1 5150 128 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 2 5012 43 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 3 1285 49 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 4 5386 39 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 5 1491 47 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 6 5079 44 PHYSIOPATHOLOGY OF NONALCOHOLIC FATTY LIVER DISEASE: FROM DIET TO NUTRIGENOMICS. PURPOSE OF REVIEW: NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS THE MOST COMMON CAUSE OF CHRONIC LIVER DISEASE WORLDWIDE AND IS STRONGLY ASSOCIATED WITH METABOLIC DISORDERS, SUCH AS OBESITY, TYPE 2 DIABETES MELLITUS, AND METABOLIC SYNDROME, TO THE EXTENT THAT A NEW DEFINITION OF METABOLIC ASSOCIATED FATTY LIVER DISEASE HAS BEEN PROPOSED. RECENT FINDINGS: INSULIN RESISTANCE, WORSENED BY A HIGH-FAT AND HIGH-CARBOHYDRATE DIET, IS THE KEY TO THE PHYSIOPATHOLOGY OF HEPATIC STEATOSIS. THIS IS DRIVEN BY SEVERAL MECHANISMS THAT ARE MOSTLY ACTIVATED AT A GENETIC LEVEL, SUCH AS DE-NOVO LIPOGENESIS AND TRIGLYCERIDE SYNTHESIS. THEREFORE, MANY DIET REGIMENS HAVE BEEN STUDIED, ALTHOUGH SIGNIFICANT CONTROVERSIES REMAIN REGARDING THEIR METABOLIC EFFECTS AND LONG-TERM SUSTAINABILITY. SUMMARY: IN THIS REVIEW, WE SUMMARIZED THE ROLE AND EFFECTS OF THE MAIN MACRONUTRIENTS ON THE DEVELOPMENT OF NAFLD AND DISCUSSED THE MOLECULAR MECHANISMS INVOLVED. WE ALSO DISCUSSED THE IMPORTANCE OF GENETIC POLYMORPHISMS, EPIGENETIC ALTERATIONS, AND DYSBIOSIS TO DETERMINE IF LIFESTYLE MODIFICATION AND A SPECIFIC DIETARY REGIMEN COULD BE AN ESSENTIAL PART OF NAFLD TREATMENT. 2022 7 1721 39 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 8 4369 36 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 4722 39 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 10 6092 38 THE EFFECTS OF EPIGENETIC MODIFICATION ON THE OCCURRENCE AND PROGRESSION OF LIVER DISEASES AND THE INVOLVED MECHANISM. INTRODUCTION: EPIGENETIC MODIFICATION IS A TYPE OF GENE EXPRESSION AND REGULATION THAT DOES NOT INVOLVE CHANGES IN DNA SEQUENCES. AN INCREASING NUMBER OF STUDIES HAVE PROVEN THAT EPIGENETIC MODIFICATIONS PLAY AN IMPORTANT ROLE IN THE OCCURRENCE AND PROGRESSION OF LIVER DISEASES THROUGH THE GENE REGULATION AND PROTEIN EXPRESSIONS OF HEPATOCELLULAR LIPID METABOLISM, INFLAMMATORY REACTION, CELL PROLIFERATION, AND ACTIVATION, ETC.AREAS COVERED: IN THIS STUDY, WE ELABORATED AND ANALYZED THE UNDERLYING FUNCTIONAL MECHANISM OF EPIGENETIC MODIFICATION IN ALCOHOLIC LIVER DISEASE (ALD), NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), LIVER FIBROSIS (LF), VIRAL HEPATITIS, HEPATOCELLULAR CARCINOMA (HCC), AND RESEARCH PROGRESS OF RECENT YEARS.EXPERT OPINION: THE FURTHER UNDERSTANDING OF EPIGENETIC MECHANISMS THAT CAN REGULATE GENE EXPRESSION AND CELL PHENOTYPE LEADS TO NEW INSIGHTS