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 formtRNA m1A modification regulates cholesterol biosynthesis to promote antitumor immunity of CD8+ T cells
Miao S, Li H, Song X, Liu Y, Wang G, Kan C, Ye Y, Liu R, Li H. tRNA m1A modification regulates cholesterol biosynthesis to promote antitumor immunity of CD8+ T cells. Journal Of Experimental Medicine 2025, 222: e20240559. PMID: 39873720, PMCID: PMC11774205, DOI: 10.1084/jem.20240559.Peer-Reviewed Original ResearchConceptsCD8+ T cellsT cellsTumor-killing functionTransfer RNARegulating cholesterol biosynthesisAntitumor immunityCapacity of CD8+ T cellsActivation of CD8+ T cellsCholesterol biosynthesisM1A modificationTumor-killing capacityAntitumor responseATP citrate lyaseCancer immunotherapyCD8Effector functionsMetabolic reprogrammingProtein translationBiosynthetic demandsCitrate lyaseIn vitro assaysIn vivoPosttranscriptional mechanismsRegulatory checkpointsBiosynthesis
2024
Cholesterol promotes IFNG mRNA expression in CD4+ effector/memory cells by SGK1 activation
Hanin A, Comi M, Sumida T, Hafler D. Cholesterol promotes IFNG mRNA expression in CD4+ effector/memory cells by SGK1 activation. Life Science Alliance 2024, 7: e202402890. PMID: 39366761, PMCID: PMC11452476, DOI: 10.26508/lsa.202402890.Peer-Reviewed Original ResearchConceptsCentral nervous systemT cellsEffector/memory cellsCentral nervous system milieuT cell environmentCD4 T cellsIFNG mRNA expressionCXCR3<sup>+</sup> cellsT cell homeostasisInhibition of SGK1Targeting lipid pathwaysMaintenance of immune surveillanceSerum/glucocorticoid-regulated kinaseImmune surveillanceHealthy donorsCytotoxic capacityEffector responsesInflammatory conditionsSGK1 activityMRNA expressionNervous systemSGK1Metabolic conditionsLipid pathwaysTissue adaptationAn emerging antibacterial nanovaccine for enhanced chemotherapy by selectively eliminating tumor-colonizing bacteria
Chen L, Kang Z, Shen J, Zhao R, Miao Y, Zhang L, Zheng Z, Zhang Z, Liu N, Wang C, Fang H, Zhou J, Wang Y, Liu Z, Yang Y, Chen Q. An emerging antibacterial nanovaccine for enhanced chemotherapy by selectively eliminating tumor-colonizing bacteria. Science Bulletin 2024, 69: 2565-2579. PMID: 38918142, DOI: 10.1016/j.scib.2024.06.016.Peer-Reviewed Original ResearchConceptsF. nucleatumColorectal cancerEffective antigen presentationEnhance chemotherapy efficacyT cell activationReduce cancer metastasisPoor treatment outcomesIncreased cancer cell growthCancer cell growthOral anaerobesDendritic cellsFusobacterium nucleatumChemotherapy efficacyAntitumor effectAntigen presentationBiomimetic nanovaccinesEnhanced chemotherapyNanovaccineAlum adjuvantCpG oligonucleotidesTreatment outcomesImmune responseImmune progressionTherapeutic effectVaccine effectivenessHealth Factors Associated With Development and Severity of Poststroke Dysphagia: An Epidemiological Investigation
Krekeler B, Schieve H, Khoury J, Ding L, Haverbusch M, Alwell K, Adeoye O, Ferioloi S, Mackey J, Woo D, Flaherty M, La Rosa F, Demel S, Star M, Coleman E, Walsh K, Slavin S, Jasne A, Mistry E, Kleindorfer D, Kissela B. Health Factors Associated With Development and Severity of Poststroke Dysphagia: An Epidemiological Investigation. Journal Of The American Heart Association 2024, 13: e033922. PMID: 38533959, PMCID: PMC11179757, DOI: 10.1161/jaha.123.033922.Peer-Reviewed Original ResearchMeSH KeywordsAdultCholesterolDeglutition DisordersHemorrhagic StrokeHumansLeukoencephalopathiesStrokeConceptsHistory of high cholesterolDysphagia statusLogistic regressionFactors associated with reduced riskHealth risk factorsPopulation-based studyFactors associated with increased riskNational Institutes of Health Stroke Scale scoreMultivariate logistic regressionRisk of dysphagiaPoststroke dysphagiaHemorrhagic stroke casesStroke Scale scoreStroke casesDevelopment of dysphagiaStroke recoveryPercutaneous endoscopic gastrostomy tube placementBlack raceRight hemisphere strokeHemorrhagic strokeHigh cholesterolRisk factorsAcute strokeFactors associated with developmentChart reviewMediating Factors in the Association of Maternal Educational Level With Pregnancy Outcomes
