1 5915 124 TARGETING A PHOSPHO-STAT3-MIRNAS PATHWAY IMPROVES VESICULAR HEPATIC STEATOSIS IN AN IN VITRO AND IN VIVO MODEL. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A LEADING CAUSE OF CHRONIC LIVER DISEASE. ALTHOUGH GENETIC PREDISPOSITION AND EPIGENETIC FACTORS CONTRIBUTE TO THE DEVELOPMENT OF NAFLD, OUR UNDERSTANDING OF THE MOLECULAR MECHANISM INVOLVED IN THE PATHOGENESIS OF THE DISEASE IS STILL EMERGING. HERE WE INVESTIGATED A POSSIBLE ROLE OF A MICRORNAS-STAT3 PATHWAY IN THE INDUCTION OF HEPATIC STEATOSIS. DIFFERENTIATED HEPARG CELLS TREATED WITH THE FATTY ACID SODIUM OLEATE (FATTY DHEPARG) RECAPITULATED FEATURES OF LIVER VESICULAR STEATOSIS AND ACTIVATED A CELL-AUTONOMOUS INFLAMMATORY RESPONSE, INDUCING STAT3-TYROSINE-PHOSPHORYLATION. WITH A GENOME-WIDE APPROACH (CHROMATIN IMMUNOPRECIPITATION SEQUENCING), MANY PHOSPHO-STAT3 BINDING SITES WERE IDENTIFIED IN FATTY DHEPARG CELLS AND SEVERAL STAT3 AND/OR NAFLD-REGULATED MICRORNAS SHOWED INCREASED EXPRESSION LEVELS, INCLUDING MIR-21. INNOVATIVE CARS (COHERENT ANTI-STOKES RAMAN SCATTERING) MICROSCOPY REVEALED THAT CHEMICAL INHIBITION OF STAT3 ACTIVITY DECREASED LIPID ACCUMULATION AND DEREGULATED STAT3-RESPONSIVE MICRORNAS, INCLUDING MIR-21, IN LIPID OVERLOADED DHEPARG CELLS. WE WERE ABLE TO SHOW IN VIVO THAT REDUCING PHOSPHO-STAT3-MIR-21 LEVELS IN C57/BL6 MICE LIVER, BY LONG-TERM TREATMENT WITH METFORMIN, PROTECTED MICE FROM AGING-DEPENDENT HEPATIC VESICULAR STEATOSIS. OUR RESULTS IDENTIFIED A MICRORNAS-PHOSPHOSTAT3 PATHWAY INVOLVED IN THE DEVELOPMENT OF HEPATIC STEATOSIS, WHICH MAY REPRESENT A MOLECULAR MARKER FOR BOTH DIAGNOSIS AND THERAPEUTIC TARGETING. 2018 2 2735 30 EXPLORING THE RELATIONSHIP BETWEEN EPIGENETIC DNA METHYLATION AND CARDIAC FIBROSIS THROUGH RAMAN MICROSPECTROSCOPY. CARDIOMYOPATHIES ARE ASSOCIATED WITH FIBROTIC REMODELING OF THE HEART, WHICH IS CHARACTERIZED BY THE EXCESSIVE ACCUMULATION OF COLLAGEN TYPE I (COL I) DUE TO CHRONIC INFLAMMATION AND SUSPECTED EPIGENETIC INFLUENCES. DESPITE THE SEVERITY AND HIGH MORTALITY RATE OF CARDIAC FIBROSIS, CURRENT TREATMENT OPTIONS ARE OFTEN INADEQUATE, UNDERSCORING THE IMPORTANCE OF GAINING A DEEPER UNDERSTANDING OF THE DISEASE'S UNDERLYING MOLECULAR AND CELLULAR MECHANISMS. IN THIS STUDY, THE EXTRACELLULAR MATRIX (ECM) AND NUCLEI IN FIBROTIC AREAS OF DIFFERENT CARDIOMYOPATHIES WERE MOLECULARLY CHARACTERIZED BY RAMAN MICROSPECTROSCOPY AND IMAGING AND COMPARED