IN EPIGENETIC CONTROL OF CHRONIC LIVER DISEASE. CURRENTLY, HEPATOLOGISTS ARE EXPLORING THE ROLE OF DNA METHYLATION, HISTONE/CHROMATIN MODIFICATION, AND NON-CODING RNA IN SPECIFIC LIVER PATHOLOGY. THESE FINDINGS HAVE LED TO ADVANCES IN DIRECT EPIGENETIC BIOMARKER TESTING OF PATIENT TISSUE OR BODY FLUID SPECIMENS, AS WELL AS QUANTITATIVE ANALYSIS. BASED ON THESE FINDINGS, DRUG VALIDATION OF SOME TARGETS INVOLVED IN THE EPIGENETIC MECHANISM OF LIVER DISEASE IS GRADUALLY BEING CARRIED OUT CLINICALLY. 2020 11 6106 32 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 12 3293 42 HIGH FAT DIET-TRIGGERED NON-ALCOHOLIC FATTY LIVER DISEASE: A REVIEW OF PROPOSED MECHANISMS. OBESITY IS CHARACTERIZED BY THE DEPOSITION OF EXCESSIVE BODY FAT, AND IS CAUSED BY ENERGY IMBALANCE, ESPECIALLY WHEN CONSUMING FAT-RICH DIETS. HIGH FAT DIET (HFD)-ASSOCIATED OBESITY IS GREATLY COMMON IN PATIENTS WITH NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) THAT IS EMERGING AS ONE OF THE MOST UNIVERSAL CAUSES OF LIVER DISEASE WORLDWIDE, ESPECIALLY IN WESTERN COUNTRIES. IN SPITE OF ITS HIGH PREVALENCE, ONLY A SMALL PROPORTION OF AFFECTED INDIVIDUALS WILL BECOME INFLAMED, FOLLOWED BY FIBROSIS AND CHRONIC LIVER DISEASES, AND MOST PATIENTS ONLY SHOW SIMPLE STEATOSIS. IN THIS CASE, THE FULL COMPREHENSION OF THE MECHANISMS UNDERLYING THE PROGRESSION OF NAFLD IS OF EXTREME SIGNIFICANCE; IN SPITE OF PROGRESS IN THIS FIELD, AWARENESS ON THE DEVELOPMENT OF NAFLD IS STILL INCOMPLETE. TRADITIONALLY, LIVER STEATOSIS IS COMMONLY CONNECTED WITH HFD, OBESITY, AND INSULIN RESISTANCE (IR). RECENTLY, VARIOUS POSSIBLE MECHANISMS HAVE BEEN PUT FORWARD FOR LIVER DAMAGE, INCLUDING ENDOPLASMIC RETICULUM STRESS, PERTURBATION OF AUTOPHAGY, MITOCHONDRIAL DYSFUNCTION, HEPATOCELLULAR APOPTOSIS, GUT MICROBIOTA IMBALANCE, DYSREGULATION OF MICRORNAS, AND GENETIC/EPIGENETIC RISK FACTORS, AS WELL AS AN INCREASE IN INFLAMMATORY RESPONSES, AMONG MANY OTHERS. COLLECTIVELY, THESE PROPOSED MECHANISMS ALLOW FOR A VARIETY OF HITS ACTING TOGETHER ON SUBJECTS TO MEDIATED NAFLD AND WILL OFFER A MORE ACCURATE EXPLANATION FOR PROGRESSION OF NAFLD. THEREFORE, THIS REVIEW SUMMARIZES THE PRESENT INFORMATION CONCERNING NAFLD AFTER HFD EXPOSURE, AS WELL AS DISCUSSES POSSIBLE MECHANISMS THROUGH WHICH IT MAY ARISE. 2020 13 1128 44 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 14 2954 43 GENETIC AND EPIGENETIC FACTORS DETERMINING NAFLD RISK. BACKGROUND: HEPATIC STEATOSIS IS A COMMON CHRONIC LIVER DISEASE THAT CAN PROGRESS INTO MORE SEVERE STAGES OF NAFLD OR PROMOTE THE DEVELOPMENT OF LIFE-THREATENING SECONDARY DISEASES FOR SOME OF THOSE AFFECTED. THESE INCLUDE THE LIVER ITSELF (NONALCOHOLIC STEATOHEPATITIS OR NASH; FIBROSIS AND CIRRHOSIS, AND HEPATOCELLULAR CARCINOMA) OR OTHER ORGANS SUCH AS THE VESSELS AND THE