1 4326 110 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 2 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 3 1721 42 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 4 4314 44 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 5 5386 42 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 6 4722 45 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 7 1285 50 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 8 4720 43 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 9 2287 46 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 10 6106 40 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 11 6264 39 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 12 4464 49 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 13 5807 44 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 14 3022 43 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 15 5079 48 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 16 4108 38 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 17 3293 44 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 18 4369 35 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 19 74 56 A MULTIDISCIPLINARY APPROACH AND CURRENT PERSPECTIVE OF NONALCOHOLIC FATTY LIVER DISEASE: A SYSTEMATIC REVIEW. IN RECENT TIMES, NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) HAS BEEN CONSIDERED ONE OF THE MAJOR CAUSES OF LIVER DISEASE ACROSS THE WORLD. NAFLD IS DEFINED AS THE DEPOSITION OF TRIGLYCERIDES IN THE LIVER AND IS ASSOCIATED WITH OBESITY AND METABOLIC SYNDROME. HYPERINSULINEMIA, INSULIN RESISTANCE (IR), FATTY LIVER, HEPATOCYTE INJURY, UNBALANCED PROINFLAMMATORY CYTOKINES, MITOCHONDRIAL DYSFUNCTION, OXIDATIVE STRESS, LIVER INFLAMMATION, AND FIBROSIS ARE THE MAIN PATHOGENESIS IN NAFLD. RECENT STUDIES SUGGEST THAT THE ACTION OF INTESTINAL MICROBIOTA THROUGH CHRONIC INFLAMMATION, INCREASED INTESTINAL PERMEABILITY, AND ENERGY UPTAKE PLAYS A VITAL ROLE IN NAFLD. MOREOVER, POLYCYSTIC OVARIAN SYNDROME ALSO CAUSES NAFLD DEVELOPMENT THROUGH IR. AGE, GENDER, RACE, ETHNICITY, SLEEP, DIET, SEDENTARY LIFESTYLE, AND GENETIC AND EPIGENETIC PATHWAYS ARE SOME CONTRIBUTING FACTORS OF NAFLD THAT CAN EXACERBATE THE RISK OF LIVER CIRRHOSIS AND HEPATOCELLULAR CARCINOMA (HCC) AND EVENTUALLY LEAD TO DEATH. NAFLD HAS VARIOUS PRESENTATIONS, INCLUDING FATIGUE, UNEXPLAINED WEIGHT LOSS, BLOATING, UPPER ABDOMINAL PAIN, DECREASED APPETITE, HEADACHE, ANXIETY, POOR SLEEP, INCREASED THIRST, PALPITATION, AND A FEELING OF WARMTH. SOME STUDIES HAVE SHOWN THAT NAFLD WITH SEVERE CORONAVIRUS DISEASE 2019 (COVID-19) HAS POOR OUTCOMES. THE GOLD STANDARD FOR NAFLD DIAGNOSIS IS LIVER BIOPSY. OTHER DIAGNOSTIC TOOLS ARE IMAGING TESTS, SERUM BIOMARKERS, MICROBIOTA MARKERS, AND TESTS FOR EXTRAHEPATIC COMPLICATIONS. THERE ARE NO SPECIFIC TREATMENTS FOR NAFLD. THEREFORE, THE MAIN CONCERN FOR NAFLD IS TREATING THE COMORBID CONDITIONS SUCH AS ANTI-DIABETIC AGENTS FOR TYPE 2 DIABETES MELLITUS, STATINS TO REDUCE HCC PROGRESSION, ANTIOXIDANTS TO PREVENT HEPATOCELLULAR DAMAGE, AND BARIATRIC SURGERY FOR PATIENTS WITH A BMI OF >40 KG/M(2) AND >35 KG/M(2) WITH COMORBIDITIES. LIFESTYLE AND DIETARY CHANGES ARE CONSIDERED PREVENTIVE STRATEGIES AGAINST NAFLD ADVANCEMENT. INADEQUATE TREATMENT OF NAFLD FURTHER LEADS TO CARDIAC CONSEQUENCES, SLEEP APNEA, CHRONIC KIDNEY DISEASE, AND INFLAMMATORY BOWEL DISEASE. IN THIS SYSTEMATIC REVIEW, WE HAVE BRIEFLY DISCUSSED THE RISK FACTORS, PATHOGENESIS, CLINICAL FEATURES, AND NUMEROUS CONSEQUENCES OF NAFLD. WE HAVE ALSO REVIEWED VARIOUS GUIDELINES FOR NAFLD DIAGNOSIS ALONG WITH EXISTING THERAPEUTIC STRATEGIES FOR THE MANAGEMENT AND PREVENTION OF THE DISEASE. 2022 20 3270 37 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