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, PMCID: PMC12067271, DOI: 10.1073/pnas.2502978122.Peer-Reviewed Original ResearchConceptsCholine-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 formATGL links insulin dysregulation to insulin resistance in adolescents with obesity and hepatosteatosis
Slusher A, Santoro N, Vash-Margita A, Galderisi A, Hu P, Tokoglu F, Li Z, Tarabra E, Strober J, Vatner D, Shulman G, Caprio S. ATGL links insulin dysregulation to insulin resistance in adolescents with obesity and hepatosteatosis. Journal Of Clinical Investigation 2025, 135: e184740. PMID: 40091831, PMCID: PMC11910223, DOI: 10.1172/jci184740.Peer-Reviewed Original ResearchConceptsHyperinsulinemic-euglycemic clampSubcutaneous adipose tissueInsulin resistanceAdipose triglyceride lipaseInsulin infusionOral glucose tolerance testAbdominal fat distributionGlucose tolerance testMeasuring abdominal fat distributionLower liver fatActivating adipose triglyceride lipaseMetabolic disease riskLiver fat contentEctopic lipid storageFUNDINGThis workAdipose tissue lipolysisInhibition of adipose tissue lipolysisSubcutaneous adipose tissue samplesFat distributionTolerance testInsulin exposureLiver fatInfusionGlycerol turnoverAdipose tissueDeletion of sphingosine 1-phosphate receptor 1 in myeloid cells reduces hepatic inflammatory macrophages and attenuates MASH
Parthasarathy G, Venkatesan N, Sidhu G, Song M, Liao C, Barrow F, Mauer A, Sehrawat T, Nakao Y, Daniel P, Dasgupta D, Pavelko K, Revelo X, Malhi H. Deletion of sphingosine 1-phosphate receptor 1 in myeloid cells reduces hepatic inflammatory macrophages and attenuates MASH. Hepatology Communications 2025, 9: e0613. PMID: 39899672, DOI: 10.1097/hc9.0000000000000613.Peer-Reviewed Original ResearchConceptsMyeloid cellsMonocyte-derived macrophagesHigh-fatLiver injuryProinflammatory monocyte-derived macrophagesReceptor 1Cell-specific knockout miceMass cytometryT cell subsetsSphingosine 1-phosphate receptor 1Cardiometabolic risk factorsS1P receptor 1Accumulation of monocyte-derived macrophagesImmune cell typesWild-typeLiver inflammatory infiltrationGene ontology pathway analysisWild-type controlsDevelopment of steatohepatitisSphingosine 1-phosphateMitogen-activated protein kinase pathwayT cellsIntrahepatic macrophagesInflammatory infiltrateKnockout miceMortality, Hepatic Decompensation, and Cardiovascular Outcomes in Lean vs. Non-lean MASLD Cirrhosis: A Veterans Affairs Cohort Study
Njei B, Mezzacappa C, John B, Serper M, Kaplan D, Taddei T, Mahmud N. Mortality, Hepatic Decompensation, and Cardiovascular Outcomes in Lean vs. Non-lean MASLD Cirrhosis: A Veterans Affairs Cohort Study. Digestive Diseases And Sciences 2025, 70: 802-813. PMID: 39779587, PMCID: PMC11839701, DOI: 10.1007/s10620-024-08764-4.Peer-Reviewed Original ResearchConceptsNon-lean individualsAll-cause mortalityMajor adverse cardiovascular eventsIncreased risk of all-cause mortalityRisk of all-cause mortalityVeterans Health AdministrationRisk of hepatic decompensationPrevalence of diabetesRisk of cardiovascular mortalityHepatic decompensationHigher mortality riskCardiovascular-related mortalityCox proportional hazards modelsCohort study of patientsCardiovascular outcomesIncident major adverse cardiovascular eventsRetrospective cohort study of patientsProportional hazards modelNon-HispanicRetrospective cohort studyCompeting risk regressionHealth AdministrationMultivariate Cox proportional hazards modelLean individualsAssessed associations
2024
Identification of hepatic steatosis among persons with and without HIV using natural language processing
