1 3931 84 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 2 4501 25 MORPHOGENS AND HEPATIC STELLATE CELL FATE REGULATION IN CHRONIC LIVER DISEASE. HEPATIC STELLATE CELLS (HSC) ARE THE LIVER MESENCHYMAL CELL TYPE WHICH RESPONDS TO HEPATOCELLULAR DAMAGE AND PARTICIPATES IN WOUND HEALING. ALTHOUGH HSC MYOFIBROBLASTIC TRANS-DIFFERENTIATION (ACTIVATION) IS IMPLICATED IN EXCESSIVE EXTRACELLULAR MATRIX DEPOSITION, MOLECULAR UNDERSTANDING OF THIS PHENOTYPIC SWITCH FROM THE VIEWPOINT OF CELL FATE REGULATION IS LIMITED. RECENT STUDIES DEMONSTRATE THE ROLES OF ANTI-ADIPOGENIC MORPHOGENS (WNT, NECDIN, SHH) IN EPIGENETIC REPRESSION OF THE HSC DIFFERENTIATION GENE PPARGAMMA AS A CAUSAL EVENT IN HSC ACTIVATION. THESE MORPHOGENS HAVE POSITIVE CROSS-INTERACTIONS WHICH CONVERGE TO EPIGENETIC REPRESSION OF PPARGAMMA INVOLVING THE METHYL-CPG BINDING PROTEIN MECP2. HOWEVER, THESE MORPHOGENS EXPRESSED BY ACTIVATED HSC MAY ALSO PARTICIPATE IN CROSS-TALK BETWEEN HSC AND HEPATOBLASTS/HEPATOCYTES TO SUPPORT LIVER REGENERATION, AND THEIR ABERRANT REGULATION MAY CONTRIBUTE TO LIVER TUMORIGENESIS. IMPLICATIONS OF HSC-DERIVED MORPHOGENS IN THESE POSSIBILITIES ARE DISCUSSED. 2012 3 699 24 BROMODOMAIN PROTEIN 4 IS A KEY MOLECULAR DRIVER OF TGFBETA1-INDUCED HEPATIC STELLATE CELL ACTIVATION. LIVER FIBROSIS IS CHARACTERIZED BY THE EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX IN LIVER. CHRONIC LIVER INJURY INDUCES THE ACTIVATION OF HEPATIC STELLATE CELL (HSCS), A KEY STEP IN LIVER FIBROGENESIS. THE ACTIVATED HSC IS THE PRIMARY SOURCE OF ECM AND CONTRIBUTES SIGNIFICANTLY TO LIVER FIBROSIS. TGFBETA1 IS THE MOST POTENT PRO-FIBROTIC CYTOKINE. BROMODOMAIN PROTEIN 4 (BRD4), AN EPIGENETIC READER OF HISTONE ACETYLATION MARKS, WAS CRUCIAL FOR PROFIBROTIC GENE EXPRESSION IN HSCS. THE PRESENT STUDY AIMED TO INVESTIGATE THE ROLES OF BRD4 IN TGFBETA1-DEPENDENT HSC ACTIVATION AND LIVER FIBROSIS, FOCUSING ON TGFBETA1-INDUCED ALTERATIONS OF THE LEVELS OF THE FIBROTIC-RELATED IMPORTANT PROTEINS IN HSCS BY EMPLOYING THE HETEROZYGOUS TGFBETA1 KNOCKOUT MICE AND BRD4 KNOCKDOWN IN VIVO AND IN VITRO. RESULTS REVEALED THAT BRD4 PROTEIN LEVEL WAS SIGNIFICANTLY UPREGULATED BY TGFBETA1 AND BRD4 KNOCKDOWN REDUCED TGFBETA1-INDUCED HSC ACTIVATION AND LIVER FIBROSIS. BRD4 WAS REQUIRED FOR THE INFLUENCES OF TGFBETA1 ON PDGFBETA RECEPTOR AND ON THE PATHWAYS OF SMAD3, STAT3, AND AKT. BRD4 ALSO MEDIATED TGFBETA1-INDUCED INCREASES IN HISTONE ACETYLTRANSFERASE P300, THE PIVOTAL PRO-INFLAMMATORY NFKB P65, AND TISSUE INHIBITOR OF METALLOPROTEINASE 1 WHEREAS BRD4 REDUCED CASPASE-3 PROTEIN LEVELS IN HSCS DURING LIVER INJURY, INDEPENDENT OF TGFBETA1. FURTHER EXPERIMENTS INDICATED THE INTERACTION BETWEEN TGFBETA1-INDUCED BRD4 AND NFKB P65 IN HSCS AND IN LIVER OF TAA-INDUCED LIVER INJURY. HUMAN CIRRHOTIC LIVERS WERE DEMONSTRATED A PARALLEL INCREASE IN THE PROTEIN LEVELS OF BRD4 AND NFKB P65 IN HSCS. THIS STUDY REVEALED THAT BRD4 WAS A KEY MOLECULAR DRIVER OF TGFBETA1-INDUCED HSC ACTIVATION AND LIVER FIBROSIS. 2023 4 692 27 BRD4 PROMOTES HEPATIC STELLATE CELLS ACTIVATION AND HEPATIC FIBROSIS VIA MEDIATING P300/H3K27AC/PLK1 AXIS. HEPATIC FIBROSIS (HF) IS A REVERSIBLE WOUND-HEALING RESPONSE CHARACTERIZED BY EXCESSIVE EXTRACELLULAR MATRIX (ECM) DEPOSITION AND SECONDARY TO PERSISTENT CHRONIC INJURY. BROMODOMAIN PROTEIN 4 (BRD4) COMMONLY FUNCTIONS AS A "READER" TO REGULATE EPIGENETIC MODIFICATIONS INVOLVED IN VARIOUS BIOLOGICAL AND PATHOLOGICAL EVENTS, BUT THE MECHANISM OF HF REMAINS UNCLEAR. IN THIS STUDY, WE ESTABLISHED A CCL(4)-INDUCED HF MODEL AND SPONTANEOUS RECOVERY MODEL IN MICE AND FOUND ABERRANT