Rogne T, Gill D, Liew Z, Shi X, Stensrud V, Nilsen T, Burgess S. Mediating Factors in the Association of Maternal Educational Level With Pregnancy Outcomes. JAMA Network Open 2024, 7: e2351166. PMID: 38206626, PMCID: PMC10784860, DOI: 10.1001/jamanetworkopen.2023.51166.Peer-Reviewed Original ResearchMeSH KeywordsBirth WeightCholesterolCohort StudiesDiabetes Mellitus, Type 2Educational StatusFemaleGenome-Wide Association StudyHumansHyperemesis GravidarumInfant, NewbornLipoproteins, HDLMediation AnalysisMendelian Randomization AnalysisPre-EclampsiaPregnancyPregnancy OutcomePregnancy, EctopicPremature BirthConceptsCardiometabolic risk factorsBody mass indexOffspring birth weightEducational attainmentMendelian randomizationHigh-density lipoprotein cholesterol levelsSystolic blood pressureInverse variance-weighted methodModifiable cardiometabolic risk factorsPregnancy outcomesCohort studyLipoprotein cholesterol levelsMR-Egger regressionMass indexUnivariable MR analysisEffects of educational attainmentAssociated with increased risk of adverse pregnancy outcomesPublic health interventionsMaternal education levelLower educational attainmentRisk factorsRisk of adverse pregnancy outcomesGenome-wide association studiesAssociated with increased riskBirth weight
2023
Cholesterol-dependent homeostatic regulation of very long chain sphingolipid synthesis
Kim Y, Mavodza G, Senkal C, Burd C. Cholesterol-dependent homeostatic regulation of very long chain sphingolipid synthesis. Journal Of Cell Biology 2023, 222: e202308055. PMID: 37787764, PMCID: PMC10547602, DOI: 10.1083/jcb.202308055.Peer-Reviewed Original ResearchConceptsPlasma membraneEpidermal growth factor receptor signalingMembrane lipid homeostasisGrowth factor receptor signalingAcute cholesterol depletionCellular cholesterol homeostasisPlasma membrane cholesterol contentCellular cholesterol levelsMembrane lipid packingSterol-responsive elementMembrane cholesterol contentProtein translationCytoplasmic leafletCholesterol depletionSphingolipid synthesisGolgi apparatusProtein pathwayResponsive elementLipid homeostasisRegulatory axisReceptor signalingLysosome membraneSphingomyelin synthesisAccumulation of cholesterolMetabolic axisPer- and Polyfluoroalkyl Substances (PFAS) and Lipid Trajectories in Women 45–56 Years of Age: The Study of Women’s Health Across the Nation
Kang H, Ding N, Karvonen-Gutierrez C, Mukherjee B, Calafat A, Park S. Per- and Polyfluoroalkyl Substances (PFAS) and Lipid Trajectories in Women 45–56 Years of Age: The Study of Women’s Health Across the Nation. Environmental Health Perspectives 2023, 131: 087004. PMID: 37552133, PMCID: PMC10408595, DOI: 10.1289/ehp12351.Peer-Reviewed Original ResearchConceptsStudy of Women's HealthOdds ratioWomen's HealthMidlife womenConfidence intervalsFavorable blood lipid profileEstimate odds ratiosAdverse effects of PFASSerum PFAS concentrationsLatent class growth modelingLongitudinal trajectoriesAssociated with totalMenopausal transitionAssociated with trajectoriesLow-density lipoprotein (LDL) cholesterolHigh-density lipoprotein (HDL) cholesterolLipid trajectoriesAverage follow-upBlood total cholesterolBlood lipid profileTriglycerides trajectoriesEpidemiological studiesPositive associationBlood lipidsLDL cholesterolSfxn5 Regulation of Actin Polymerization for Neutrophil Spreading Depends on a Citrate-Cholesterol-PI(4,5)P2 Pathway.
