2025
An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis
El Bounkari O, Zan C, Yang B, Ebert S, Wagner J, Bugar E, Kramer N, Bourilhon P, Kontos C, Zarwel M, Sinitski D, Milic J, Jansen Y, Kempf W, Sachs N, Maegdefessel L, Ji H, Gokce O, Riols F, Haid M, Gerra S, Hoffmann A, Brandhofer M, Avdic M, Bucala R, Megens R, Willemsen N, Messerer D, Schulz C, Bartelt A, Harm T, Rath D, Döring Y, Gawaz M, Weber C, Kapurniotu A, Bernhagen J. An atypical atherogenic chemokine that promotes advanced atherosclerosis and hepatic lipogenesis. Nature Communications 2025, 16: 2297. PMID: 40055309, PMCID: PMC11889166, DOI: 10.1038/s41467-025-57540-z.Peer-Reviewed Original ResearchConceptsApoE-/- miceHyperlipidemic apoE-/- miceCoronary artery diseaseDecreased plasma lipid levelsPlasma lipid levelsHepatic lipid accumulationAtherogenic chemokinesFoam-cell formationFLIM-FRET microscopyArtery diseasePlasma concentrationsVascular inflammationInflammatory conditionsMetabolic dysfunctionAtherosclerotic patientsLipid accumulationAdvanced atherosclerosisMyocardial infarctionLipid levelsSuppressed hepatic lipid accumulationAdvanced atherogenesisCarotid plaquesDisease severityIschemic strokeChemokines
2021
Intracellular C3 prevents hepatic steatosis by promoting autophagy and very‐low‐density lipoprotein secretion
Li Y, Sha Y, Wang H, He L, Li L, Wen S, Sheng L, Hu W, Zhou H. Intracellular C3 prevents hepatic steatosis by promoting autophagy and very‐low‐density lipoprotein secretion. The FASEB Journal 2021, 35: e22037. PMID: 34762761, DOI: 10.1096/fj.202100856r.Peer-Reviewed Original ResearchConceptsVery-low-density lipoprotein secretionVery-low-density lipoproteinProtein disulfide isomeraseExpression of protein disulfide isomeraseMicrosomal TG transfer proteinPathogen recognitionHepatic lipid accumulationDisulfide isomeraseEndoplasmic reticulumIntracellular functionsAutophagy-relatedExtracellular milieuDisrupt interactionsVLDL secretionTransfer proteinLipoprotein secretionLipid accumulationIntracellular C3C3<sup>-/-</sup> miceComplement component C3C3 knockoutHepatic steatosisConvergence pointWild type miceKnockoutHepatocyte-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice
Singh AK, Chaube B, Zhang X, Sun J, Citrin KM, Canfrán-Duque A, Aryal B, Rotllan N, Varela L, Lee RG, Horvath TL, Price N, Suárez Y, Fernandez-Hernando C. Hepatocyte-specific suppression of ANGPTL4 improves obesity-associated diabetes and mitigates atherosclerosis in mice. Journal Of Clinical Investigation 2021, 131 PMID: 34255741, PMCID: PMC8409581, DOI: 10.1172/jci140989.Peer-Reviewed Original ResearchDiet-induced obesityGlucose intoleranceHigh-fat fed conditionsLipoprotein lipaseExcess hepatic lipid accumulationSystemic metabolic dysfunctionRole of ANGPTL4Liver lipid metabolismHepatic lipid accumulationTargeted pharmacologic therapyANGPTL4 gene expressionMetabolic turnover studiesHepatic lipase activityObesity-associated diabetesFatty acidsNovel inhibition strategiesPharmacologic therapyLiver steatosisLiver damageLipoprotein remnantsCholesterol levelsMetabolic dysfunctionHepatic uptakeANGPTL4 deficiencyHL activityDeletion of the diabetes candidate gene Slc16a13 in mice attenuates diet-induced ectopic lipid accumulation and insulin resistance
Schumann T, König J, von Loeffelholz C, Vatner DF, Zhang D, Perry RJ, Bernier M, Chami J, Henke C, Kurzbach A, El-Agroudy NN, Willmes DM, Pesta D, de Cabo R, O´Sullivan J, Simon E, Shulman GI, Hamilton BS, Birkenfeld AL. Deletion of the diabetes candidate gene Slc16a13 in mice attenuates diet-induced ectopic lipid accumulation and insulin resistance. Communications Biology 2021, 4: 826. PMID: 34211098, PMCID: PMC8249653, DOI: 10.1038/s42003-021-02279-8.Peer-Reviewed Original ResearchMeSH KeywordsAMP-Activated Protein KinasesAnimalsDiabetes Mellitus, Type 2Diet, High-FatGene ExpressionGenetic Predisposition to DiseaseHumansInsulin ResistanceLipid MetabolismLiverMice, Inbred C57BLMice, KnockoutMitochondriaMonocarboxylic