Torgersen J, Skanderson M, Kidwai-Khan F, Carbonari D, Tate J, Park L, Bhattacharya D, Lim J, Taddei T, Justice A, Re V. Identification of hepatic steatosis among persons with and without HIV using natural language processing. Hepatology Communications 2024, 8: e0468. PMID: 38896066, PMCID: PMC11186806, DOI: 10.1097/hc9.0000000000000468.Peer-Reviewed Original ResearchConceptsImaging ReportingSteatotic liver diseaseHIV statusHepatic steatosisPrevalence of metabolic comorbiditiesImaging studiesVeterans Aging Cohort StudyCompare patient characteristicsPositive predictive valueAlcohol use disorderAging Cohort StudyIdentification of hepatic steatosisHIV infectionHepatitis BMetabolic comorbiditiesNatural language processing algorithmsRadiological studiesCohort studyPatient characteristicsClinical reviewLiver diseaseHIVPredictive valueUse disorderClinical image reportsImpact of HIV Infection on Liver and Cardiovascular Outcomes in Veterans With Metabolic Dysfunction-Associated Steatotic Liver Disease
Wong R, Yang Z, Yeoh A, Do A, Ahmed A, Cheung R. Impact of HIV Infection on Liver and Cardiovascular Outcomes in Veterans With Metabolic Dysfunction-Associated Steatotic Liver Disease. The American Journal Of Gastroenterology 2024, 119: 1841-1848. PMID: 38477465, DOI: 10.14309/ajg.0000000000002760.Peer-Reviewed Original ResearchConceptsImpact of HIV infectionAntiretroviral therapyIncidence of cirrhosisAdverse cardiovascular eventsHIV infectionHepatocellular carcinomaAssociated with greater riskCardiovascular diseaseOverall survivalCardiovascular eventsLiver diseaseSteatotic liver diseaseConcurrent HIV infectionDecreased overall survivalRisk of cirrhosisRisk of liverGreater riskLiver disease progressionPropensity-matched cohortScore-matched cohortCardiovascular disease outcomesUS veteransCardiovascular outcomesDisease progressionPrimary outcomeImpact of Longitudinal Alcohol Use Patterns on Long-Term Risk of Cirrhosis Among US Veterans With Steatotic Liver Disease
Wong R, Yang Z, Cheung R, Singal A, Do A, Ahmed A, Yeoh A. Impact of Longitudinal Alcohol Use Patterns on Long-Term Risk of Cirrhosis Among US Veterans With Steatotic Liver Disease. Gastroenterology 2024, 166: 1156-1165.e4. PMID: 38428619, DOI: 10.1053/j.gastro.2024.02.032.Peer-Reviewed Original ResearchConceptsRisk of cirrhosisHigh-risk alcoholIncidence of cirrhosisHigh-risk alcohol useLiver diseaseSteatotic liver diseaseLong-term riskAlcohol Use Disorders Identification Test-ConciseAlcohol useFollow-upRisk of liver disease progressionLow-risk alcohol useAbstractText Label="RESULTS">Liver disease progressionAlcohol use assessmentImpact of alcohol useUS veteransBaseline alcohol useAlcohol use patternsDisease progressionCirrhosisReducing alcohol usePatientsLongitudinal alcohol useNo alcohol
2023
Lysophosphatidic acid triggers inflammation in the liver and white adipose tissue in rat models of 1-acyl-sn-glycerol-3-phosphate acyltransferase 2 deficiency and overnutrition
Sakuma I, Gaspar R, Luukkonen P, Kahn M, Zhang D, Zhang X, Murray S, Golla J, Vatner D, Samuel V, Petersen K, Shulman G. Lysophosphatidic acid triggers inflammation in the liver and white adipose tissue in rat models of 1-acyl-sn-glycerol-3-phosphate acyltransferase 2 deficiency and overnutrition. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2312666120. PMID: 38127985, PMCID: PMC10756285, DOI: 10.1073/pnas.2312666120.Peer-Reviewed Original ResearchAdvancing diagnosis and management of liver disease in adults through exome sequencing
