2025
Liver lipid droplet cholesterol content is a key determinant of metabolic dysfunction–associated steatohepatitis
Sakuma I, Gaspar R, Nasiri A, Dufour S, Kahn M, Zheng J, LaMoia T, Guerra M, Taki Y, Kawashima Y, Yimlamai D, Perelis M, Vatner D, Petersen K, Huttasch M, Knebel B, Kahl S, Roden M, Samuel V, Tanaka T, Shulman G. Liver lipid droplet cholesterol content is a key determinant of metabolic dysfunction–associated steatohepatitis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2025, 122: e2502978122. PMID: 40310463, DOI: 10.1073/pnas.2502978122.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCholesterolDiet, High-FatFatty LiverHumansLipid DropletsLipid MetabolismLiverLiver CirrhosisMaleMiceMice, Inbred C57BLNon-alcoholic Fatty Liver DiseaseConceptsCholine-deficient l-amino acid-defined high-fat dietBempedoic acidLiver fibrosisLiver diseaseL-amino acid-defined high-fat dietAdvanced liver diseaseCholesterol contentHSD17B13 variantsHigh-fat dietTotal liver cholesterol contentTreated miceActivate signaling pathwaysVariant rs738409Liver cholesterol contentLiver lipidsFibrotic responsePromote inflammationTherapeutic approachesSteatotic liver diseaseDietary cholesterol supplementationFibrosisHuman liver samplesI148MAntisense oligonucleotidesProgressive formLiver Fibrosis and Cardiovascular Events
Nso N, Bookani K, Trimingham M, Orji R, Njei B, Balasubramanian S, Pursnani A. Liver Fibrosis and Cardiovascular Events. Southern Medical Journal 2025, 118: 19-25. PMID: 39753232, DOI: 10.14423/smj.0000000000001769.Peer-Reviewed Original ResearchMeSH KeywordsCardiovascular DiseasesHumansLiver CirrhosisNon-alcoholic Fatty Liver DiseaseRisk FactorsSeverity of Illness IndexConceptsLiver fibrosis scoresNonalcoholic fatty liver diseaseRisk of cardiovascular eventsNAFLD fibrosis scoreCardiovascular eventsAll-cause mortalityFibrosis scoreLiver fibrosisSystematic reviewFibrosis-4Noninvasive liver fibrosis scoresLiver diseaseCardiovascular mortalityHigh risk of cardiovascular eventsNonalcoholic fatty liver disease fibrosis scoreRelevant prospective studiesSeverity of liver fibrosisNational Institutes of Health toolCardiovascular diseaseHigher liver fibrosis scoresSpectrum of cardiovascular diseasesFibrosis-4 scoreSeverity of fibrosisCardiovascular event occurrenceChronic liver disease
2024
Integrative multiomic analysis identifies distinct molecular subtypes of NAFLD in a Chinese population
Ding J, Liu H, Zhang X, Zhao N, Peng Y, Shi J, Chen J, Chi X, Li L, Zhang M, Liu W, Zhang L, Ouyang J, Yuan Q, Liao M, Tan Y, Li M, Xu Z, Tang W, Xie C, Li Y, Pan Q, Xu Y, Cai S, Byrne C, Targher G, Ouyang X, Zhang L, Jiang Z, Zheng M, Sun F, Chai J. Integrative multiomic analysis identifies distinct molecular subtypes of NAFLD in a Chinese population. Science Translational Medicine 2024, 16: eadh9940. PMID: 39504356, DOI: 10.1126/scitranslmed.adh9940.Peer-Reviewed Original ResearchMeSH KeywordsCarcinoma, HepatocellularChinaEast Asian PeopleFemaleHumansLiverLiver CirrhosisLiver NeoplasmsMaleMetabolomicsMiddle AgedNon-alcoholic Fatty Liver DiseaseProteomicsSignal TransductionConceptsNonalcoholic fatty liver diseaseWhole-genome sequencingHepatocellular carcinomaMolecular subtypesLiver cirrhosisChinese cohort of patientsInfiltration of M1Risk of liver cirrhosisSerum metabolic analysisClinical diagnosisSubtype of nonalcoholic fatty liver diseaseCohort of patientsDevelopment of liver cirrhosisHepatocellular carcinoma developmentIntegrative multiomic analysisHealth care burdenFatty liver diseaseExpression of CYP1A2Urine specimensTreatment strategiesChinese cohortImpaired outcomeM2 macrophagesIntegrative multiomicsLiver diseaseValidation of a whole slide image management system for metabolic‐associated steatohepatitis for clinical trials