BRD4 EXPRESSION, WHICH WAS CONSISTENT WITH THE RESULTS IN HUMAN HEPATIC STELLATE CELLS (HSCS)- LX2 CELLS IN VITRO. SUBSEQUENTLY, WE FOUND THAT DISTRICTION AND INHIBITION OF BRD4 RESTRAINED TGFBETA-INDUCED TRANS-DIFFERENTIATION OF LX2 CELLS INTO ACTIVATED, PROLIFERATIVE MYOFIBROBLASTS AND ACCELERATED APOPTOSIS, AND BRD4 OVEREXPRESSION BLOCKED MDI-INDUCED LX2 CELLS INACTIVATION AND PROMOTED THE PROLIFERATION AND INHIBITED APOPTOSIS OF INACTIVATED CELLS. ADDITIONALLY, ADENO-ASSOCIATED VIRUS SEROTYPE 8-LOADED SHORT HAIRPIN RNA-MEDIATED BRD4 KNOCKDOWN IN MICE SIGNIFICANTLY ATTENUATED CCL(4)-INDUCED FIBROTIC RESPONSES INCLUDING HSCS ACTIVATION AND COLLAGEN DEPOSITION. MECHANISTICALLY, BRD4 DEFICIENCY INHIBITED PLK1 EXPRESSION IN ACTIVATED LX2 CELLS, AND CHIP AND CO-IP ASSAYS REVEALED THAT BRD4 REGULATION OF PLK1 WAS DEPENDENT ON P300-MEDIATED ACETYLATION MODIFICATION FOR H3K27 ON THE PLK1 PROMOTER. IN CONCLUSION, BRD4 DEFICIENCY IN THE LIVER ALLEVIATES CCL(4)-INDUCED HF IN MICE, AND BRD4 PARTICIPATES IN THE ACTIVATION AND REVERSAL OF HSCS THROUGH POSITIVELY REGULATING THE P300/H3K27AC/PLK1 AXIS, PROVIDING A POTENTIAL INSIGHT FOR HF THERAPY. 2023 5 3245 23 HEPATIC STELLATE CELLS AS KEY TARGET IN LIVER FIBROSIS. PROGRESSIVE LIVER FIBROSIS, INDUCED BY CHRONIC VIRAL AND METABOLIC DISORDERS, LEADS TO MORE THAN ONE MILLION DEATHS ANNUALLY VIA DEVELOPMENT OF CIRRHOSIS, ALTHOUGH NO ANTIFIBROTIC THERAPY HAS BEEN APPROVED TO DATE. TRANSDIFFERENTIATION (OR "ACTIVATION") OF HEPATIC STELLATE CELLS IS THE MAJOR CELLULAR SOURCE OF MATRIX PROTEIN-SECRETING MYOFIBROBLASTS, THE MAJOR DRIVER OF LIVER FIBROGENESIS. PARACRINE SIGNALS FROM INJURED EPITHELIAL CELLS, FIBROTIC TISSUE MICROENVIRONMENT, IMMUNE AND SYSTEMIC METABOLIC DYSREGULATION, ENTERIC DYSBIOSIS, AND HEPATITIS VIRAL PRODUCTS CAN DIRECTLY OR INDIRECTLY INDUCE STELLATE CELL ACTIVATION. DYSREGULATED INTRACELLULAR SIGNALING, EPIGENETIC CHANGES, AND CELLULAR STRESS RESPONSE REPRESENT CANDIDATE TARGETS TO DEACTIVATE STELLATE CELLS BY INDUCING REVERSION TO INACTIVATED STATE, CELLULAR SENESCENCE, APOPTOSIS, AND/OR CLEARANCE BY IMMUNE CELLS. CELL TYPE- AND TARGET-SPECIFIC PHARMACOLOGICAL INTERVENTION TO THERAPEUTICALLY INDUCE THE DEACTIVATION WILL ENABLE MORE EFFECTIVE AND LESS TOXIC PRECISION ANTIFIBROTIC THERAPIES. 2017 6 1764 23 EARLY-IMMEDIATE GENE EGR1 IS ASSOCIATED WITH TGFBETA1 REGULATION OF EPIGENETIC READER BROMODOMAIN-CONTAINING PROTEIN 4 VIA THE CANONICAL SMAD3 SIGNALING IN HEPATIC STELLATE CELLS IN VITRO AND IN VIVO. UPON CHRONIC DAMAGE TO THE LIVER, MULTIPLE CYTOKINES STIMULATE HEPATIC STELLATE CELLS (HSCS), CAUSING THE ALTERATIONS OF GENE EXPRESSION PROFILES AND THUS LEADING TO HSC ACTIVATION, A KEY STEP IN LIVER FIBROGENESIS. ACTIVATED HSCS ARE THE DOMINANT CONTRIBUTORS TO LIVER FIBROSIS. BROMODOMAIN CONTAINING PROTEIN 4 (BRD4), AN IMPORTANT EPIGENETIC READER, WAS DEMONSTRATED TO CONCENTRATE ON HUNDREDS OF ENHANCERS ASSOCIATED WITH GENES INVOLVED IN MULTIPLE PROFIBROTIC PATHWAYS, THEREBY DIRECTING HSC ACTIVATION AND THE FIBROTIC RESPONSES. THE PRESENT STUDIES WERE DESIGNED TO EXAMINE THE EFFECT OF TRANSFORMING GROWTH FACTOR BETA-1 (TGFBETA1), THE MOST POTENT PRO-FIBROTIC CYTOKINE, ON BRD4 EXPRESSION IN HSCS AND, IF SO, ELUCIDATED THE UNDERLYING MECHANISMS IN VITRO AND IN VIVO. THE EXPERIMENTS EMPLOYED THE HETEROGENEOUS TGFBETA1 KNOCKOUT (TGFBETA1(+/-) ) MICE, GENE KNOCKDOWN IN VIVO, AND A MODEL OF THIOACETAMIDE (TAA)-INDUCED LIVER INJURY. THE RESULTS REVEALED THAT TGFBETA1 ENHANCED BRD4 EXPRESSION IN HSCS, WHICH WAS MEDIATED, AT LEAST, BY SMAD3 SIGNALING AND EARLY-IMMEDIATE GENE EGR1 (EARLY GROWTH