Acid TransportersNon-alcoholic Fatty Liver DiseaseObesityOxygen ConsumptionConceptsMitochondrial respirationGenome-wide association studiesNovel susceptibility genesLipid accumulationPlasma membraneAMPK activationAssociation studiesPhysiological functionsEctopic lipid accumulationReduced hepatic lipid accumulationSusceptibility genesLactate transporterMonocarboxylate transportersPotential targetGenesTransportersDeletionLipid contentHepatic lipid accumulationPotential importanceKnockout miceRespirationHepatic insulin sensitivityMCT13AccumulationTime‐restricted feeding combined with aerobic exercise training can prevent weight gain and improve metabolic disorders in mice fed a high‐fat diet
Vieira R, Muñoz V, Junqueira R, de Oliveira F, Gaspar R, Nakandakari S, de Oliveira Costa S, Torsoni M, da Silva A, Cintra D, de Moura L, Ropelle E, Zaghloul I, Mekary R, Pauli J. Time‐restricted feeding combined with aerobic exercise training can prevent weight gain and improve metabolic disorders in mice fed a high‐fat diet. The Journal Of Physiology 2021, 600: 797-813. PMID: 33450053, DOI: 10.1113/jp280820.Peer-Reviewed Original ResearchConceptsTime-restricted feedingHigh-fat dietAerobic exercise trainingMale Swiss miceHigh-fat diet feedingFatty acid oxidationSwiss miceExercise trainingMetabolic disordersDiet feedingLiver metabolismAE trainingAcid oxidationLower serum triglyceridesHepatic lipid accumulationHepatic lipid contentImproved hepatic metabolismLipogenic gene expressionSerum triglyceridesAdiposity gainBody adiposityGlycaemic homeostasisInsulin sensitivityHepatic metabolismGlucose metabolism
2020
Reduced Nogo expression inhibits diet-induced metabolic disorders by regulating ChREBP and insulin activity
Zhang S, Guo F, Yu M, Yang X, Yao Z, Li Q, Wei Z, Feng K, Zeng P, Zhao D, Li X, Zhu Y, Miao QR, Iwakiri Y, Chen Y, Han J, Duan Y. Reduced Nogo expression inhibits diet-induced metabolic disorders by regulating ChREBP and insulin activity. Journal Of Hepatology 2020, 73: 1482-1495. PMID: 32738448, DOI: 10.1016/j.jhep.2020.07.034.Peer-Reviewed Original ResearchConceptsDiet-induced metabolic disordersHepatic lipid accumulationInsulin sensitivityMetabolic disordersInsulin resistanceNogo expressionNon-alcoholic fatty liver diseaseDiet-induced body weight gainInsulin activityDiet-induced glucose intoleranceLipid accumulationFatty liver diseaseHigh-fructose dietGrowth factor 21Littermate control miceDe novo lipogenesisHigh-carbohydrate dietBody weight gainCarbohydrate-responsive element-binding proteinExpression of ChREBPChREBP activityEndoplasmic reticulum stressMetabolic complicationsGlucose intoleranceLiver diseaseNIK links inflammation to hepatic steatosis by suppressing PPARα in alcoholic liver disease
Li Y, Chen M, Zhou Y, Tang C, Zhang W, Zhong Y, Chen Y, Zhou H, Sheng L. NIK links inflammation to hepatic steatosis by suppressing PPARα in alcoholic liver disease. Theranostics 2020, 10: 3579-3593. PMID: 32206109, PMCID: PMC7069072, DOI: 10.7150/thno.40149.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsEthanolFatty AcidsFatty LiverHepatocytesInflammationLiver Diseases, AlcoholicMaleMAP Kinase Kinase 1MAP Kinase Kinase 2MiceMice, Inbred C57BLMitogen-Activated Protein Kinase 1Mitogen-Activated Protein Kinase 3Oxidation-ReductionPhosphorylationPPAR alphaProtein Serine-Threonine KinasesSignal TransductionConceptsAlcoholic liver diseaseFatty acid oxidationAlcoholic steatosisHepatic fatty acid oxidationHepatocyte-specific deletionHepatic steatosisLiver diseasePPARα agonistAcid oxidationBinge ethanol feedingMain pathological featuresHepatic lipid accumulationEthanol-fed miceRegulation of PPARαRole of NIKALD therapyInflammatory cytokinesPathological featuresUnderlying pathogenesisPharmacological interventionsSteatosisEthanol feedingInflammationPharmacological inhibitionPPARα
2019
The SGLT2 inhibitor dapagliflozin attenuates the activity of ROS-NLRP3 inflammasome axis in steatohepatitis with diabetes mellitus.