Zheng M, Hakim A, Konkwo C, Deaton A, Ward L, Genetics A, Silveira M, Assis D, Liapakis A, Jaffe A, Jiang Z, Curry M, Lai M, Cho M, Dykas D, Bale A, Mistry P, Vilarinho S. Advancing diagnosis and management of liver disease in adults through exome sequencing. EBioMedicine 2023, 95: 104747. PMID: 37566928, PMCID: PMC10433007, DOI: 10.1016/j.ebiom.2023.104747.Peer-Reviewed Original ResearchConceptsLiver diseaseWhole-exome sequencingUnknown etiologyTertiary referral academic medical centerReferral academic medical centerExome sequencingLiver disease patientsManagement of adultsAcademic health care centerComprehensive clinical evaluationHealth care centersAcademic medical centerGenetic variantsRare genetic variantsAdult patientsLiver centersHepatic steatosisDisease patientsClinical evaluationCare centerFamily historyMedical CenterClinical valueAdult medicinePatientsPerformance of an automated deep learning algorithm to identify hepatic steatosis within noncontrast computed tomography scans among people with and without HIV
Torgersen J, Akers S, Huo Y, Terry J, Carr J, Ruutiainen A, Skanderson M, Levin W, Lim J, Taddei T, So‐Armah K, Bhattacharya D, Rentsch C, Shen L, Carr R, Shinohara R, McClain M, Freiberg M, Justice A, Re V. Performance of an automated deep learning algorithm to identify hepatic steatosis within noncontrast computed tomography scans among people with and without HIV. Pharmacoepidemiology And Drug Safety 2023, 32: 1121-1130. PMID: 37276449, PMCID: PMC10527049, DOI: 10.1002/pds.5648.Peer-Reviewed Original ResearchConceptsSevere hepatic steatosisHepatic steatosisHIV statusLiver attenuationHounsfield unitsPredictive valueRadiologist assessmentUS Veterans Health AdministrationNoncontrast abdominal CTVeterans Health AdministrationCross-sectional studySample of patientsNegative predictive valueReal-world studyPositive predictive valueAbdominal CTLiver fatTomography scanSteatosisCT imagesHealth AdministrationPharmacoepidemiologic studiesRadiologist reviewHIVPercent agreementEffects of Ethanolic and Aqueous Extracts of Garcinia gardneriana Leaves in an In Vivo Experimental Model Induced by a Hyperlipidic Diet
do Espirito Santo B, Santana L, Kato W, de Araújo F, Tatara M, Croda J, Bogo D, de Cássia Freitas K, de Cássia Avellaneda Guimarães R, Hiane P, Pott A, de Oliveira Filiú W, de Faria B, de Oliveira Figueiredo P, do Nascimento V, Ayres F, de Oliveira Bastos P. Effects of Ethanolic and Aqueous Extracts of Garcinia gardneriana Leaves in an In Vivo Experimental Model Induced by a Hyperlipidic Diet. Nutrients 2023, 15: 1308. PMID: 36986038, PMCID: PMC10051817, DOI: 10.3390/nu15061308.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDiet, High-FatEthanolFatty LiverGarciniaMicePlant ExtractsPlants, MedicinalWaterConceptsMonocyte chemoattractant protein-1 concentrationsChemoattractant protein-1 concentrationsNon-communicable chronic diseasesExperimental modelProtein-1 concentrationsHigh-fat dietHigh-density lipoproteinPossible metabolic alterationsVivo experimental modelsEffect of ethanolicAqueous extractTotal cholesterolInterleukin-10Microvesicular steatosisHepatic steatosisInsulin resistanceBlood glucoseSwiss miceHyperlipidic dietChronic diseasesDensity lipoproteinMetabolic alterationsControl groupWeight gainEthanolic extract
2022
Heterogeneity of hepatic steatosis definitions and reporting of donor liver frozen sections among pathologists: A multicenter survey
Ho S, Kuo E, Allende D, Wang HL, Westerhoff M, Graham RP, Saxena R, Gonzalez RS, Fiel MI, Yang Z, Zhang X, Liu X. Heterogeneity of hepatic steatosis definitions and reporting of donor liver frozen sections among pathologists: A multicenter survey. Liver Transplantation 2022, 28: 1540-1542. PMID: 35377545, DOI: 10.1002/lt.26466.Peer-Reviewed Original ResearchLipidomics and Redox Lipidomics Indicate Early Stage Alcohol‐Induced Liver Damage