HEART (CARDIOVASCULAR DISEASE) OR THE ISLETS OF LANGERHANS (TYPE 2 DIABETES). IN ADDITION TO ELEVATED CALORIC INTAKE AND A SEDENTARY LIFESTYLE, GENETIC AND EPIGENETIC PREDISPOSITION CONTRIBUTE TO THE DEVELOPMENT OF NAFLD AND THE SECONDARY DISEASES. SCOPE OF REVIEW: WE PRESENT DATA FROM GENOME-WIDE ASSOCIATION STUDIES (GWAS) AND FUNCTIONAL STUDIES IN RODENTS WHICH DESCRIBE POLYMORPHISMS IDENTIFIED IN GENES RELEVANT FOR THE DISEASE AS WELL AS CHANGES CAUSED BY ALTERED DNA METHYLATION AND GENE REGULATION VIA SPECIFIC MIRNAS. THE REVIEW ALSO PROVIDES INFORMATION ON THE CURRENT STATUS OF THE USE OF GENETIC AND EPIGENETIC FACTORS AS RISK MARKERS. MAJOR CONCLUSION: WITH OUR OVERVIEW WE PROVIDE AN INSIGHT INTO THE GENETIC AND EPIGENETIC LANDSCAPE OF NAFLD AND ARGUE ABOUT THE APPLICABILITY OF CURRENTLY DEFINED RISK SCORES FOR RISK STRATIFICATION AND CONCLUDE THAT FURTHER EFFORTS ARE NEEDED TO MAKE THE SCORES MORE USABLE AND MEANINGFUL. 2021 15 2287 47 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 16 4314 35 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 17 394 38 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 18 2502 33 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 19 4720 46 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 20 3022 39 GENETICS AND EPIGENETICS PURPOSE IN NONALCOHOLIC FATTY LIVER DISEASE. INTRODUCTION: NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) COMPRISES A BROAD SPECTRUM OF DISEASES, WHICH CAN PROGRESS FROM BENIGN STEATOSIS TO NONALCOHOLIC STEATOHEPATITIS, LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA. NAFLD IS THE MOST COMMON CHRONIC LIVER DISEASE IN DEVELOPED COUNTRIES, AFFECTING APPROXIMATELY 25% OF THE GENERAL POPULATION. INSULIN RESISTANCE, ADIPOSE TISSUE DYSFUNCTION, MITOCHONDRIAL AND ENDOPLASMIC RETICULUM STRESS, CHRONIC INFLAMMATION, GENETIC AND EPIGENETIC FACTORS ARE NAFLD TRIGGERS THAT CONTROL THE DISEASE SUSCEPTIBILITY AND PROGRESSION. AREAS COVERED: IN RECENT YEARS A LARGE NUMBER OF INVESTIGATIONS HAVE BEEN CARRIED OUT TO ELUCIDATE GENETIC AND EPIGENETIC FACTORS IN THE DISEASE PATHOGENESIS, AS WELL AS THE SEARCH FOR DIAGNOSTIC MARKERS AND THERAPEUTIC TARGETS. THIS PAPER OBJECTIVE IS TO REPORT THE MOST STUDIED GENETIC AND EPIGENETIC VARIANTS AROUND NAFLD. EXPERT OPINION: NAFLD LEAD TO VARIOUS COMORBIDITIES, WHICH HAVE A CONSIDERABLE IMPACT ON THE PATIENT WELLNESS AND LIFE QUALITY, AS WELL AS ON THE COSTS THEY GENERATE FOR THE COUNTRY'S HEALTH SERVICES. IT IS ESSENTIAL TO CONTINUE WITH MOLECULAR RESEARCH, SINCE IT COULD BE USED AS A CLINICAL TOOL FOR PROGNOSIS AND DISEASE SEVERITY. SPECIFICALLY, IN THE FIELD OF HEPATOLOGY, PLASMA MIRNAS COULD PROVIDE A NOVEL TOOL IN LIVER DISEASES DIAGNOSIS AND MONITORING, REPRESENTING AN ALTERNATIVE TO INVASIVE DIAGNOSTIC PROCEDURES. 2020