Zhang H, Meng L, Liu Y, Jiang J, He Z, Qin J, Wang C, Yang M, He K, Yang J, Chen K, He Q, Tang W, Fan S, Ren C. Sfxn5 Regulation of Actin Polymerization for Neutrophil Spreading Depends on a Citrate-Cholesterol-PI(4,5)P2 Pathway. The Journal Of Immunology 2023, 211: 462-473. PMID: 37326485, DOI: 10.4049/jimmunol.2200863.Peer-Reviewed Original ResearchConceptsRegulation of actin polymerizationActin polymerizationNeutrophil spreadingCell spreadingLevels of phosphatidylinositol 4,5-bisphosphatePromote actin polymerizationNeutrophil actin polymerizationPhysiological cellular functionsPhosphatidylinositol 4,5-bisphosphateCytosolic citrateSmall interfering RNA transfectionFamily proteinsSFXN5Acetyl-CoAPI(4,5)P2 levelsMitochondrial membraneSpreading neutrophilsMetabolite transportCellular functionsMorpholino injectionCellular phenotypesCitrate transporterPlasma membraneDownstream metabolic productsDecreased neutrophil recruitmentSREBP2 regulates the endothelial response to cytokines via direct transcriptional activation of KLF6
Fowler J, Boutagy N, Zhang R, Horikami D, Whalen M, Romanoski C, Sessa W. SREBP2 regulates the endothelial response to cytokines via direct transcriptional activation of KLF6. Journal Of Lipid Research 2023, 64: 100411. PMID: 37437844, PMCID: PMC10407908, DOI: 10.1016/j.jlr.2023.100411.Peer-Reviewed Original ResearchConceptsDirect transcriptional activationTranscriptional activationEndothelial cellsChemokine expressionChromatin immunoprecipitation sequencingCholesterol homeostasisSterol-responsive genesPro-inflammatory chemokinesLipid-lowering drugsAdaptive immune responsesPro-inflammatory genesTranscription factor SREBP2Endogenous cholesterol synthesisImmunoprecipitation sequencingResponsive genesMechanism of actionPromoter regionCardiovascular riskAtherosclerotic diseaseInflammatory phenotypeImmune modulationCardiovascular diseaseImmune responseInflammatory stimuliI interferonPancoronary plaque characteristics and clinical outcomes in acute coronary syndrome patients with cancer history
Wang C, Tian X, Feng X, Demuyakor A, Hu S, Wang Y, Li L, Cui L, Dong F, Dai J, Lei F, Xu Y, Du Z, Shi M, Liu J, Xing L, E M. Pancoronary plaque characteristics and clinical outcomes in acute coronary syndrome patients with cancer history. Atherosclerosis 2023, 378: 117118. PMID: 37127496, DOI: 10.1016/j.atherosclerosis.2023.03.023.Peer-Reviewed Original ResearchConceptsAcute coronary syndrome patientsAcute coronary syndromeMaximum lipid arcOptical coherence tomographyThin-cap fibroatheromaCancer historyFibrous cap thicknessPercutaneous coronary interventionNonculprit lesionsLipid arcPrevalence of high-risk plaqueIncidence of thin-cap fibroatheromaCulprit lesionPrevalence of acute coronary syndromeHigh-risk plaque featuresHigher incidencePlaque characteristicsTime of percutaneous coronary interventionAssociated with high mortalityCharacteristics of coronary plaquesLipid indicesAbsence of cancer historyCoronary syndrome patientsNon-culprit lesionsIncidence of calcificationThe association between nonalcoholic fatty liver disease and corrected QT interval prolongation among generally healthy Iranian population: Fasa Cohort Study (FACS)