Pulaski H, Mehta S, Manigat L, Kaufman S, Hou H, Nalbantoglu I, Zhang X, Curl E, Taliano R, Kim T, Torbenson M, Glickman J, Resnick M, Patel N, Taylor C, Bedossa P, Montalto M, Beck A, Wack K. Validation of a whole slide image management system for metabolic‐associated steatohepatitis for clinical trials. The Journal Of Pathology Clinical Research 2024, 10: e12395. PMID: 39294925, PMCID: PMC11410674, DOI: 10.1002/2056-4538.12395.Peer-Reviewed Original ResearchMeSH KeywordsBiopsyClinical Trials as TopicHumansImage Interpretation, Computer-AssistedLiverNon-alcoholic Fatty Liver DiseaseObserver VariationReproducibility of ResultsConceptsClinical trialsAssessment of disease activityOverall percent agreementLiver biopsyDisease activityPathological assessmentWashout periodHistological assessmentEndpoint assessmentGold standardPercent agreementScoring systemExpert pathologistsSteatohepatitisAverage agreementDigital scoresPathologistsTrialsElectrocardiographic abnormalities in patients with metabolic dysfunction-associated steatotic liver disease: A systematic review and meta-analysis
Dimala C, Nso N, Wasserlauf J, Njei B. Electrocardiographic abnormalities in patients with metabolic dysfunction-associated steatotic liver disease: A systematic review and meta-analysis. Current Problems In Cardiology 2024, 49: 102580. PMID: 38653446, DOI: 10.1016/j.cpcardiol.2024.102580.Peer-Reviewed Original ResearchConceptsNon-alcoholic fatty liver diseaseElectrocardiographic abnormalitiesLiver diseaseECG abnormalitiesSteatotic liver diseaseMultiple ECG abnormalitiesPersistent heart blockEarly cardiac involvementCardiac risk stratificationShorter QRS durationT-wave inversionBundle branch blockSystematic reviewPrevalent atrial fibrillationStatistically significant associationFatty liver diseaseCardiac involvementQTc prolongationFragmented QRSSystematic review of studiesQRS durationHeart blockRisk stratificationAtrial fibrillationConduction defectsAn explainable machine learning model for prediction of high-risk nonalcoholic steatohepatitis
Njei B, Osta E, Njei N, Al-Ajlouni Y, Lim J. An explainable machine learning model for prediction of high-risk nonalcoholic steatohepatitis. Scientific Reports 2024, 14: 8589. PMID: 38615137, PMCID: PMC11016071, DOI: 10.1038/s41598-024-59183-4.Peer-Reviewed Original ResearchMeSH KeywordsAdultArtificial IntelligenceElasticity Imaging TechniquesHumansMachine LearningNon-alcoholic Fatty Liver DiseaseNutrition SurveysConceptsNational Health and Nutrition Examination SurveyRisk of progression to cirrhosisClinical risk indexHealth and Nutrition Examination SurveyControlled attenuation parameter valuesNovel therapeutic optionsLiver stiffness measurementProgression to cirrhosisAspartate aminotransferase levelsNutrition Examination SurveyResource-limited settingsFIB-4Fibrosis scorePlatelet countAminotransferase levelsTherapeutic optionsWaist circumferenceClinically applicable modelExamination SurveyNonalcoholic steatohepatitisFAST scoreEarly identificationElastography measurementsStiffness measurementPatientsLetter to the Editor: Concerns regarding the use of fatty liver index in studies of lean NAFLD
Zahrawi F, Mehal W. Letter to the Editor: Concerns regarding the use of fatty liver index in studies of lean NAFLD. Hepatology 2024, 79: e129-e129. PMID: 38214551, DOI: 10.1097/hep.0000000000000754.Peer-Reviewed Original Research
2023
The effect of endoscopic gastric plication on portosystemic pressure gradient in patients with nonalcoholic fatty liver disease and compensated advanced chronic liver disease