Leng W, Wu M, Pan H, Lei X, Chen L, Wu Q, Ouyang X, Liang Z. The SGLT2 inhibitor dapagliflozin attenuates the activity of ROS-NLRP3 inflammasome axis in steatohepatitis with diabetes mellitus. Annals Of Translational Medicine 2019, 7: 429. PMID: 31700865, PMCID: PMC6803170, DOI: 10.21037/atm.2019.09.03.Peer-Reviewed Original ResearchHFD/streptozotocinHigh-fat dietDiabetes mellitusExperimental steatohepatitisHepatic damageNOD-like receptor family pyrin domainSodium-glucose cotransporter 2 inhibitorsGlucose cotransporter 2 inhibitorsDiabetic liver injuryEfficacy of dapagliflozinROS-NLRP3 inflammasomeSGLT2 inhibitor dapagliflozinHepatic reactive oxygen speciesCotransporter 2 inhibitorsReactive oxygen speciesFamily pyrin domainHepatic lipid accumulationSterile inflammatory responseMajor clinical consequencesDAPA treatmentDM patientsInhibitor dapagliflozinLiver injuryLiver diseaseLiver steatosisAdipose glucocorticoid action influences whole‐body metabolism via modulation of hepatic insulin action
Abulizi A, Camporez JP, Jurczak MJ, Høyer KF, Zhang D, Cline GW, Samuel VT, Shulman GI, Vatner DF. Adipose glucocorticoid action influences whole‐body metabolism via modulation of hepatic insulin action. The FASEB Journal 2019, 33: 8174-8185. PMID: 30922125, PMCID: PMC6593882, DOI: 10.1096/fj.201802706r.Peer-Reviewed Original ResearchConceptsWhole-body metabolismHepatic insulin actionHepatic insulin resistanceGlucocorticoid actionHepatic steatosisHepatic glycogen synthesisInsulin resistanceAdipose lipolysisFood intakeInsulin actionAdipose triglyceride lipase expressionGlucose-dependent organsReceptor knockout miceOral glucose challengeHepatic lipid accumulationHigh-fat dietHyperinsulinemic-euglycemic conditionsGlycogen synthesisProtein kinase B phosphorylationInsulin responseGlucose challengeHepatic insulin responseHepatic insulinMetabolic cagesSteatosis
2018
Rho kinase/AMPK axis regulates hepatic lipogenesis during overnutrition
Huang H, Lee S, Sousa-Lima I, Kim S, Hwang W, Dagon Y, Yang W, Cho S, Kang M, Seo J, Shibata M, Cho H, Belew G, Bhin J, Desai B, Ryu M, Shong M, Li P, Meng H, Chung B, Hwang D, Kim M, Park K, Macedo M, White M, Jones J, Kim Y. Rho kinase/AMPK axis regulates hepatic lipogenesis during overnutrition. Journal Of Clinical Investigation 2018, 128: 5335-5350. PMID: 30226474, PMCID: PMC6264719, DOI: 10.1172/jci63562.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseFatty liver diseaseHepatic lipid accumulationLiver diseaseInsulin resistanceRisk factorsNovo lipogenesisObesity-related metabolic disordersLipid accumulationObesity-induced steatosisChronic liver diseaseObese diabetic miceDiet-induced obesityMajor risk factorSevere hepatic steatosisHigh-fat dietDe novo lipogenesisThermogenic gene expressionRho kinase 1Antidiabetes drugsDiabetic miceHepatic steatosisActivation of AMPKHepatocellular carcinomaMetabolic disorders
2017
Hepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans
Horst K, Gilijamse PW, Versteeg RI, Ackermans MT, Nederveen AJ, la Fleur SE, Romijn JA, Nieuwdorp M, Zhang D, Samuel VT, Vatner DF, Petersen KF, Shulman GI, Serlie MJ. Hepatic Diacylglycerol-Associated Protein Kinase Cε Translocation Links Hepatic Steatosis to Hepatic Insulin Resistance in Humans. Cell Reports 2017, 19: 1997-2004. PMID: 28591572, PMCID: PMC5469939, DOI: 10.1016/j.celrep.2017.05.035.Peer-Reviewed Original ResearchConceptsHepatic insulin resistanceInsulin resistanceHepatic steatosisObese subjectsPKCε activationTissue-specific insulin sensitivityHepatic ceramide contentPeripheral insulin resistanceHepatic lipid accumulationPathogenesis of NAFLDLiver biopsyIntrahepatic triglyceridesLiver fatInsulin sensitivityAdipose tissueTranslational evidenceSteatosisLipid accumulationCeramide contentPKCε translocationSubjectsMolecular mechanismsDiacylglycerol contentHumansActivation