Koelmel JP, Tan WY, Li Y, Bowden JA, Ahmadireskety A, Patt AC, Orlicky DJ, Mathé E, Kroeger NM, Thompson DC, Cochran JA, Golla JP, Kandyliari A, Chen Y, Charkoftaki G, Guingab‐Cagmat J, Tsugawa H, Arora A, Veselkov K, Kato S, Otoki Y, Nakagawa K, Yost RA, Garrett TJ, Vasiliou V. Lipidomics and Redox Lipidomics Indicate Early Stage Alcohol‐Induced Liver Damage. Hepatology Communications 2022, 6: 513-525. PMID: 34811964, PMCID: PMC8870008, DOI: 10.1002/hep4.1825.Peer-Reviewed Original ResearchConceptsAlcoholic fatty liver diseaseEthanol-treated miceFatty liver diseaseAlcohol consumption altersRegulation of triglycerideLiver lipidomeRegulation of phosphatidylcholineHepatic inflammationLiver biopsyLiver diseaseComprehensive time-course studyLiver damageHistological signsEarly biomarkersHistological markersMouse modelTime-course studyLiver tissueTriglyceridesHistological analysisEarly detectionLipid accumulationLiverMajor lipid classesDiet model
2021
Development of a Scoring System to Differentiate Amiodarone-Induced Liver Injury From Alcoholic Steatohepatitis
González IA, Fuller LD, Zhang X, Papke DJ, Zhao L, Zhang D, Liao X, Liu X, Fiel MI, Zhang X. Development of a Scoring System to Differentiate Amiodarone-Induced Liver Injury From Alcoholic Steatohepatitis. American Journal Of Clinical Pathology 2021, 157: 434-442. PMID: 34596220, DOI: 10.1093/ajcp/aqab142.Peer-Reviewed Original ResearchMeSH KeywordsAmiodaroneChemical and Drug Induced Liver Injury, ChronicFatty LiverFatty Liver, AlcoholicHumansLiverConceptsAmiodarone-induced liver injuryAlcoholic steatohepatitisScoring systemLiver injuryTest cohortDifferent histologic featuresHepatocyte ballooning degenerationMallory-Denk bodiesNeutrophilic inflammationHistologic featuresPericellular fibrosisMacrovesicular steatosisBallooning degenerationHistologic differencesLiver parenchymaCohortSteatohepatitisInjuryFurther validationInitial studyZone 1SatellitosisCholestasisSteatosisInflammationIsthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis
Jiang Z, Zhao M, Voilquin L, Jung Y, Aikio MA, Sahai T, Dou FY, Roche AM, Carcamo-Orive I, Knowles JW, Wabitsch M, Appel EA, Maikawa CL, Camporez JP, Shulman GI, Tsai L, Rosen ED, Gardner CD, Spiegelman BM, Svensson KJ. Isthmin-1 is an adipokine that promotes glucose uptake and improves glucose tolerance and hepatic steatosis. Cell Metabolism 2021, 33: 1836-1852.e11. PMID: 34348115, PMCID: PMC8429235, DOI: 10.1016/j.cmet.2021.07.010.Peer-Reviewed Original ResearchConceptsFatty liver diseaseAdipose glucose uptakeGlucose toleranceLiver diseaseHepatic steatosisGlucose uptakeDiet-induced obese miceImpaired glucose toleranceInsulin-like growth factor receptorType 2 diabetesHepatic lipid synthesisIsthmin 1Growth factor receptorObese miceInsulin sensitivityTherapeutic dosingMouse modelGlucoregulatory functionGlucose regulationUnmet needTherapeutic potentialDiabetesLipid accumulationPI3K-AktFactor receptorTherapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH
Goedeke L, Shulman GI. Therapeutic potential of mitochondrial uncouplers for the treatment of metabolic associated fatty liver disease and NASH. Molecular Metabolism 2021, 46: 101178. PMID: 33545391, PMCID: PMC8085597, DOI: 10.1016/j.molmet.2021.101178.Peer-Reviewed Original ResearchConceptsFatty liver diseaseLiver diseaseSmall molecule mitochondrial uncouplersTherapeutic potentialMitochondrial uncouplerNon-human primate studiesType 2 diabetesWide therapeutic indexSystemic toxicity concernsTreatment of MetabolicCell-specific effectsInsulin resistanceTherapeutic indexMetabolic diseasesNonalcoholic hepatosteatosisSustained increaseToxicity concernsPrimate studiesDiseaseTherapeutic developmentMitochondrial inefficiencyNutrient oxidationATP productionTreatmentTissueApobec1 complementation factor overexpression promotes hepatic steatosis, fibrosis and hepatocellular cancer