RESPONSE-1). TGFBETA1-INDUCED SMAD3 SIGNALING INCREASED EGR1 EXPRESSION AND PROMOTED EGR1 BINDING TO BRD4 PROMOTER AT A SITE AROUND -111 BP, PROMOTING BRD4 EXPRESSION. EGR1 KNOCKDOWN REDUCED BRD4 EXPRESSION IN HSCS IN A MOUSE MODEL OF TAA-INDUCED LIVER INJURY AND LESSENED LIVER FIBROSIS. DOUBLE FLUORESCENCE STAINING DEMONSTRATED A STRONG INCREASE IN BRD4 EXPRESSION IN ACTIVATED HSCS IN FIBROTIC AREAS OF THE HUMAN LIVERS, PARALLELING THE UPREGULATION OF P-SMAD3 AND EGR1. THIS RESEARCH SUGGESTED NOVEL MOLECULAR EVENTS UNDERLYING THE ROLES OF THE MASTER PRO-FIBROTIC CYTOKINE TGFBETA1 IN HSC ACTIVATION AND LIVER FIBROGENESIS. 2022 7 4976 30 PATHOPHYSIOLOGICAL MECHANISMS OF HEPATIC STELLATE CELLS ACTIVATION IN LIVER FIBROSIS. LIVER FIBROSIS IS A COMPLEX PATHOLOGICAL PROCESS CONTROLLED BY A VARIETY OF CELLS, MEDIATORS AND SIGNALING PATHWAYS. HEPATIC STELLATE CELLS PLAY A CENTRAL ROLE IN THE DEVELOPMENT OF LIVER FIBROSIS. IN CHRONIC LIVER DISEASE, HEPATIC STELLATE CELLS UNDERGO DRAMATIC PHENOTYPIC ACTIVATION AND ACQUIRE FIBROGENIC PROPERTIES. THIS REVIEW FOCUSES ON THE PATHOPHYSIOLOGICAL MECHANISMS OF HEPATIC STELLATE CELLS ACTIVATION IN LIVER FIBROSIS. THEY ENTER THE CELL CYCLE UNDER THE INFLUENCE OF VARIOUS TRIGGERS. THE "INITIATION" PHASE OF HEPATIC STELLATE CELLS ACTIVATION OVERLAPS AND CONTINUES WITH THE "PERPETUATION" PHASE, WHICH IS CHARACTERIZED BY A PRONOUNCED INFLAMMATORY AND FIBROGENIC REACTION. THIS IS FOLLOWED BY A RESOLUTION PHASE IF THE INJURY SUBSIDES. KNOWLEDGE OF THESE PATHOPHYSIOLOGICAL MECHANISMS PAVED THE WAY FOR DRUGS AIMED AT PREVENTING THE DEVELOPMENT AND PROGRESSION OF LIVER FIBROSIS. IN THIS RESPECT, IMPAIRMENTS IN INTRACELLULAR SIGNALING, EPIGENETIC CHANGES AND CELLULAR STRESS RESPONSE CAN BE THE TARGETS OF THERAPY WHERE THE GOAL IS TO DEACTIVATE HEPATIC STELLATE CELLS. POTENTIAL ANTIFIBROTIC THERAPY MAY FOCUS ON INDUCING HEPATIC STELLATE CELLS TO RETURN TO AN INACTIVE STATE THROUGH CELLULAR AGING, APOPTOSIS, AND/OR CLEARANCE BY IMMUNE CELLS, AND SERVE AS POTENTIAL ANTIFIBROTIC THERAPY. IT IS ESPECIALLY IMPORTANT TO PREVENT THE FORMATION OF LIVER CIRRHOSIS SINCE THE ONLY RADICAL APPROACH TO ITS TREATMENT IS LIVER TRANSPLANTATION WHICH CAN BE PERFORMED IN ONLY A LIMITED NUMBER OF COUNTRIES. 2022 8 4108 16 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 9 2545 26 EPIGENETICS IN LIVER FIBROSIS: COULD HDACS BE A THERAPEUTIC TARGET? CHRONIC LIVER DISEASES (CLD) REPRESENT A WORLDWIDE HEALTH PROBLEM. WHILE CLDS MAY HAVE DIVERSE ETIOLOGIES, A COMMON PATHOGENIC DENOMINATOR IS THE PRESENCE OF LIVER FIBROSIS. CIRRHOSIS, THE END-STAGE OF CLD, IS CHARACTERIZED BY EXTENSIVE FIBROSIS AND IS MARKEDLY ASSOCIATED WITH THE DEVELOPMENT OF HEPATOCELLULAR CARCINOMA. THE MOST IMPORTANT EVENT IN HEPATIC FIBROGENESIS IS THE ACTIVATION OF HEPATIC STELLATE CELLS (HSC) FOLLOWING LIVER INJURY. ACTIVATED HSCS ACQUIRE A MYOFIBROBLAST-LIKE PHENOTYPE BECOMING PROLIFERATIVE, FIBROGENIC, AND CONTRACTILE CELLS. WHILE TRANSIENT ACTIVATION OF HSCS IS PART OF THE PHYSIOLOGICAL MECHANISMS OF TISSUE REPAIR, PROTRACTED ACTIVATION OF A WOUND HEALING REACTION LEADS TO ORGAN FIBROSIS. THE PHENOTYPIC CHANGES OF ACTIVATED HSCS INVOLVE EPIGENETIC MECHANISMS MEDIATED BY NON-CODING RNAS (NCRNA) AS WELL AS BY CHANGES IN DNA METHYLATION AND HISTONE MODIFICATIONS. DURING CLD THESE EPIGENETIC MECHANISMS BECOME DEREGULATED, WITH ALTERATIONS IN THE EXPRESSION AND ACTIVITY OF EPIGENETIC MODULATORS. HERE WE PROVIDE AN OVERVIEW OF THE EPIGENETIC ALTERATIONS INVOLVED IN FIBROGENIC HSCS TRANSDIFFERENTIATION WITH PARTICULAR FOCUS ON HISTONES ACETYLATION CHANGES. WE ALSO DISCUSS RECENT STUDIES SUPPORTING THE PROMISING THERAPEUTIC POTENTIAL OF HISTONE DEACETYLASE INHIBITORS IN LIVER FIBROSIS. 