Naderi A, Farjam M, Sani M, Abdollahi A, Alkamel A, Keshavarzian O, Tabrizi R. The association between nonalcoholic fatty liver disease and corrected QT interval prolongation among generally healthy Iranian population: Fasa Cohort Study (FACS). Clinical Cardiology 2023, 46: 615-621. PMID: 37016545, PMCID: PMC10270276, DOI: 10.1002/clc.24015.Peer-Reviewed Original ResearchMeSH KeywordsCholesterolCohort StudiesFemaleHumansIranMaleNon-alcoholic Fatty Liver DiseaseRisk FactorsConceptsFasa Cohort StudyCohort studyRisk of nonalcoholic fatty liver diseaseNonalcoholic fatty liver diseaseRegression analysisPhysical activityFatty liver indexLogistic regression analysisQTc intervalSmoking statusOdds ratioHypertension statusLinear regression analysisFatty liver diseaseInterval prolongationIranian populationRisk factorsHealthy Iranian populationNAFLD criteriaHealthy populationCorrected QT interval prolongationLiver diseaseParticipantsConfoundingProlonged QTc intervalOverexpression of NgBR inhibits high-fat diet–induced atherosclerosis in ApoE-deficiency mice
Gong K, Wang M, Wang D, Gao Y, Ma L, Yang X, Zhu X, Chen S, Zhang M, Li H, Chen Y, Hu W, Miao Q, Iwakiri Y, Liao C, Duan Y, Han J. Overexpression of NgBR inhibits high-fat diet–induced atherosclerosis in ApoE-deficiency mice. Hepatology Communications 2023, 7: e0048. PMID: 36996002, PMCID: PMC10069848, DOI: 10.1097/hc9.0000000000000048.Peer-Reviewed Original ResearchConceptsNgBR overexpressionScavenger receptor type BIHigh-fat diet-induced atherosclerosisApolipoprotein E deficient miceApoE deficiency miceApoE-/- miceDiet-induced atherosclerosisHigh-fat dietLevels of cholesterolBile acid synthesisCholesterol synthesis genesInflammatory factorsVascular inflammationProtein kinase αSinus lesionsHepatic steatosisAortic rootRisk factorsDeficient miceAtherosclerosis treatmentFree fatty acidsCholesterol metabolismAtherosclerosisAcid synthesisAAV injection
2022
Macrophage-Derived 25-Hydroxycholesterol Promotes Vascular Inflammation, Atherogenesis, and Lesion Remodeling
Canfrán-Duque A, Rotllan N, Zhang X, Andrés-Blasco I, Thompson B, Sun J, Price N, Fernández-Fuertes M, Fowler J, Gómez-Coronado D, Sessa W, Giannarelli C, Schneider R, Tellides G, McDonald J, Fernández-Hernando C, Suárez Y. Macrophage-Derived 25-Hydroxycholesterol Promotes Vascular Inflammation, Atherogenesis, and Lesion Remodeling. Circulation 2022, 147: 388-408. PMID: 36416142, PMCID: PMC9892282, DOI: 10.1161/circulationaha.122.059062.Peer-Reviewed Original ResearchConceptsLipid-loaded macrophagesLineage-tracing mouse modelsSREBP transcriptional activityCholesterol biosynthetic intermediatesWestern diet feedingAccessible cholesterolDifferent macrophage populationsTranscriptomic analysisKey immune regulatorsPlasma membraneAtherosclerosis progressionImmune activationTranscriptional activityGene expressionDiet feedingInflammatory responseMouse bone marrowLiver X receptorBiosynthetic intermediatesSterol metabolismApoptosis susceptibilityToll-like receptor 4Proinflammatory gene expressionHuman coronary atherosclerotic lesionsMouse atherosclerotic plaquesGene Sequencing Identifies Perturbation in Nitric Oxide Signaling as a Nonlipid Molecular Subtype of Coronary Artery Disease