WITH THE CONTROL MYOCARDIUM. PATIENT SAMPLES WERE OBTAINED FROM HEART TISSUE AFFECTED BY ISCHEMIA, HYPERTROPHY, AND DILATED CARDIOMYOPATHY AND ANALYZED FOR FIBROSIS THROUGH CONVENTIONAL HISTOLOGY AND MARKER-INDEPENDENT RAMAN MICROSPECTROSCOPY (RMS). PROMINENT DIFFERENCES BETWEEN CONTROL MYOCARDIUM AND CARDIOMYOPATHIES WERE REVEALED BY SPECTRAL DECONVOLUTION OF COL I RAMAN SPECTRA. STATISTICALLY SIGNIFICANT DIFFERENCES WERE IDENTIFIED IN THE AMIDE I REGION OF SPECTRAL SUBPEAK AT 1,608 CM(-1), WHICH IS A REPRESENTATIVE ENDOGENOUS MARKER FOR ALTERATIONS IN THE STRUCTURAL CONFORMATION OF COL I FIBERS. MOREOVER, EPIGENETIC 5MC DNA MODIFICATION WAS IDENTIFIED WITHIN CELL NUCLEI BY MULTIVARIATE ANALYSIS. A STATISTICALLY SIGNIFICANT INCREASE IN SIGNAL INTENSITIES OF SPECTRAL FEATURES INDICATIVE OF DNA METHYLATION WAS DETECTED IN CARDIOMYOPATHIES IN ACCORDANCE WITH IMMUNOFLUORESCENCE 5MC STAINING. OVERALL, RMS IS A VERSATILE TECHNOLOGY IN THE DISCRIMINATION OF CARDIOMYOPATHIES BASED ON MOLECULAR EVALUATION OF COL I AND NUCLEI WHILE PROVIDING INSIGHTS INTO THE PATHOGENESIS OF THE DISEASES.NEW & NOTEWORTHY CARDIOMYOPATHIES ARE ASSOCIATED WITH SEVERE FIBROTIC REMODELING OF THE HEART, WHICH IS CHARACTERIZED BY THE EXCESSIVE ACCUMULATION OF COLLAGEN TYPE I (COL I). IN THIS STUDY, WE USED MARKER-INDEPENDENT RAMAN MICROSPECTROSCOPY (RMS) TO GAIN A DEEPER UNDERSTANDING OF THE DISEASE'S UNDERLYING MOLECULAR AND CELLULAR MECHANISMS. 2023 3 4573 22 MYOCARDIAL INFARCTION-ASSOCIATED TRANSCRIPT, A LONG NONCODING RNA, IS OVEREXPRESSED DURING DILATED CARDIOMYOPATHY DUE TO CHRONIC CHAGAS DISEASE. LONG NONCODING RNAS (LNCRNAS) MODULATE GENE EXPRESSION AT THE EPIGENETIC, TRANSCRIPTIONAL, AND POSTTRANSCRIPTIONAL LEVELS. DYSREGULATION OF THE LNCRNA KNOWN AS MYOCARDIAL INFARCTION-ASSOCIATED TRANSCRIPT (MIAT) HAS BEEN ASSOCIATED WITH MYOCARDIAL INFARCTION. CHAGAS DISEASE CAUSES A SEVERE INFLAMMATORY DILATED CHRONIC CARDIOMYOPATHY (CCC). WE INVESTIGATED THE ROLE OF MIAT IN CCC. A WHOLE-TRANSCRIPTOME ANALYSIS OF HEART BIOPSY SPECIMENS AND FORMALIN-FIXED, PARAFFIN-EMBEDDED SAMPLES REVEALED THAT MIAT WAS OVEREXPRESSED IN PATIENTS WITH CCC, COMPARED WITH SUBJECTS WITH NONINFLAMMATORY DILATED CARDIOMYOPATHY AND CONTROLS. THESE RESULTS WERE CONFIRMED IN A MOUSE MODEL. RESULTS SUGGEST THAT MIAT IS A SPECIFIC BIOMARKER OF CCC. 2016 4 1666 52 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 5 4326 36 