2023
The 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 functionHepatocyte 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 programInhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis
Luukkonen P, Sakuma I, Gaspar R, Mooring M, Nasiri A, Kahn M, Zhang X, Zhang D, Sammalkorpi H, Penttilä A, Orho-Melander M, Arola J, Juuti A, Zhang X, Yimlamai D, Yki-Järvinen H, Petersen K, Shulman G. Inhibition of HSD17B13 protects against liver fibrosis by inhibition of pyrimidine catabolism in nonalcoholic steatohepatitis. Proceedings Of The National Academy Of Sciences Of The United States Of America 2023, 120: e2217543120. PMID: 36669104, PMCID: PMC9942818, DOI: 10.1073/pnas.2217543120.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseLiver fibrosisLiver diseaseCommon chronic liver diseaseChronic liver diseaseFatty liver diseaseRisk of fibrosisDistinct mouse modelsPyrimidine catabolismNonalcoholic steatohepatitisMouse modelTherapeutic targetFibrosisDihydropyrimidine dehydrogenaseHuman liverA variantCommon variantsMetabolomics approachDiseaseMiceInhibitionCatabolismKnockdownSteatohepatitisGimeracil
2021
Deletion 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 sensitivityMCT13AccumulationMechanisms and disease consequences of nonalcoholic fatty liver disease
Loomba R, Friedman SL, Shulman GI. Mechanisms and disease consequences of nonalcoholic fatty liver disease. Cell 2021, 184: 2537-2564. PMID: 33989548, DOI: 10.1016/j.cell.2021.04.015.Peer-Reviewed Original ResearchMeSH KeywordsCarcinoma, HepatocellularHumansLiverLiver CirrhosisLiver NeoplasmsNon-alcoholic Fatty Liver DiseaseConceptsNonalcoholic fatty liver diseaseProgressive liver injuryFatty liver diseaseNonalcoholic steatohepatitisLiver diseaseLiver injuryHepatocellular carcinomaEffect of NAFLDHepatic stellate cell activationChronic liver diseaseBile acid toxicityStellate cell activationFibrosis progressionAdvanced subtypesMacrophage dysfunctionPathogenetic mechanismsCell activationHepatic glucoseLipid metabolismDisease consequencesDiseaseAcid toxicityCarcinomaInjuryMetabolic originTherapeutic 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 productionTreatmentTissue
2020
Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease.
Ter Horst KW, Vatner DF, Zhang D, Cline GW, Ackermans MT, Nederveen AJ, Verheij J, Demirkiran A, van Wagensveld BA, Dallinga-Thie GM, Nieuwdorp M, Romijn JA, Shulman GI, Serlie MJ. Hepatic Insulin Resistance Is Not Pathway Selective in Humans With Nonalcoholic Fatty Liver Disease. Diabetes Care 2020, 44: 489-498. PMID: 33293347, PMCID: PMC7818337, DOI: 10.2337/dc20-1644.Peer-Reviewed Original ResearchMeSH KeywordsDiabetes Mellitus, Type 2HumansInsulinInsulin ResistanceLipogenesisLiverNon-alcoholic Fatty Liver DiseaseConceptsNonalcoholic fatty liver diseaseDe novo lipogenesisFatty liver diseaseBariatric surgeryLiver diseaseImpaired insulin-mediated suppressionGlucose productionHepatic de novo lipogenesisPeripheral glucose metabolismHyperinsulinemic-euglycemic clampType 2 diabetesInsulin-mediated suppressionInsulin-resistant subjectsHepatic insulin resistanceLiver biopsy samplesSuppress glucose productionLipogenic transcription factorsInsulin-mediated regulationObese subjectsInsulin resistanceAcute increaseNovo lipogenesisGlucose metabolismBiopsy samplesParadoxical increaseMembrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice
Abulizi A, Vatner DF, Ye Z, Wang Y, Camporez JP, Zhang D, Kahn M, Lyu K, Sirwi A, Cline GW, Hussain MM, Aspichueta P, Samuel VT, Shulman GI. Membrane-bound sn-1,2-diacylglycerols explain the dissociation of hepatic insulin resistance from hepatic steatosis in MTTP knockout mice. Journal Of Lipid Research 2020, 61: 1565-1576. PMID: 32907986, PMCID: PMC7707176, DOI: 10.1194/jlr.ra119000586.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsCarrier ProteinsCell MembraneDiglyceridesGene Knockout TechniquesInsulin ResistanceLiverMiceNon-alcoholic Fatty Liver DiseaseConceptsHepatic insulin resistanceInsulin resistanceHepatic insulin sensitivityHepatic steatosisLipid-induced hepatic insulin resistancePKCε activationInsulin sensitivityKnockout miceNormal hepatic insulin sensitivityWild-type control miceHepatic ceramide contentHyperinsulinemic-euglycemic clampComprehensive metabolic phenotypingLipid dropletsHepatic DAG contentDAG contentGlucose intoleranceControl miceMTTP activityHepatic insulinAnimal modelsSteatosisAKT Ser/ThrMiceMetabolic phenotypingEffect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease
Luukkonen PK, Dufour S, Lyu K, Zhang XM, Hakkarainen A, Lehtimäki TE, Cline GW, Petersen KF, Shulman GI, Yki-Järvinen H. Effect of a ketogenic diet on hepatic steatosis and hepatic mitochondrial metabolism in nonalcoholic fatty liver disease. Proceedings Of The National Academy Of Sciences Of The United States Of America 2020, 117: 7347-7354. PMID: 32179679, PMCID: PMC7132133, DOI: 10.1073/pnas.1922344117.Peer-Reviewed Original ResearchMeSH KeywordsBody CompositionCitrate (si)-SynthaseDiet, KetogenicFatty AcidsFatty Acids, NonesterifiedFatty LiverFemaleHumansInsulinInsulin ResistanceLipoproteins, VLDLLiverMaleMiddle AgedMitochondriaNon-alcoholic Fatty Liver DiseaseObesityOverweightOxidation-ReductionPyruvate CarboxylaseTriglyceridesConceptsNonalcoholic fatty liver diseaseFatty liver diseaseIntrahepatic triglyceridesKetogenic dietHepatic insulin resistanceNonesterified fatty acidsInsulin resistanceLiver diseaseOverweight/obese subjectsHepatic mitochondrial redox stateSerum insulin concentrationsHepatic mitochondrial metabolismProton magnetic resonance spectroscopyStable isotope infusionKD dietObese subjectsFatty acidsPlasma leptinHepatic steatosisInsulin concentrationsNEFA concentrationsBody weightTriiodothyronine concentrationsIsotope infusionWeight lossGlucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis
Perry RJ, Zhang D, Guerra MT, Brill AL, Goedeke L, Nasiri AR, Rabin-Court A, Wang Y, Peng L, Dufour S, Zhang Y, Zhang XM, Butrico GM, Toussaint K, Nozaki Y, Cline GW, Petersen KF, Nathanson MH, Ehrlich BE, Shulman GI. Glucagon stimulates gluconeogenesis by INSP3R1-mediated hepatic lipolysis. Nature 2020, 579: 279-283. PMID: 32132708, PMCID: PMC7101062, DOI: 10.1038/s41586-020-2074-6.Peer-Reviewed Original ResearchConceptsHepatic steatosisType 2Nonalcoholic fatty liver diseaseDiet-induced hepatic steatosisFatty liver diseasePlasma glucagon concentrationsHepatic adipose triglyceride lipaseHepatic acetyl-CoA contentHepatic glucose productionRatio of insulinHepatic glucose metabolismInositol triphosphate receptorAdipose triglyceride lipaseMitochondrial oxidationMitochondrial fat oxidationGlucose intoleranceLiver diseaseGlucagon concentrationsInsulin resistancePortal veinAcetyl-CoA contentHepatic lipolysisGlucagon biologyGlucose metabolismKnockout mice
2019
Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Ceramides
Samuel VT, Shulman GI. Nonalcoholic Fatty Liver Disease, Insulin Resistance, and Ceramides. New England Journal Of Medicine 2019, 381: 1866-1869. PMID: 31693811, DOI: 10.1056/nejmcibr1910023.Peer-Reviewed Original ResearchControlled-release mitochondrial protonophore (CRMP) reverses dyslipidemia and hepatic steatosis in dysmetabolic nonhuman primates
Goedeke L, Peng L, Montalvo-Romeral V, Butrico GM, Dufour S, Zhang XM, Perry RJ, Cline GW, Kievit P, Chng K, Petersen KF, Shulman GI. Controlled-release mitochondrial protonophore (CRMP) reverses dyslipidemia and hepatic steatosis in dysmetabolic nonhuman primates. Science Translational Medicine 2019, 11 PMID: 31578240, PMCID: PMC6996238, DOI: 10.1126/scitranslmed.aay0284.Peer-Reviewed Original ResearchMeSH KeywordsAnimalsDelayed-Action PreparationsDiet, High-FatDyslipidemiasInsulin ResistanceLipid MetabolismMacaca mulattaMaleNon-alcoholic Fatty Liver DiseaseObesityOxidative StressProton IonophoresConceptsControlled-release mitochondrial protonophoreNonalcoholic fatty liver diseaseCRMP treatmentHepatic triglyceridesDiet-induced rodent modelReversal of hypertriglyceridemiaFatty liver diseaseNonhuman primate modelMitochondrial protonophoreEndogenous glucose productionLow-density lipoproteinMitochondrial fat oxidationHepatic inflammationMetabolic syndromeFatty liverLiver diseaseHepatic steatosisInsulin resistanceAdverse reactionsPlasma triglyceridesPrimate modelOral administrationFood intakeHepatic mitochondrial oxidationRodent models