Khera AV, Wang M, Chaffin M, Emdin CA, Samani NJ, Schunkert H, Watkins H, McPherson R, Erdmann J, Elosua R, Boerwinkle E, Ardissino D, Butterworth A, Di Angelantonio E, Naheed A, Danesh J, Chowdhury R, Krumholz H, Sheu W, Rich S, Rotter J, Chen Y, Gabriel S, Lander E, Saleheen D, Kathiresan S. Gene Sequencing Identifies Perturbation in Nitric Oxide Signaling as a Nonlipid Molecular Subtype of Coronary Artery Disease. Circulation Genomic And Precision Medicine 2022, 15: e003598. PMID: 36215124, PMCID: PMC9771961, DOI: 10.1161/circgen.121.003598.Peer-Reviewed Original ResearchMeSH KeywordsCholesterolCoronary Artery DiseaseHumansHypercholesterolemiaNitric OxidePolymorphism, GeneticConceptsMolecular subtypesCAD riskHigher systolic blood pressureCoronary artery disease patientsEndothelial nitric oxide synthase geneDamaging missense variantsRisk of CADSystolic blood pressureCoronary artery diseaseRisk of hypertensionNitric oxide synthase geneMissense variantsNitric oxide synthesisRare variantsOxide synthase geneDiscrete molecular subtypesNitric Oxide SignalingLow density lipoprotein receptor geneArtery diseaseBlood pressureEndothelial functionVascular toneDisease patientsCAD casesCholesterol concentrationsPathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway
Sokoya T, Parolek J, Foged M, Danylchuk D, Bozan M, Sarkar B, Hilderink A, Philippi M, Botto L, Terhal P, Mäkitie O, Piehler J, Kim Y, Burd C, Klymchenko A, Maeda K, Holthuis J. Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway. ELife 2022, 11: e79278. PMID: 36102623, PMCID: PMC9531943, DOI: 10.7554/elife.79278.Peer-Reviewed Original ResearchConceptsSecretory pathwayER export signalPatient-derived fibroblastsFull enzymatic activityPhysical membrane propertiesExport signalSterol gradientLipid landscapeMammalian cellsCholesterol organizationLipid orderEnzymatic activityLipid distributionOsteogenic cellsPathwayBone phenotypeSMS2Glycerophospholipid profilePathogenic variantsCellsVariantsSphingomyelinSkeletal dysplasiaERSphingolipidsThe Impact of the Affordable Care Act on Disparities in Utilization of Cardiovascular Preventive Services by Socioeconomic Status
Verma H, Javed Z, Hong JC, Mahajan S, Mszar R, Grandhi GR, Desai NR, Virani SS, Javed U, Valero-Elizondo J, Nasir K. The Impact of the Affordable Care Act on Disparities in Utilization of Cardiovascular Preventive Services by Socioeconomic Status. Population Health Management 2022, 25: 669-676. PMID: 36067118, DOI: 10.1089/pop.2021.0337.Peer-Reviewed Original ResearchConceptsPreventive servicesSocioeconomic statusAffordable Care ActNational Health Interview SurveyBlood pressure checkSmoking cessation adviceCare ActHealth Interview SurveyVulnerable population subgroupsCardiovascular preventive servicesCessation adviceGlycemic screeningCardiovascular outcomesCholesterol checkBlood pressurePressure checkStudy populationUS adultsCare disparitiesSES disparitiesSES groupStudy periodInterview SurveyPopulation subgroupsSignificant decreaseInflammatory stress signaling via NF-kB alters accessible cholesterol to upregulate SREBP2 transcriptional activity in endothelial cells