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 6651 27 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 7 4464 33 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 8 6106 36 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 9 4108 27 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 10 5386 33 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 11 2862 37 FRUCTOSE-MEDIATED EFFECTS ON GENE EXPRESSION AND EPIGENETIC MECHANISMS ASSOCIATED WITH NAFLD PATHOGENESIS. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS A CHRONIC, FREQUENTLY PROGRESSIVE CONDITION THAT DEVELOPS IN RESPONSE TO EXCESSIVE HEPATOCYTE FAT ACCUMULATION (I.E., STEATOSIS) IN THE ABSENCE OF SIGNIFICANT ALCOHOL CONSUMPTION. LIVER STEATOSIS DEVELOPS AS A RESULT OF IMBALANCED LIPID METABOLISM, DRIVEN LARGELY BY INCREASED RATES OF DE NOVO LIPOGENESIS AND HEPATIC FATTY ACID UPTAKE AND REDUCED FATTY ACID OXIDATION AND/OR DISPOSAL TO THE CIRCULATION. FRUCTOSE IS A NATURALLY OCCURRING SIMPLE SUGAR, WHICH IS MOST COMMONLY CONSUMED IN MODERN DIETS IN THE FORM OF SUCROSE, A DISACCHARIDE COMPRISED OF ONE MOLECULE OF FRUCTOSE COVALENTLY BONDED WITH ONE MOLECULE OF GLUCOSE. A NUMBER OF OBSERVATIONAL AND EXPERIMENTAL STUDIES HAVE DEMONSTRATED DETRIMENTAL EFFECTS OF DIETARY FRUCTOSE CONSUMPTION NOT ONLY ON DIVERSE METABOLIC OUTCOMES SUCH AS INSULIN RESISTANCE AND OBESITY, BUT ALSO ON HEPATIC STEATOSIS AND NAFLD-RELATED FIBROSIS. DESPITE THE COMPELLING EVIDENCE THAT EXCESSIVE FRUCTOSE CONSUMPTION IS ASSOCIATED WITH THE PRESENCE OF NAFLD AND MAY EVEN PROMOTE THE DEVELOPMENT AND PROGRESSION OF NAFLD TO MORE CLINICALLY SEVERE PHENOTYPES, THE MOLECULAR MECHANISMS BY WHICH FRUCTOSE ELICITS EFFECTS ON DYSREGULATED LIVER METABOLISM REMAIN UNCLEAR. EMERGING DATA SUGGEST THAT DIETARY FRUCTOSE MAY DIRECTLY ALTER THE EXPRESSION OF GENES INVOLVED IN LIPID METABOLISM, INCLUDING THOSE THAT INCREASE HEPATIC FAT ACCUMULATION OR REDUCE HEPATIC FAT REMOVAL. THE AIM OF THIS REVIEW IS TO SUMMARIZE THE CURRENT RESEARCH SUPPORTING A ROLE FOR DIETARY FRUCTOSE INTAKE IN THE MODULATION OF TRANSCRIPTOMIC AND EPIGENETIC MECHANISMS UNDERLYING THE PATHOGENESIS OF NAFLD. 