2020 10 4199 22 METABOLIC REPROGRAMMING AND CELL FATE REGULATION IN ALCOHOLIC LIVER DISEASE. ALCOHOLIC LIVER DISEASE (ALD) SHOULD BE DEFINED AS A LIFE-STYLE METABOLIC DISEASE. ITS PATHOGENESIS IS DRIVEN BY ALTERED CELL FATE OF BOTH PARENCHYMAL AND NON-PARENCHYMAL LIVER CELL TYPES, CONTRIBUTING TO DIFFERENT PATHOLOGIC SPECTRA. A CRITICAL TURNING POINT IN PROGRESSION OF ALD IS CHRONIC ALCOHOLIC STEATOHEPATITIS (ASH) OR ALCOHOLIC NEUTROPHILIC HEPATITIS (AH), WHICH MARKEDLY PREDISPOSES PATIENTS TO MOST DEVASTATING ALD SEQUELA, CIRRHOSIS AND LIVER CANCER. RESULTS: OUR RESEARCH IDENTIFIES THE PIVOTAL ROLES OF UNIQUE METABOLIC REPROGRAMMING IN M1 ACTIVATION OF HEPATIC MACROPHAGES (HM) AND MYOFIBROBLASTIC ACTIVATION (MF) OF HEPATIC STELLATE CELLS (HSC) IN THE GENESIS OF INFLAMMATION AND FIBROSIS, THE TWO KEY HISTOLOGICAL FEATURES OF CHRONIC ASH AND NEUTROPHILIC AH. FOR M1 HM ACTIVATION, HEIGHTENED PROINFLAMMATORY IRON REDOX SIGNALING IN ENDOSOMES OR CAVEOSOMES RESULTS FROM ALTERED IRON METABOLISM AND STORAGE, PROMOTING IKK/NF-KB ACTIVATION VIA INTERACTIVE ACTIVATION OF P21RAS, TAK1, AND PI3K. FOR MF CELL FATE REGULATION OF HSC, ACTIVATION OF THE MORPHOGEN WNT PATHWAY CAUSED BY THE NUCLEAR PROTEIN NECDIN OR THE SINGLE-PASS TRANS-MEMBRANE PROTEIN DLK1, REPROGRAMS LIPID METABOLISM VIA MECP2-MEDIATED EPIGENETIC REPRESSION OF THE KEY HSC QUIESCENCE GENE PPAR-GAMMA. CONCLUSIONS: THE FINDINGS FROM THESE STUDIES RE-ENFORCE THE IMPORTANCE OF METABOLIC REPROGRAMMING IN CELL FATE REGULATION REQUIRED FOR THE PATHOGENESIS OF ALD. 2015 11 2322 23 EPIGENETIC REGULATION OF HEPATIC STELLATE CELL ACTIVATION AND LIVER FIBROSIS. CHRONIC LIVER INJURY TO HEPATOCYTES OR CHOLANGIOCYTES, WHEN LEFT UNMANAGED, LEADS TO THE DEVELOPMENT OF LIVER FIBROSIS, A CONDITION CHARACTERIZED BY THE EXCESSIVE INTRAHEPATIC DEPOSITION OF EXTRACELLULAR MATRIX PROTEINS. ACTIVATED HEPATIC STELLATE CELLS CONSTITUTE THE PREDOMINANT SOURCE OF EXTRACELLULAR MATRIX IN FIBROTIC LIVERS AND THEIR TRANSITION FROM A QUIESCENT STATE DURING FIBROGENESIS IS ASSOCIATED WITH IMPORTANT ALTERATIONS IN THEIR TRANSCRIPTIONAL AND EPIGENETIC LANDSCAPE. AREAS COVERED: WE BRIEFLY DESCRIBE THE PROCESSES INVOLVED IN HEPATIC STELLATE CELL ACTIVATION AND DISCUSS OUR CURRENT UNDERSTANDING OF ALTERATIONS IN THE EPIGENETIC LANDSCAPE, I.E DNA METHYLATION, HISTONE MODIFICATIONS AND THE FUNCTIONAL ROLE OF NON-CODING RNAS THAT ACCOMPANY THIS KEY EVENT IN THE DEVELOPMENT OF CHRONIC LIVER DISEASE. EXPERT COMMENTARY: ALTHOUGH GREAT PROGRESS HAS BEEN MADE, OUR UNDERSTANDING OF THE EPIGENETIC REGULATION OF HEPATIC STELLATE CELL ACTIVATION IS LIMITED AND, THUS FAR, INSUFFICIENT TO ALLOW THE DEVELOPMENT OF EPIGENETIC DRUGS THAT CAN SELECTIVELY INTERRUPT LIVER FIBROSIS. 2016 12 4448 31 MOLECULAR MECHANISM AND TREATMENT OF VIRAL HEPATITIS-RELATED LIVER FIBROSIS. HEPATIC FIBROSIS IS A WOUND-HEALING RESPONSE TO VARIOUS CHRONIC STIMULI, INCLUDING VIRAL HEPATITIS B OR C INFECTION. ACTIVATED MYOFIBROBLASTS, PREDOMINANTLY DERIVED FROM THE HEPATIC STELLATE CELLS (HSCS), REGULATE THE BALANCE BETWEEN MATRIX METALLOPROTEINASES AND THEIR TISSUE INHIBITORS TO MAINTAIN EXTRACELLULAR MATRIX HOMEOSTASIS. TRANSFORMING GROWTH FACTOR-BETA AND PLATELET-DERIVED GROWTH FACTOR ARE CLASSIC PROFIBROGENIC SIGNALS THAT ACTIVATE HSC PROLIFERATION. IN ADDITION, PROINFLAMMATORY CYTOKINES AND CHEMOKINES COORDINATE MACROPHAGES, T CELLS, NK/NKT CELLS, AND LIVER SINUSOIDAL ENDOTHELIAL CELLS IN COMPLEX FIBROGENIC AND REGRESSION PROCESSES. IN