Jirapinyo P, Thompson C, Garcia-Tsao G, Zucker S, Ryou M. The effect of endoscopic gastric plication on portosystemic pressure gradient in patients with nonalcoholic fatty liver disease and compensated advanced chronic liver disease. Endoscopy 2023, 56: 56-62. PMID: 37532114, DOI: 10.1055/a-2146-8857.Peer-Reviewed Original ResearchMeSH KeywordsHumansLiverLiver CirrhosisNon-alcoholic Fatty Liver DiseasePilot ProjectsProspective StudiesTreatment OutcomeWeight LossConceptsNonalcoholic fatty liver diseaseEndoscopic gastric plicationAdvanced chronic liver diseaseFatty liver diseasePortosystemic pressure gradientChronic liver diseaseLiver diseaseTotal weight lossGastric plicationNoninvasive testsBaseline median body-mass indexMedian body mass indexPercent total weight lossWeight lossProportion of patientsProspective pilot studyBody mass indexLiver stiffness measurementWeight loss proceduresGoal of therapyHepatic decompensationSecondary outcomesPrimary outcomeMass indexPatientsPrecipitous changes in nomenclature and definitions—NAFLD becomes SLD: Implications for and expectations of AASLD journals
Malhi H, Brown R, Lim J, Reau N, Tapper E, Wong C, Gores G. Precipitous changes in nomenclature and definitions—NAFLD becomes SLD: Implications for and expectations of AASLD journals. Hepatology Communications 2023, 7: e0318. PMID: 37941420, PMCID: PMC10635597, DOI: 10.1097/hc9.0000000000000318.Peer-Reviewed Original ResearchPrecipitous changes in nomenclature and definitions—NAFLD becomes SLD: Implications for and expectations of AASLD journals
Malhi H, Brown R, Lim J, Reau N, Tapper E, Wong C, Gores G. Precipitous changes in nomenclature and definitions—NAFLD becomes SLD: Implications for and expectations of AASLD journals. Hepatology 2023, 78: 1680-1681. PMID: 37941421, DOI: 10.1097/hep.0000000000000619.Peer-Reviewed Original ResearchThe PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans
Luukkonen P, Porthan K, Ahlholm N, Rosqvist F, Dufour S, Zhang X, Lehtimäki T, Seppänen W, Orho-Melander M, Hodson L, Petersen K, Shulman G, Yki-Järvinen H. The PNPLA3 I148M variant increases ketogenesis and decreases hepatic de novo lipogenesis and mitochondrial function in humans. Cell Metabolism 2023, 35: 1887-1896.e5. PMID: 37909034, DOI: 10.1016/j.cmet.2023.10.008.Peer-Reviewed Original ResearchMeSH Keywords3-Hydroxybutyric AcidGenetic Predisposition to DiseaseHumansLipogenesisLiverMitochondriaNon-alcoholic Fatty Liver DiseaseConceptsDe novo lipogenesisHepatic de novo lipogenesisPlasma β-hydroxybutyrate concentrationsΒ-hydroxybutyrate concentrationsLiver diseaseNovo lipogenesisPNPLA3 I148M variantHepatic mitochondrial redox stateMajor genetic risk factorI148M variantFatty liver diseaseGenetic risk factorsHepatic mitochondrial dysfunctionKetogenic dietMixed mealRisk factorsHepatic metabolismHomozygous carriersM carriersMitochondrial dysfunctionCitrate synthase fluxM variantKetogenesisMitochondrial redox stateMitochondrial functionFXR agonists INT‐787 and OCA increase RECK and inhibit liver steatosis and inflammation in diet‐induced ob/ob mouse model of NASH
Di Pasqua L, Cagna M, Palladini G, Croce A, Cadamuro M, Fabris L, Perlini S, Adorini L, Ferrigno A, Vairetti M. FXR agonists INT‐787 and OCA increase RECK and inhibit liver steatosis and inflammation in diet‐induced ob/ob mouse model of NASH. Liver International 2023, 44: 214-227. PMID: 37904642, DOI: 10.1111/liv.15767.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsChenodeoxycholic AcidCollagenDiet, High-FatInflammationLiverMatrix Metalloproteinase 2Matrix Metalloproteinase 9MiceNon-alcoholic Fatty Liver DiseaseConceptsNon-alcoholic steatohepatitisHigh-fat dietOb/ob mouse modelObeticholic acidAgonist obeticholic acidSerum alanine transaminaseAlanine transaminaseMMP-2MMP-9Mouse modelCollagen depositionHepatic ischaemia/reperfusion injuryFarnesoid X receptor agonist obeticholic acidControl dietFXR agonist obeticholic acidIschaemia/reperfusion injuryHepatic stellate cell activationMMP-9 activityStellate cell activationMMP-2 expressionΑ-SMA levelsOCA administrationHFD groupReperfusion injuryLiver steatosisScreening, Diagnosis, and Staging of Non-Alcoholic Fatty Liver Disease (NAFLD): Application of Society Guidelines to Clinical Practice