2020 12 1721 31 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 13 4314 39 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 14 5234 39 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 15 6441 32 THERAPEUTIC APPROACHES FOR NONALCOHOLIC FATTY LIVER DISEASE: ESTABLISHED TARGETS AND DRUGS. NONALCOHOLIC FATTY LIVER DISEASE (NAFLD), AS A MULTISYSTEMIC DISEASE, IS THE MOST PREVALENT CHRONIC LIVER DISEASE CHARACTERIZED BY EXTREMELY COMPLEX PATHOGENIC MECHANISMS AND MULTIFACTORIAL ETIOLOGY, WHICH OFTEN DEVELOPS AS A CONSEQUENCE OF OBESITY, METABOLIC SYNDROME. PATHOPHYSIOLOGICAL MECHANISMS INVOLVED IN THE DEVELOPMENT OF NAFLD INCLUDE DIET, OBESITY, INSULIN RESISTANCE (IR), GENETIC AND EPIGENETIC DETERMINANTS, INTESTINAL DYSBIOSIS, OXIDATIVE/NITROSATIVE STRESS, AUTOPHAGY DYSREGULATION, HEPATIC INFLAMMATION, GUT-LIVER AXIS, GUT MICROBES, IMPAIRED MITOCHONDRIAL METABOLISM AND REGULATION OF HEPATIC LIPID METABOLISM. SOME OF THE NEW DRUGS FOR THE TREATMENT OF NAFLD ARE INTRODUCED HERE. ALL OF THEM ACHIEVE THERAPEUTIC OBJECTIVES BY INTERFERING WITH CERTAIN PATHOPHYSIOLOGICAL PATHWAYS OF NAFLD, INCLUDING FIBROBLAST GROWTH FACTORS (FGF) ANALOGUES, PEROXISOME PROLIFERATOR-ACTIVATED RECEPTORS (PPARS) AGONISTS, GLUCAGON-LIKE PEPTIDE-1 (GLP-1) AGONISTS, G PROTEIN-COUPLED RECEPTORS (GPCRS), SODIUM-GLUCOSE COTRANSPORTER-2 INHIBITORS (SGLT-2I), FARNESOID X RECEPTOR (FXR), FATTY ACID SYNTHASE INHIBITOR (FASNI), ANTIOXIDANTS, ETC. THIS REVIEW DESCRIBES SOME PATHOPHYSIOLOGICAL MECHANISMS OF NAFLD AND ESTABLISHED TARGETS AND DRUGS. 2023 16 3931 20 LIVER INJURY AND THE ACTIVATION OF THE HEPATIC MYOFIBROBLASTS. LIVER FIBROSIS IS A WOUND HEALING PROCESS, THE END RESULT OF CHRONIC LIVER INJURY ELICITED BY DIFFERENT NOXIOUS STIMULI. ACTIVATED HEPATIC STELLATE CELLS OR MYOFIBROBLASTS AND PORTAL MYOFIBROBLASTS ARE CONSIDERED AS THE MAIN PRODUCERS OF THE EXTRACELLULAR MATRIX IN THE LIVER. UPON LIVER INJURY THE QUIESCENT STELLATE CELLS TRANSDIFFERENTIATE INTO MYOFIBROBLASTS A PROCESS HIGHLIGHTED BY THE LOSS OF VITAMIN A STORES, UPREGULATION OF INTERSTITIAL TYPE COLLAGENS, SMOOTH MUSCLE ALPHA ACTIN, MATRIX METALLOPROTEINASES, PROTEOGLYCANS, AND THE INDUCTION OF CELL SURVIVAL PATHWAYS. ACTIVATION OF HEPATIC STELLATE CELLS IS A RESULT OF A COMPLEX INTERPLAY BETWEEN THE PARENCHYMAL CELLS, IMMUNE CELLS, EXTRACELLULAR MATRIX MECHANICS AND EXTRAHEPATIC MILIEU SUCH AS THE GUT MICROBIOME. IN THIS REVIEW WE WILL FOCUS ON THE PATHOMECHANISM OF STELLATE CELL ACTIVATION FOLLOWING CHRONIC LIVER INJURY; WITH THE AIM OF IDENTIFYING POSSIBLE TREATMENT TARGETS FOR ANTI-FIBROGENIC AGENTS. 