ADDITION, FIBROGENESIS INVOLVES ANGIOGENESIS, METABOLIC REPROGRAMMING, AUTOPHAGY, MICRORNA, AND EPIGENETIC REGULATIONS. HEPATIC INFLAMMATION IS THE DRIVING FORCE BEHIND LIVER FIBROSIS; HOWEVER, HOST SINGLE NUCLEOTIDE POLYMORPHISMS AND VIRAL FACTORS, INCLUDING THE GENOTYPE, VIRAL LOAD, VIRAL MUTATION, AND VIRAL PROTEINS, HAVE BEEN ASSOCIATED WITH FIBROSIS PROGRESSION. ELIMINATING THE UNDERLYING ETIOLOGY IS THE MOST CRUCIAL ANTIFIBROTIC THERAPY. GROWING EVIDENCE HAS INDICATED THAT PERSISTENT VIRAL SUPPRESSION WITH ANTIVIRAL THERAPY CAN RESULT IN FIBROSIS REGRESSION, REDUCED LIVER DISEASE PROGRESSION, DECREASED HEPATOCELLULAR CARCINOMA, AND IMPROVED CHANCES OF SURVIVAL. PRECLINICAL STUDIES AND CLINICAL TRIALS ARE CURRENTLY EXAMINING SEVERAL INVESTIGATIONAL AGENTS THAT TARGET KEY FIBROGENIC PATHWAYS; THE RESULTS ARE PROMISING AND SHED LIGHT ON THIS DEBILITATING ILLNESS. 2014 13 4132 25 MECHANISMS OF HEPATIC FIBROGENESIS. SUBSTANTIAL IMPROVEMENTS IN THE TREATMENT OF CHRONIC LIVER DISEASE HAVE ACCELERATED INTEREST IN UNCOVERING THE MECHANISMS UNDERLYING HEPATIC FIBROSIS AND ITS RESOLUTION. ACTIVATION OF RESIDENT HEPATIC STELLATE CELLS INTO PROLIFERATIVE, CONTRACTILE, AND FIBROGENIC CELLS IN LIVER INJURY REMAINS A DOMINANT THEME DRIVING THE FIELD. HOWEVER, SEVERAL NEW AREAS OF RAPID PROGRESS IN THE PAST 5-10 YEARS ALSO HAVE TAKEN ROOT, INCLUDING: (1) IDENTIFICATION OF DIFFERENT FIBROGENIC POPULATIONS APART FROM RESIDENT STELLATE CELLS, FOR EXAMPLE, PORTAL FIBROBLASTS, FIBROCYTES, AND BONE-MARROW-DERIVED CELLS, AS WELL AS CELLS DERIVED FROM EPITHELIAL MESENCHYMAL TRANSITION; (2) EMERGENCE OF STELLATE CELLS AS FINELY REGULATED DETERMINANTS OF HEPATIC INFLAMMATION AND IMMUNITY; (3) ELUCIDATION OF MULTIPLE PATHWAYS CONTROLLING GENE EXPRESSION DURING STELLATE CELL ACTIVATION INCLUDING TRANSCRIPTIONAL, POST-TRANSCRIPTIONAL, AND EPIGENETIC MECHANISMS; (4) RECOGNITION OF DISEASE-SPECIFIC PATHWAYS OF FIBROGENESIS; (5) RE-EMERGENCE OF HEPATIC MACROPHAGES AS DETERMINANTS OF MATRIX DEGRADATION IN FIBROSIS RESOLUTION AND THE IMPORTANCE OF MATRIX CROSS-LINKING AND SCAR MATURATION IN DETERMINING REVERSIBILITY; AND (6) HINTS THAT HEPATIC STELLATE CELLS MAY CONTRIBUTE TO HEPATIC STEM CELL BEHAVIOR, CANCER, AND REGENERATION. CLINICAL AND TRANSLATIONAL IMPLICATIONS OF THESE ADVANCES HAVE BECOME CLEAR, AND HAVE BEGUN TO IMPACT SIGNIFICANTLY ON THE MANAGEMENT AND OUTLOOK OF PATIENTS WITH CHRONIC LIVER DISEASE. 2008 14 5939 31 TARGETING MECHANOTRANSDUCTION AT THE TRANSCRIPTIONAL LEVEL: YAP AND BRD4 ARE NOVEL THERAPEUTIC TARGETS FOR THE REVERSAL OF LIVER FIBROSIS. LIVER FIBROSIS IS THE RESULT OF A DEREGULATED WOUND HEALING PROCESS CHARACTERIZED BY THE EXCESSIVE DEPOSITION OF EXTRACELLULAR MATRIX. HEPATIC STELLATE CELLS (HSCS), WHICH ARE ACTIVATED IN RESPONSE TO LIVER INJURY, ARE THE MAJOR SOURCE OF EXTRACELLULAR MATRIX AND DRIVE THE WOUND HEALING PROCESS. HOWEVER, CHRONIC LIVER DAMAGE LEADS TO PERPETUAL HSC ACTIVATION, PROGRESSIVE FORMATION OF PATHOLOGICAL SCAR TISSUE AND ULTIMATELY, CIRRHOSIS AND ORGAN FAILURE. HSC ACTIVATION IS TRIGGERED LARGELY IN RESPONSE TO MECHANOSIGNALING FROM THE MICROENVIRONMENT, WHICH INDUCES A PROFIBROTIC NUCLEAR TRANSCRIPTION PROGRAM THAT PROMOTES HSC PROLIFERATION AND EXTRACELLULAR MATRIX SECRETION THEREBY SETTING UP A POSITIVE FEEDBACK LOOP LEADING TO MATRIX STIFFENING AND SELF-SUSTAINED, PATHOLOGICAL, HSC ACTIVATION. DESPITE THE SIGNIFICANT PROGRESS IN OUR UNDERSTANDING OF LIVER FIBROSIS, THE MOLECULAR MECHANISMS THROUGH WHICH THE EXTRACELLULAR MATRIX PROMOTES HSC ACTIVATION ARE NOT WELL UNDERSTOOD AND NO EFFECTIVE THERAPIES HAVE BEEN APPROVED