Ilagan-Ying Y, Banini B, Do A, Lam R, Lim J. Screening, Diagnosis, and Staging of Non-Alcoholic Fatty Liver Disease (NAFLD): Application of Society Guidelines to Clinical Practice. Current Gastroenterology Reports 2023, 25: 213-224. PMID: 37768417, DOI: 10.1007/s11894-023-00883-8.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsConceptsNon-alcoholic fatty liver diseaseNon-invasive testsFatty liver diseaseLiver diseaseCommon chronic liver diseaseNonalcoholic fatty liver diseaseCurrent expert guidelinesHigh-risk patientsChronic liver diseaseSteatotic liver diseaseClinical practice implicationsHepatic decompensationLiver biopsySociety guidelinesSpecialty referralsNovel therapiesExpert guidelinesLiver cancerDisease awarenessObesity epidemicSerum indicesClinical practiceScreening toolDiseaseDiagnosisHepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis
Mooring M, Yeung G, Luukkonen P, Liu S, Akbar M, Zhang G, Balogun O, Yu X, Mo R, Nejak-Bowen K, Poyurovsky M, Booth C, Konnikova L, Shulman G, Yimlamai D. Hepatocyte CYR61 polarizes profibrotic macrophages to orchestrate NASH fibrosis. Science Translational Medicine 2023, 15: eade3157. PMID: 37756381, PMCID: PMC10874639, DOI: 10.1126/scitranslmed.ade3157.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDiabetes Mellitus, Type 2Disease Models, AnimalFibrosisHepatocytesInterleukin-1 Receptor-Associated KinasesLiverMacrophagesMiceMice, Inbred C57BLMice, KnockoutNF-kappa BNon-alcoholic Fatty Liver DiseaseConceptsNonalcoholic steatohepatitisLiver inflammationNonalcoholic fatty liver diseaseProgression of NASHCysteine-rich angiogenic inducer 61Fatty liver diseaseLiver-specific knockout miceImproved glucose toleranceType 2 diabetesGlucose toleranceLiver diseaseNASH progressionProfibrotic macrophagesProinflammatory propertiesReduced fibrosisCardiovascular diseaseProfibrotic phenotypeFibrotic developmentKnockout miceNF-κBMetabolic diseasesNASH dietPDGFB expressionFibrosisProfibrotic programTime-restricted feeding combined with resistance exercise prevents obesity and improves lipid metabolism in the liver of mice fed a high-fat diet
Damasceno de Lima R, Fudoli Lins Vieira R, Rosetto Muñoz V, Chaix A, Azevedo Macedo A, Calheiros Antunes G, Felonato M, Rosseto Braga R, Castelo Branco Ramos Nakandakari S, Calais Gaspar R, Ramos da Silva A, Esper Cintra D, Pereira de Moura L, Mekary R, Rochete Ropelle E, Pauli J. Time-restricted feeding combined with resistance exercise prevents obesity and improves lipid metabolism in the liver of mice fed a high-fat diet. AJP Endocrinology And Metabolism 2023, 325: e513-e528. PMID: 37755454, DOI: 10.1152/ajpendo.00129.2023.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDiet, High-FatHumansLipid MetabolismLiverMetabolic DiseasesMiceMice, Inbred C57BLNon-alcoholic Fatty Liver DiseaseObesityResistance TrainingRNA, MessengerWeight GainConceptsNonalcoholic fatty liver diseaseResistance exercise trainingTime-restricted feedingFatty liver diseaseHigh-fat dietLiver diseaseExercise trainingWeight gainGlycemic homeostasisMetabolic disordersEffects of TRFCommon liver diseaseDiet-induced obesityMajor risk factorEnergy expenditureFatty acid oxidation genesLiver of miceAccumulation of fatBody weight gainRespiratory exchange rateAccumulation of lipidsLower mRNA expressionRT groupPrevents obesityRisk factorsBioactive signalling lipids as drivers of chronic liver diseases
Kaffe E, Tisi A, Magkrioti C, Aidinis V, Mehal W, Flavell R, Maccarrone M. Bioactive signalling lipids as drivers of chronic liver diseases. Journal Of Hepatology 2023, 80: 140-154. PMID: 37741346, DOI: 10.1016/j.jhep.2023.08.029.Peer-Reviewed Original ResearchMeSH KeywordsCarcinoma, HepatocellularHumansLiverLiver Diseases, AlcoholicLiver NeoplasmsNon-alcoholic Fatty Liver DiseasePhospholipidsConceptsChronic liver diseaseLiver diseasePrevalent chronic liver diseaseBioactive lipidsPotential therapeutic targetG protein-coupled receptorsProtein-coupled receptorsTherapeutic targetPoly-unsaturated fatty acidsMalignant transformationPotent modulatorEnergy homeostasisDiseaseCell proliferationSignaling lipidsTissue repairReceptorsFatty acidsMultiple cellular functionsLipidsBioactive roleBioactive signaling lipidsInflammationProgressionExercise Does Not Independently Improve Histological Outcomes in Biopsy-Proven Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis
Chen G, Banini B, Do A, Gunderson C, Zaman S, Lim J. Exercise Does Not Independently Improve Histological Outcomes in Biopsy-Proven Non-Alcoholic Fatty Liver Disease: A Systematic Review and Meta-Analysis. Genes 2023, 14: 1811. PMID: 37761951, PMCID: PMC10531443, DOI: 10.3390/genes14091811.Peer-Reviewed Original ResearchConceptsNon-alcoholic fatty liver diseaseBiopsy-proven non-alcoholic fatty liver diseaseEffects of exerciseFatty liver diseaseHistological outcomesLiver histologyLiver diseaseClinical trialsHistological endpointsSystematic reviewSignificant histopathological improvementNAFLD activity scoreImpact of exerciseIndependent effectsRandom-effects modelSystematic literature searchHistopathological improvementExercise interventionActivity scoreClinical endpointsPooled estimatesMeta-AnalysisTotal participantsLiterature searchComparison groupMKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention
Qiu B, Lawan A, Xirouchaki C, Yi J, Robert M, Zhang L, Brown W, Fernández-Hernando C, Yang X, Tiganis T, Bennett A. MKP1 promotes nonalcoholic steatohepatitis by suppressing AMPK activity through LKB1 nuclear retention. Nature Communications 2023, 14: 5405. PMID: 37669951, PMCID: PMC10480499, DOI: 10.1038/s41467-023-41145-5.Peer-Reviewed Original ResearchMeSH KeywordsAMP-Activated Protein KinasesAnimalsInflammationMaleMiceMitogen-Activated Protein Kinase 14Non-alcoholic Fatty Liver DiseasePhosphorylationProtein Serine-Threonine KinasesHumanized mouse liver reveals endothelial control of essential hepatic metabolic functions
Kaffe E, Roulis M, Zhao J, Qu R, Sefik E, Mirza H, Zhou J, Zheng Y, Charkoftaki G, Vasiliou V, Vatner D, Mehal W, AlcHepNet, Kluger Y, Flavell R. Humanized mouse liver reveals endothelial control of essential hepatic metabolic functions. Cell 2023, 186: 3793-3809.e26. PMID: 37562401, PMCID: PMC10544749, DOI: 10.1016/j.cell.2023.07.017.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsEndothelial CellsFibrosisHepatocytesHumansKupffer CellsLiverMiceNon-alcoholic Fatty Liver DiseaseConceptsMetabolic functionsSpecies-specific interactionsKey metabolic functionsCell-autonomous mechanismsNon-alcoholic fatty liver diseaseMajor metabolic hubNon-parenchymal cellsMetabolic hubHuman hepatocytesMicroenvironmental regulationHuman diseasesHuman-specific aspectsHuman pathologiesHomeostatic processesSpecies mismatchCholesterol uptakeFatty liver diseaseParacrine mannerHuman immuneBile acid conjugationSinusoidal endothelial cellsHepatic metabolic functionMouse liverEndothelial cellsCellsNonalcoholic liver disease: Epidemiology, risk factors, natural history, and management strategies
Agyapong G, Dashti F, Banini B. Nonalcoholic liver disease: Epidemiology, risk factors, natural history, and management strategies. Annals Of The New York Academy Of Sciences 2023, 1526: 16-29. PMID: 37400359, PMCID: PMC10524684, DOI: 10.1111/nyas.15012.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMeSH KeywordsDisease ProgressionFibrosisHumansLiverLiver CirrhosisNon-alcoholic Fatty Liver DiseaseRisk FactorsUnited StatesConceptsNonalcoholic fatty liver diseaseNonalcoholic fatty liverLiver diseaseRisk factorsCommon chronic liver diseaseEnd-stage liver diseaseNatural historyNAFLD risk factorsChronic liver diseaseFatty liver diseaseCurrent management strategiesClinicopathologic spectrumLiver transplantationNonalcoholic steatohepatitisProgressive fibrosisFatty liverHepatocellular cancerLeading indicationDiseaseUnited StatesManagement strategiesCirrhosisSteatohepatitisTransplantationFibrosis
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