2014
Long‐term therapeutic silencing of miR‐33 increases circulating triglyceride levels and hepatic lipid accumulation in mice
Goedeke L, Salerno A, Ramírez CM, Guo L, Allen RM, Yin X, Langley SR, Esau C, Wanschel A, Fisher EA, Suárez Y, Baldán A, Mayr M, Fernández-Hernando C. Long‐term therapeutic silencing of miR‐33 increases circulating triglyceride levels and hepatic lipid accumulation in mice. EMBO Molecular Medicine 2014, 6: 1133-1141. PMID: 25038053, PMCID: PMC4197861, DOI: 10.15252/emmm.201404046.Peer-Reviewed Original ResearchConceptsHigh-fat dietFatty acid synthaseMiR-33Chronic inhibitionTriglyceride levelsTherapeutic silencingHigh-density lipoprotein levelsAcetyl-CoA carboxylaseLipid accumulationAtherosclerotic vascular diseaseHepatic lipid accumulationRegression of atherosclerosisModerate hepatic steatosisLiver of miceNon-human primatesLipoprotein levelsHepatic steatosisVascular diseaseLong-term effectsStrong inverse correlationPersistent inhibitionVivo increaseCholesterol transportMiceAdverse effects
2012
5-Cholesten-3β,25-Diol 3-Sulfate Decreases Lipid Accumulation in Diet-Induced Nonalcoholic Fatty Liver Disease Mouse Model
Xu L, Kim JK, Bai Q, Zhang X, Kakiyama G, Min HK, Sanyal AJ, Pandak WM, Ren S. 5-Cholesten-3β,25-Diol 3-Sulfate Decreases Lipid Accumulation in Diet-Induced Nonalcoholic Fatty Liver Disease Mouse Model. Molecular Pharmacology 2012, 83: 648-658. PMID: 23258548, PMCID: PMC3583496, DOI: 10.1124/mol.112.081505.Peer-Reviewed Original ResearchMeSH KeywordsAcetyl-CoA CarboxylaseAcetyltransferasesAnimalsCholesterol EstersDiet, High-Fatfas ReceptorFatty AcidsFatty LiverFemaleGene ExpressionGlucose Tolerance TestGlycerol-3-Phosphate O-AcyltransferaseHydroxycholesterolsInflammationInsulinInsulin ResistanceInterleukin-1alphaInterleukin-1betaLipid MetabolismLipidsLiverMiceMice, Inbred C57BLNon-alcoholic Fatty Liver DiseaseSignal TransductionSterol Regulatory Element Binding Protein 1Tumor Necrosis Factor-alphaConceptsNonalcoholic fatty liver diseaseHigh-fat dietLong-term treatmentAcute treatmentTolerance testLipid accumulationMouse modelDiet-induced NAFLD mouse modelNonalcoholic fatty liver disease (NAFLD) mouse modelSREBP-1cLipid homeostasisFatty liver diseaseLiver X receptor αNAFLD mouse modelGlucose tolerance testSerum lipid levelsInsulin tolerance testHepatic lipid accumulationDisease mouse modelDecreases lipid accumulationTumor necrosis factorLipid-induced inflammationAcetyl-CoA carboxylase 1X receptor αSREBP-1c expression
2011
Influence of the Hepatic Eukaryotic Initiation Factor 2α (eIF2α) Endoplasmic Reticulum (ER) Stress Response Pathway on Insulin-mediated ER Stress and Hepatic and Peripheral Glucose Metabolism*
Birkenfeld AL, Lee HY, Majumdar S, Jurczak MJ, Camporez JP, Jornayvaz FR, Frederick DW, Guigni B, Kahn M, Zhang D, Weismann D, Arafat AM, Pfeiffer AF, Lieske S, Oyadomari S, Ron D, Samuel VT, Shulman GI. Influence of the Hepatic Eukaryotic Initiation Factor 2α (eIF2α) Endoplasmic Reticulum (ER) Stress Response Pathway on Insulin-mediated ER Stress and Hepatic and Peripheral Glucose Metabolism*. Journal Of Biological Chemistry 2011, 286: 36163-36170. PMID: 21832042, PMCID: PMC3196114, DOI: 10.1074/jbc.m111.228817.Peer-Reviewed Original ResearchConceptsHepatic glucose productionInsulin sensitivityInsulin resistanceCaloric excessER stressHigh-fat diet-fed miceBasal plasma glucose concentrationsGlucose productionIGFBP-3 levelsHepatic ERPeripheral glucose metabolismTissue insulin sensitivityDiet-fed miceHepatic lipid accumulationHigh-fat dietHyperinsulinemic-euglycemic clampHepatic insulin sensitivityInfusion of insulinPlasma glucose concentrationEndoplasmic reticulum stress response pathwayEndoplasmic reticulum stressInsulin-stimulated muscleIGFBP-3Fat dietMuscle glucose
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