TO DATE THAT CAN TARGET THIS EARLY, REVERSIBLE, STAGE IN LIVER FIBROSIS. SEVERAL NEW LINES OF INVESTIGATION NOW PROVIDE IMPORTANT INSIGHT INTO THIS AREA OF STUDY AND IDENTIFY TWO NUCLEAR TARGETS WHOSE INHIBITION HAS THE POTENTIAL OF REVERSING LIVER FIBROSIS BY INTERFERING WITH HSC ACTIVATION: YES-ASSOCIATED PROTEIN (YAP), A TRANSCRIPTIONAL CO-ACTIVATOR AND EFFECTOR OF THE MECHANOSENSITIVE HIPPO PATHWAY, AND BROMODOMAIN-CONTAINING PROTEIN 4 (BRD4), AN EPIGENETIC REGULATOR OF GENE EXPRESSION. YAP AND BRD4 ACTIVITY IS INDUCED IN RESPONSE TO MECHANICAL STIMULATION OF HSCS AND EACH PROTEIN INDEPENDENTLY CONTROLS WAVES OF EARLY GENE EXPRESSION NECESSARY FOR HSC ACTIVATION. SIGNIFICANTLY, INHIBITION OF EITHER PROTEIN CAN REVERT THE CHRONIC ACTIVATION OF HSCS AND IMPEDE PATHOLOGICAL PROGRESSION OF LIVER FIBROSIS IN CLINICALLY RELEVANT MODEL SYSTEMS. IN THIS REVIEW WE WILL DISCUSS THE ROLES OF THESE NUCLEAR CO-ACTIVATORS IN HSC ACTIVATION, THEIR MECHANISM OF ACTION IN THE FIBROTIC PROCESS IN THE LIVER AND OTHER ORGANS, AND THE POTENTIAL OF TARGETING THEIR ACTIVITY WITH SMALL MOLECULE DRUGS FOR FIBROSIS REVERSAL. 2016 15 2817 23 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 16 6757 32 WNT SIGNALING IN LIVER FIBROSIS: PROGRESS, CHALLENGES AND POTENTIAL DIRECTIONS. LIVER FIBROSIS IS A COMMON WOUND-HEALING RESPONSE TO CHRONIC LIVER INJURIES, INCLUDING ALCOHOLIC OR DRUG TOXICITY, PERSISTENT VIRAL INFECTION, AND GENETIC FACTORS. MYOFIBROBLASTIC TRANSDIFFERENTIATION (MTD) IS THE PIVOTAL EVENT DURING LIVER FIBROGENESIS, AND RESEARCH IN THE PAST FEW YEARS HAS IDENTIFIED KEY MEDIATORS AND MOLECULAR MECHANISMS RESPONSIBLE FOR MTD OF HEPATIC STELLATE CELLS (HSCS). HSCS ARE UNDIFFERENTIATED CELLS WHICH PLAY AN IMPORTANT ROLE IN LIVER REGENERATION. RECENT EVIDENCE DEMONSTRATES THAT HSCS DERIVE FROM MESODERM AND AT LEAST IN PART VIA SEPTUM TRANSVERSUM AND MESOTHELIUM, AND HSCS EXPRESS MARKERS FOR DIFFERENT CELL TYPES WHICH DERIVE FROM MULTIPOTENT MESENCHYMAL PROGENITORS. THERE IS A REGULATORY COMMONALITY BETWEEN DIFFERENTIATION OF ADIPOCYTES AND THAT OF HSC, AND THE SHIFT FROM ADIPOGENIC TO MYOGENIC OR NEURONAL PHENOTYPE CHARACTERIZES HSC MTD. CENTRAL OF THIS SHIFT IS A LOSS OF EXPRESSION OF THE MASTER ADIPOGENIC REGULATOR PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR GAMMA (PPARGAMMA). RESTORED EXPRESSION OF PPARGAMMA AND/OR OTHER ADIPOGENIC TRANSCRIPTION GENES CAN REVERSE MYOFIBROBLASTIC HSCS TO DIFFERENTIATED CELLS. VERTEBRATE WNT AND DROSOPHILA WINGLESS ARE HOMOLOGOUS GENES, AND THEIR TRANSLATED PROTEINS HAVE BEEN SHOWN TO PARTICIPATE IN THE REGULATION OF CELL PROLIFERATION, CELL POLARITY, CELL DIFFERENTIATION, AND OTHER BIOLOGICAL ROLES. MORE RECENTLY, WNT SIGNALING IS IMPLICATED IN HUMAN FIBROSING DISEASES, SUCH AS PULMONARY FIBROSIS, RENAL FIBROSIS, AND LIVER FIBROSIS. BLOCKING THE CANONICAL WNT SIGNAL PATHWAY WITH THE CO-RECEPTOR ANTAGONIST DICKKOPF-1 (DKK1) ABROGATES THESE EPIGENETIC REPRESSIONS AND RESTORES THE GENE PPARGAMMA EXPRESSION AND HSC DIFFERENTIATION. THE IDENTIFIED MORPHOGEN MEDIATED EPIGENETIC REGULATION OF PPARGAMMA AND HSC DIFFERENTIATION ALSO SERVES AS NOVEL THERAPEUTIC TARGETS FOR LIVER FIBROSIS AND LIVER REGENERATION. IN CONCLUSION, THE WNT SIGNALING PROMOTES LIVER FIBROSIS BY ENHANCING HSC ACTIVATION AND SURVIVAL, AND WE HEREIN DISCUSS WHAT WE CURRENTLY KNOW AND WHAT WE EXPECT WILL COME IN THIS FIELD IN THE NEXT FUTURE. 