFTING MORE TOWARDS EPIGENETIC DRUGS. THIS REVIEW PROVIDES A CONCISE OVERVIEW OF THE EPIGENETIC REGULATION OF NAFLD WITH A FOCUS ON PPARALPHA REGULATION AND HIGHLIGHTS RECENTLY IDENTIFIED EPIGENETIC INTERACTION PARTNERS OF PPARALPHA. 2022