Blanc V, Riordan JD, Soleymanjahi S, Nadeau J, Nalbantoglu I, Xie Y, Molitor EA, Madison BB, Brunt EM, Mills JC, Rubin DC, Ng I, Ha Y, Roberts LR, Davidson NO. Apobec1 complementation factor overexpression promotes hepatic steatosis, fibrosis and hepatocellular cancer. Journal Of Clinical Investigation 2021, 131 PMID: 33445170, PMCID: PMC7773377, DOI: 10.1172/jci138699.Peer-Reviewed Original ResearchConceptsHuman hepatocellular cancerHigh-fructose dietHepatocellular cancerNonalcoholic fatty liver diseaseFatty liver diseaseExpression of mRNALipogenic gene expressionSpontaneous fibrosisAdvanced fibrosisLiver diseaseLiver functionHepatic steatosisInflammatory pathwaysInflammatory responseFed chowLong-term effectsTissue microarrayHepatic proliferationMRNA expressionFactor overexpressionReduced survivalFibrosisOxidative stressExtracellular matrix organizationSteatosis
2020
Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance
He F, Huang Y, Song Z, Zhou HJ, Zhang H, Perry RJ, Shulman GI, Min W. Mitophagy-mediated adipose inflammation contributes to type 2 diabetes with hepatic insulin resistance. Journal Of Experimental Medicine 2020, 218: e20201416. PMID: 33315085, PMCID: PMC7927432, DOI: 10.1084/jem.20201416.Peer-Reviewed Original ResearchMeSH KeywordsAdipocytesAdipose TissueAnimalsDiabetes Mellitus, Type 2Diet, High-FatEnergy MetabolismFatty LiverGene DeletionGene TargetingGluconeogenesisHomeostasisHumansHyperglycemiaInflammationInsulin ResistanceLipogenesisLiverMaleMice, Inbred C57BLMice, KnockoutMitochondriaMitophagyNF-kappa BOxidative StressPhenotypeReactive Oxygen SpeciesSequestosome-1 ProteinSignal TransductionThioredoxinsConceptsHepatic insulin resistanceWhite adipose tissueInsulin resistanceAdipose inflammationType 2 diabetes mellitusLipid metabolic disordersNF-κB inhibitorAdipose-specific deletionWhole-body energy homeostasisAltered fatty acid metabolismFatty acid metabolismT2DM progressionT2DM patientsDiabetes mellitusReactive oxygen species pathwayHepatic steatosisMetabolic disordersNF-κBP62/SQSTM1Adipose tissueHuman adipocytesEnergy homeostasisExcessive mitophagyOxygen species pathwayInflammationHepatocellular neoplasms arising in genetic metabolic disorders: steatosis is common in both the tumor and background liver
Cheng L, Jain D, Kakar S, Torbenson MS, Wu TT, Yeh MM. Hepatocellular neoplasms arising in genetic metabolic disorders: steatosis is common in both the tumor and background liver. Human Pathology 2020, 108: 93-99. PMID: 33245984, DOI: 10.1016/j.humpath.2020.11.012.Peer-Reviewed Original ResearchConceptsGenetic metabolic disordersMetabolic disordersHepatocellular neoplasmsBackground liverType 1Ornithine carbamyl transferase deficiencyRare genetic metabolic disorderRare case reportBackground liver parenchymaGlycogen storage disease type 1Hereditary tyrosinemia type 1Disease type 1Tyrosinemia type 1Younger patientsRetrospective studyCase reportCommon findingLiver parenchymaSteatosisTransferase deficiencyPathological characterizationNeoplasmsTumorsDisordersPatientsKnockout of sulfatase 2 is associated with decreased steatohepatitis and fibrosis in a mouse model of nonalcoholic fatty liver disease
Kim TH, Banini BA, Asumda FZ, Campbell NA, Hu C, Moser CD, Shire AM, Han S, Ma C, Krishnan A, Mounajjed T, White TA, Gores GJ, LeBrasseur NK, Charlton MR, Roberts LR. Knockout of sulfatase 2 is associated with decreased steatohepatitis and fibrosis in a mouse model of nonalcoholic fatty liver disease. AJP Gastrointestinal And Liver Physiology 2020, 319: g333-g344. PMID: 32683952, PMCID: PMC7509257, DOI: 10.1152/ajpgi.00150.2019.Peer-Reviewed Original ResearchConceptsFast food dietStandard chow dietWT miceDiet-induced steatohepatitisNonalcoholic steatohepatitisSulfatase 2Hepatic fibrosisMouse modelStandard chow diet ad libitumChow diet ad libitumNonalcoholic fatty liver diseaseDiet-induced mouse modelConditions of overnutritionProtein expressionFatty liver diseasePotential therapeutic mechanismWild-type miceDiet ad libitumThreefold increaseLiver diseaseChow dietKO miceLiver fibrosisSteatohepatitisMurine model
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