Fowler JWM, Zhang R, Tao B, Boutagy NE, Sessa WC. Inflammatory stress signaling via NF-kB alters accessible cholesterol to upregulate SREBP2 transcriptional activity in endothelial cells. ELife 2022, 11: e79529. PMID: 35959888, PMCID: PMC9395194, DOI: 10.7554/elife.79529.Peer-Reviewed Original ResearchConceptsAcute inflammatory responseEndothelial cellsCholesterol homeostasisInflammatory stressInflammatory responsePro-inflammatory cytokinesSite of injuryCholesterol biosynthetic gene expressionNF-κB DNA bindingHuman endothelial cellsMultiple sclerosisInflammatory activationPrimary human endothelial cellsVascular endotheliumNF-κB-inducible genesTissue damageInducible targetAberrant activationRole of cholesterolSREBP2 activationMicrobial infectionsCholesterolKey transcription regulatorHomeostasisLeukocytesCirculating microRNAs as putative mediators in the association between short-term exposure to ambient air pollution and cardiovascular biomarkers
Chen H, Zhang S, Yu B, Xu Y, Rappold A, Diaz-Sanchez D, Samet J, Tong H. Circulating microRNAs as putative mediators in the association between short-term exposure to ambient air pollution and cardiovascular biomarkers. Ecotoxicology And Environmental Safety 2022, 239: 113604. PMID: 35576800, PMCID: PMC9167781, DOI: 10.1016/j.ecoenv.2022.113604.Peer-Reviewed Original ResearchConceptsExposure to ambient air pollutionAmbient air pollutionExposure to air pollutionAir pollutionShort-term exposure to ambient PM<sub>2.5</sub> waExposure to ambient PM<sub>2.5</sub>Short-term exposure to ambient fine particulate matterShort-term exposure to ambient air pollutionAmbient PM<sub>2.5</sub>Exposure to ambient fine particulate matterAmbient fine particulate matterEffects of exposure to air pollutionAir quality monitoring stationsEffects of air pollution exposureFine particulate matterQuality monitoring stationsAir pollutant concentrationsResearch Triangle area of North CarolinaAir pollution exposureTriangle area of North CarolinaBlood lipid biomarkersResearch Triangle areaPollutant concentrationsParticulate matterPollution exposureBiallelic Variants in Lanosterol Synthase (LSS) Cause Palmoplantar Keratoderma-Congenital Alopecia Syndrome Type 2
Yang F, Jiang X, Zhu Y, Lee M, Xu Z, Zhang J, Li Q, Lin M, Wang H, Lin Z. Biallelic Variants in Lanosterol Synthase (LSS) Cause Palmoplantar Keratoderma-Congenital Alopecia Syndrome Type 2. Journal Of Investigative Dermatology 2022, 142: 2687-2694.e2. PMID: 35413293, DOI: 10.1016/j.jid.2022.03.023.Peer-Reviewed Original ResearchConceptsLanosterol synthaseBiallelic variantsType 2N-terminally truncated proteinLanosterol synthase genesAlternative translation initiationEarly-onset cataractLoss of enzymatic activityCholesterol biosynthesis pathwayPremature stop codonAutosomal recessive disorderCholesterol synthesis pathwayEx vivo studiesType 2 casesLanosterol levelsBiosynthesis pathwayTranslation initiationSplice siteStop codonClinical featuresGenetic basisCornified envelope formationRecessive disorderCausative genesSynthesis pathway
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