2017
Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms
Ferrandino G, Kaspari RR, Spadaro O, Reyna-Neyra A, Perry RJ, Cardone R, Kibbey RG, Shulman GI, Dixit VD, Carrasco N. Pathogenesis of hypothyroidism-induced NAFLD is driven by intra- and extrahepatic mechanisms. Proceedings Of The National Academy Of Sciences Of The United States Of America 2017, 114: e9172-e9180. PMID: 29073114, PMCID: PMC5664516, DOI: 10.1073/pnas.1707797114.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseDe novo lipogenesisAdipose tissue lipolysisHepatic insulin resistanceThyroid hormonesHypothyroid miceImpaired suppressionInsulin resistanceTissue lipolysisInsulin secretionHigh thyroid-stimulating hormone levelsRegulation of THThyroid-stimulating hormone levelsLipid utilizationFatty liver diseaseSerum glucose levelsEndogenous glucose productionLow thyroid hormoneFatty acidsHepatic lipid utilizationLiver diseaseSevere hypothyroidismHormone levelsProfound suppressionGlucose levels
2014
The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes
Perry RJ, Samuel VT, Petersen KF, Shulman GI. The role of hepatic lipids in hepatic insulin resistance and type 2 diabetes. Nature 2014, 510: 84-91. PMID: 24899308, PMCID: PMC4489847, DOI: 10.1038/nature13478.Peer-Reviewed Reviews, Practice Guidelines, Standards, and Consensus StatementsMeSH KeywordsAnimalsDiabetes Mellitus, Type 2DiglyceridesFatty LiverHumansHyperglycemiaInsulin ResistanceLipid MetabolismLipidsLipodystrophyLipogenesisLiverMuscle, SkeletalNon-alcoholic Fatty Liver DiseaseTriglyceridesConceptsType 2 diabetesHepatic insulin resistanceNon-alcoholic fatty liver diseaseFatty liver diseaseInsulin resistanceLiver diseaseHepatic lipidsHealth care costsInflammatory signalingTherapeutic approachesMortality rateDiabetesRelated epidemicsProtein kinase CεDiseaseCellular modificationsEpidemicLipid speciesMorbidityLipidsDiacylglycerol activationMice
2013
Direct assessment of hepatic mitochondrial oxidative and anaplerotic fluxes in humans using dynamic 13C magnetic resonance spectroscopy
Befroy DE, Perry RJ, Jain N, Dufour S, Cline GW, Trimmer JK, Brosnan J, Rothman DL, Petersen KF, Shulman GI. Direct assessment of hepatic mitochondrial oxidative and anaplerotic fluxes in humans using dynamic 13C magnetic resonance spectroscopy. Nature Medicine 2013, 20: 98-102. PMID: 24317120, PMCID: PMC3947269, DOI: 10.1038/nm.3415.Peer-Reviewed Original ResearchReversal of Hypertriglyceridemia, Fatty Liver Disease, and Insulin Resistance by a Liver-Targeted Mitochondrial Uncoupler
Perry RJ, Kim T, Zhang XM, Lee HY, Pesta D, Popov VB, Zhang D, Rahimi Y, Jurczak MJ, Cline GW, Spiegel DA, Shulman GI. Reversal of Hypertriglyceridemia, Fatty Liver Disease, and Insulin Resistance by a Liver-Targeted Mitochondrial Uncoupler. Cell Metabolism 2013, 18: 740-748. PMID: 24206666, PMCID: PMC4104686, DOI: 10.1016/j.cmet.2013.10.004.Peer-Reviewed Original ResearchMeSH Keywords2,4-DinitrophenolAnimalsDiet, High-FatEthersFatty LiverHypertriglyceridemiaInsulin ResistanceLiverMaleMiceMice, Inbred C57BLNon-alcoholic Fatty Liver DiseaseRatsRats, Sprague-DawleyTreatment OutcomeConceptsNonalcoholic fatty liver diseaseFatty liver diseaseInsulin resistanceLiver diseaseMetabolic syndromeFatty liverSystemic toxicityWhole-body insulin resistanceMajor predisposing conditionReversal of hypertriglyceridemiaTreatment of hypertriglyceridemiaType 2 diabetesMuscle insulin resistanceWide therapeutic indexPredisposing conditionRat modelProtein kinase C epsilonHypertriglyceridemiaTherapeutic indexFed ratsBeneficial effectsLiverPKCθ activitySyndromeMitochondrial uncoupler