2013 17 4712 30 NON-ALCOHOLIC FATTY LIVER DISEASE: METABOLIC, GENETIC, EPIGENETIC AND ENVIRONMENTAL RISK FACTORS. NON-ALCOHOLIC FATTY LIVER DISEASE (NAFLD) IS ONE OF THE MOST FREQUENT CAUSES OF CHRONIC LIVER DISEASE IN THE WESTERN WORLD, PROBABLY DUE TO THE GROWING PREVALENCE OF OBESITY, METABOLIC DISEASES, AND EXPOSURE TO SOME ENVIRONMENTAL AGENTS. IN CERTAIN PATIENTS, SIMPLE HEPATIC STEATOSIS CAN PROGRESS TO NON-ALCOHOLIC STEATOHEPATITIS (NASH), WHICH CAN SOMETIMES LEAD TO LIVER CIRRHOSIS AND ITS COMPLICATIONS INCLUDING HEPATOCELLULAR CARCINOMA. UNDERSTANDING THE MECHANISMS THAT CAUSE THE PROGRESSION OF NAFLD TO NASH IS CRUCIAL TO BE ABLE TO CONTROL THE ADVANCEMENT OF THE DISEASE. THE MAIN HYPOTHESIS CONSIDERS THAT IT IS DUE TO MULTIPLE FACTORS THAT ACT TOGETHER ON GENETICALLY PREDISPOSED SUBJECTS TO SUFFER FROM NAFLD INCLUDING INSULIN RESISTANCE, NUTRITIONAL FACTORS, GUT MICROBIOTA, AND GENETIC AND EPIGENETIC FACTORS. IN THIS ARTICLE, WE WILL DISCUSS THE EPIDEMIOLOGY OF NAFLD, AND WE OVERVIEW SEVERAL TOPICS THAT INFLUENCE THE DEVELOPMENT OF THE DISEASE FROM SIMPLE STEATOSIS TO LIVER CIRRHOSIS AND ITS POSSIBLE COMPLICATIONS. 2021 18 74 32 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 19 6393 34 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 20 2817 25 FIBROSIS IN THE LIVER: ACUTE PROTECTION AND CHRONIC DISEASE. THE UNDERSTANDING OF THE CELLULAR AND MOLECULAR MECHANISMS OF THE FIBROTIC WOUND-HEALING RESPONSE OF THE LIVER HAS MADE DRAMATIC PROGRESS IN THE PAST 20 YEARS. HEPATIC STELLATE CELLS (HSCS), WHICH AFTER LIVER INJURY PROLIFERATE AND TRANSDIFFERENTIATE TO MYOFIBROBLASTS, HAVE EMERGED AS THE PRIMARY SOURCE OF THE FIBROTIC RESPONSE, EVEN THOUGH OTHER FIBROGENIC CELLS MAY ALSO CONTRIBUTE TO THE PRODUCTION OF EXTRACELLULAR MATRIX (ECM). ADVANCES IN THE UNDERSTANDING OF HSC REGULATION INCLUDE APOPTOTIC SIGNALING, ANGIOGENIC SIGNALING, AND RESPONSES TO OXIDATIVE STRESS. THE ECM HAS EMERGED NOT ONLY AS A STRUCTURAL SCAFFOLD, BUT ALSO AS A DYNAMIC AND INTERACTIVE MATRIX REGULATING STELLATE CELL ACTIVATION. ADDITIONALLY, THE INNATE IMMUNE SYSTEM AND IMMUNE SIGNALING, AS WELL AS A BROADENING UNDERSTANDING OF THE TRANSCRIPTIONAL REGULATION INCLUDING MICRORNAS AND EPIGENETIC EVENTS OFFER POTENTIAL THERAPEUTIC TARGETS. UNRAVELING GENETIC DETERMINANTS RELATED TO MECHANISMS OF HEPATIC FIBROGENESIS PROMISE INDIVIDUALIZED THERAPY OR PREVENTION. HEPATIC FIBROSIS AND CIRRHOSIS HAVE EMERGED AS TREATABLE AND POTENTIALLY REVERSIBLE CONSEQUENCE OF CHRONIC LIVER DISEASE. 2010