2013 17 3330 33 HISTONE DEACETYLASE INHIBITOR GIVINOSTAT ALLEVIATES LIVER FIBROSIS BY REGULATING HEPATIC STELLATE CELL ACTIVATION. HEPATIC FIBROSIS, A COMMON PATHOLOGICAL MANIFESTATION OF CHRONIC LIVER INJURY, IS GENERALLY CONSIDERED TO BE THE END RESULT OF AN INCREASE IN EXTRACELLULAR MATRIX PRODUCED BY ACTIVATED HEPATIC STELLATE CELLS (HSCS). THE AIM OF THE PRESENT STUDY WAS TO TARGET THE MECHANISMS UNDERLYING HSC ACTIVATION IN ORDER TO PROVIDE A POWERFUL THERAPEUTIC STRATEGY FOR THE PREVENTION AND TREATMENT OF LIVER FIBROSIS. IN THE PRESENT STUDY, A HIGH?THROUGHPUT SCREENING ASSAY WAS ESTABLISHED, AND THE HISTONE DEACETYLASE INHIBITOR GIVINOSTAT WAS IDENTIFIED AS A POTENT INHIBITOR OF HSC ACTIVATION IN VITRO. GIVINOSTAT SIGNIFICANTLY INHIBITED HSC ACTIVATION IN VIVO, AMELIORATED CARBON TETRACHLORIDE?INDUCED MOUSE LIVER FIBROSIS AND LOWERED PLASMA AMINOTRANSFERASES. TRANSCRIPTOMIC ANALYSIS REVEALED THE MOST SIGNIFICANTLY REGULATED GENES IN THE GIVINOSTAT TREATMENT GROUP IN COMPARISON WITH THOSE IN THE SOLVENT GROUP, AMONG WHICH, DERMOKINE (DMKN), MESOTHELIN (MSLN) AND UROPLAKIN?3B (UPK3B) WERE IDENTIFIED AS POTENTIAL REGULATORS OF HSC ACTIVATION. GIVINOSTAT SIGNIFICANTLY REDUCED THE MRNA EXPRESSION OF DMKN, MSLN AND UPK3B IN BOTH A MOUSE LIVER FIBROSIS MODEL AND IN HSC?LX2 CELLS. KNOCKDOWN OF ANY OF THE AFOREMENTIONED GENES INHIBITED THE TGF?BETA1?INDUCED EXPRESSION OF ALPHA?SMOOTH MUSCLE ACTIN AND COLLAGEN TYPE I, INDICATING THAT THEY ARE CRUCIAL FOR HSC ACTIVATION. IN SUMMARY, USING A NOVEL STRATEGY TARGETING HSC ACTIVATION, THE PRESENT STUDY IDENTIFIED A POTENTIAL EPIGENETIC DRUG FOR THE TREATMENT OF HEPATIC FIBROSIS AND REVEALED NOVEL REGULATORS OF HSC ACTIVATION. 2021 18 4747 24 NOVEL MODULATORS OF HEPATOSTEATOSIS, INFLAMMATION AND FIBROGENESIS. ALCOHOLIC STEATOSIS, INSTEAD OF BEING INNOCUOUS, PLAYS A CRITICAL ROLE IN LIVER INFLAMMATION AND FIBROGENESIS. THE SEVERITY OF FATTY LIVER IS GOVERNED BY THE CONCERTED BALANCE BETWEEN LIPID TRANSPORT, SYNTHESIS, AND DEGRADATION. WHEREAS SCAVENGER RECEPTOR CLASS B, TYPE I (SR-B1) IS CRITICAL FOR REVERSE CHOLESTEROL UPTAKE BY THE LIVER, PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA (PPARGAMMA) COACTIVATOR-1ALPHA AND -BETA (PGC1ALPHA AND PGC1BETA) ARE CRITICAL FOR LIPID DEGRADATION AND SYNTHESIS, RESPECTIVELY. BECAUSE BETAINE IS A LIPOTROPIC AGENT, WE HAVE EVALUATED ITS EFFECTS ON ALCOHOLIC STEATOSIS. BETAINE EFFECTIVELY PREVENTED CHRONIC ALCOHOL-MEDIATED (I) IMPAIRED SR-B1 GLYCOSYLATION, PLASMA MEMBRANE LOCALIZATION, AND CONSEQUENT IMPAIRED CHOLESTEROL TRANSPORT; AND (II) UP REGULATION OF PGC-1BETA, STEROL REGULATORY ELEMENT-BINDING PROTEIN 1C AND DOWNSTREAM LIPOGENIC GENES WITH CONCOMITANT INCREASED LIVER CHOLESTEROL, TRIGLYCERIDES AND HEPATIC LIPID SCORE. SIMILARLY, BECAUSE OF ITS ANTI-INFLAMMATORY AND ANTI-FIBROTIC EFFECTS IN OTHER ORGANS, WE EVALUATED THE PROTECTIVE EFFECTS OF THYMOSIN BETA4 (TBETA4) AGAINST CARBON TETRACHLORIDE (CCL4)-INDUCED HEPATOTOXICITY IN RAT. TBETA4 PREVENTED CCL4-INDUCED (I) NECROSIS, INFLAMMATORY INFILTRATION AND UP-REGULATION OF ALPHA1(2)COLLAGEN, ALPHA-SMOOTH MUSCLE ACTIN (ALPHA-SMA), PLATELET DERIVED GROWTH FACTOR BETA (PDGF-BETA) RECEPTOR AND FIBRONECTIN MRNA EXPRESSION; (II) DOWN-REGULATION OF ADIPOGENIC GENE, PPARGAMMA AND THE UP-REGULATION OF EPIGENETIC REPRESSOR GENE, METHYL CPG BINDING PROTEIN 2 (MECP2) MRNA LEVELS, SUGGESTING THAT THE ANTI-FIBROGENIC ACTIONS OF TBETA4 INVOLVE THE PREVENTION OF TRANS-DIFFERENTIATION OF QUIESCENT HEPATIC STELLATE CELLS INTO MYO-FIBROBLASTS LARGELY BY UP-REGULATING PPARGAMMA AND BY DOWN-REGULATING MECP2 GENES. WE THEREFORE CONCLUDE THAT BETAINE AND TBETA4 CAN EFFECTIVELY PROTECT AGAINST ALCOHOLIC HEPATOSTEATOSIS AND HEPATIC FIBROGENESIS, RESPECTIVELY. 2014 19 98 28 A PROOF-OF-CONCEPT FOR EPIGENETIC THERAPY OF TISSUE FIBROSIS: INHIBITION OF LIVER FIBROSIS PROGRESSION BY 3-DEAZANEPLANOCIN A. THE PROGRESSION OF FIBROSIS IN CHRONIC LIVER DISEASE IS DEPENDENT UPON HEPATIC STELLATE CELLS (HSCS) TRANSDIFFERENTIATING TO A MYOFIBROBLAST-LIKE PHENOTYPE. THIS PIVOTAL PROCESS IS CONTROLLED BY ENZYMES THAT REGULATE HISTONE METHYLATION AND CHROMATIN STRUCTURE, WHICH MAY BE TARGETS FOR DEVELOPING ANTI-FIBROTICS. THERE IS LIMITED PRE-CLINICAL EXPERIMENTAL SUPPORT FOR THE POTENTIAL TO THERAPEUTICALLY MANIPULATE EPIGENETIC REGULATORS IN FIBROSIS. IN ORDER TO LEARN IF EPIGENETIC TREATMENT CAN HALT THE PROGRESSION OF PRE-ESTABLISHED LIVER FIBROSIS, WE TREATED MICE WITH THE HISTONE METHYLTRANSFERASE INHIBITOR 3-DEAZANEPLANOCIN A (DZNEP) IN A NAKED FORM OR BY SELECTIVELY TARGETING HSC-DERIVED MYOFIBROBLASTS VIA AN ANTIBODY-LIPOSOME-DZNEP TARGETING VEHICLE. WE DISCOVERED THAT DZNEP TREATMENT INHIBITED MULTIPLE HISTONE METHYLATION MODIFICATIONS, INDICATIVE OF A BROADER SPECIFICITY THAN PREVIOUSLY REPORTED. THIS BROAD EPIGENETIC REPRESSION WAS ASSOCIATED WITH THE SUPPRESSION OF FIBROSIS PROGRESSION AS ASSESSED BOTH HISTOLOGICALLY AND BIOCHEMICALLY. THE ANTI-FIBROTIC EFFECT OF DZNEP WAS REPRODUCED WHEN THE DRUG WAS SELECTIVELY TARGETED TO HSC-DERIVED MYOFIBROBLASTS. THEREFORE, THE IN VIVO MODULATION OF HSC HISTONE METHYLATION IS SUFFICIENT TO HALT PROGRESSION OF FIBROSIS IN THE CONTEXT OF CONTINUOUS LIVER DAMAGE. THIS DISCOVERY AND OUR NOVEL HSC-TARGETING VEHICLE, WHICH AVOIDS THE UNWANTED EFFECTS OF EPIGENETIC DRUGS ON PARENCHYMAL LIVER CELLS, REPRESENTS AN IMPORTANT PROOF-OF-CONCEPT FOR EPIGENETIC TREATMENT OF LIVER FIBROSIS. 2017 20 2219 30 EPIGENETIC MODIFICATIONS IN HEPATIC STELLATE CELLS CONTRIBUTE TO LIVER FIBROSIS. LIVER FIBROSIS REPRESENTS THE FINAL COMMON PATHWAY OF VIRTUALLY ALL TYPES OF CHRONIC LIVER DISEASES, AND IT HAS BEEN A MAJOR PUBLIC HEALTH CONCERN. MANY GENES HAVE BEEN DEMONSTRATED TO BE INVOLVED IN THE PATHOGENESIS OF LIVER FIBROSIS, WHILE THE MECHANISMS UNDERLYING GENE REGULATION STILL NEEDS FURTHER RESEARCH. ON THE OTHER HAND, HEPATIC STELLATE CELLS (HSCS) ARE QUIESCENT CELLS IN THE PERISINUSOIDAL SPACE IN LIVER. HSCS FACILITATE HEPATOCYTES INTERACTIONS VIA RELEASING SOLUBLE INFLAMMATORY FACTORS AND PRODUCING EXTRACELLULAR MATRIX. HSCS CAN BE ACTIVATED IN RESPONSE TO LIVER INJURY, AND THEY DIFFERENTIATE TO MYOFIBROBLASTS, WHICH GREATLY CONTRIBUTE TO THE FIBROGENESIS PROCESS. VARIOUS EPIGENETIC PROCEDURES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION AND FORMATION OF PARTICULAR CHROMATIN STRUCTURE, PLAY CRUCIAL ROLES IN THE GENE TRANSCRIPTIONAL EXPRESSION IN HSCS, REGULATING VARIOUS VITAL PROCESSES. FOR INSTANCE, EPIGENETIC MODULATION ON THE PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR GAMMA (PPAR-GAMMA) GENE PROMOTER ACCOUNTS FOR HSC DIFFERENTIATION THROUGH INTERACTING PATHWAYS. ABERRANT EXPRESSION OF A SERIES OF HISTONES AND CHEMOKINES IN ACTIVATED HSCS CAN AGGRAVATE INFLAMMATION AND OXIDATIVE STRESS, WHICH IN TURN PROMOTES DIFFERENTIATION OF HSCS TO MYOFIBROBLASTS AND ENHANCES THE WHOLE FIBROGENESIS PROCESS. DEGRADATION OF EXTRACELLULAR MATRIX IS ALSO REGULATED THROUGH EPIGENETIC MODULATION ON MATRIX ASSOCIATED ENZYMES. MOREOVER, FIBROSIS-RELATED EPIGENETIC MODIFICATIONS IN THE PARENTAL GENERATION MAY BE INHERITED TO THEIR OFFSPRING. IN THIS REVIEW, WE FIRSTLY SUMMARIZE THE VITAL EPIGENETIC MODIFICATIONS OF FIBROSIS-RELATED GENES IN HSCS, AND HIGHLIGHT SPECIFIC NUCLEIC ACID SEQUENCES AND STRUCTURES IN GENE PROMOTERS AS IMPORTANT ACTION SITES, WHICH MAY PROVIDE INDICATORS FOR LIVER FIBROSIS DIAGNOSIS IN THE FUTURE. 2013