2024
Ceramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway
Xu W, Zhang D, Ma Y, Gaspar R, Kahn M, Nasiri A, Murray S, Samuel V, Shulman G. Ceramide synthesis inhibitors prevent lipid-induced insulin resistance through the DAG-PKCε-insulin receptorT1150 phosphorylation pathway. Cell Reports 2024, 43: 114746. PMID: 39302831, DOI: 10.1016/j.celrep.2024.114746.Peer-Reviewed Original ResearchLipid-induced hepatic insulin resistanceHepatic insulin resistancePhosphorylation pathwayAntisense oligonucleotidesCeramide synthesis inhibitorsLipid-induced insulin resistanceMyriocin treatmentCeramide synthesisDihydroceramide desaturaseInsulin resistanceHepatic ceramideMyriocinCeramideCeramide contentInsulin-sensitizing effectsPhosphorylationHepatic insulin sensitivityPathwaySynthetic pathwayDES1Glucose productionSynthesis inhibitorDGAT2DesaturaseInhibition
2020
Membrane-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 ResearchConceptsHepatic 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 phenotyping
2013
CGI-58 knockdown sequesters diacylglycerols in lipid droplets/ER-preventing diacylglycerol-mediated hepatic insulin resistance
Cantley JL, Yoshimura T, Camporez JP, Zhang D, Jornayvaz FR, Kumashiro N, Guebre-Egziabher F, Jurczak MJ, Kahn M, Guigni BA, Serr J, Hankin J, Murphy RC, Cline GW, Bhanot S, Manchem VP, Brown JM, Samuel VT, Shulman GI. CGI-58 knockdown sequesters diacylglycerols in lipid droplets/ER-preventing diacylglycerol-mediated hepatic insulin resistance. Proceedings Of The National Academy Of Sciences Of The United States Of America 2013, 110: 1869-1874. PMID: 23302688, PMCID: PMC3562813, DOI: 10.1073/pnas.1219456110.Peer-Reviewed Original ResearchMeSH Keywords1-Acylglycerol-3-Phosphate O-AcyltransferaseAdipose Tissue, WhiteAnimalsCell MembraneDiet, High-FatDiglyceridesEndoplasmic ReticulumGene ExpressionGene Knockdown TechniquesHumansImmunoblottingInjections, IntraperitonealInsulin ResistanceLipidsLiverMaleMiceMice, Inbred C57BLOligonucleotides, AntisenseProtein Kinase C-epsilonProtein TransportReverse Transcriptase Polymerase Chain ReactionConceptsHepatic insulin resistanceInsulin resistanceHepatic steatosisCGI-58 knockdownHigh-fat fed miceHyperinsulinemic-euglycemic clamp studiesSevere hepatic steatosisCGI-58 expressionFat-fed miceLipid-induced hepatic insulin resistanceChanarin-Dorfman syndromeComparative gene identification-58Lipid droplet-associated proteinAdipose triglyceride lipaseDroplet-associated proteinAntisense oligonucleotide treatmentInsulin sensitivityASO treatmentClamp studiesLipotoxic conditionsKnockdown miceCGI-58PKCε activationMiceTriglyceride lipase
2011
Regulation of hepatic fat and glucose oxidation in rats with lipid‐induced hepatic insulin resistance
Alves TC, Befroy DE, Kibbey RG, Kahn M, Codella R, Carvalho RA, Petersen K, Shulman GI. Regulation of hepatic fat and glucose oxidation in rats with lipid‐induced hepatic insulin resistance. Hepatology 2011, 53: 1175-1181. PMID: 21400553, PMCID: PMC3077048, DOI: 10.1002/hep.24170.Peer-Reviewed Original ResearchConceptsLipid-induced hepatic insulin resistanceHepatic insulin resistanceInsulin resistanceTricarboxylic acid fluxFatty acid oxidationPyruvate dehydrogenaseHyperinsulinemic-euglycemic clampHyperinsulinemic-hyperglycemic clampInfusion of somatostatinSubstrate availabilityHigh-fat dietPlasma glucose concentrationRegulationCritical rolePyruvate dehydrogenase fluxHepatic fatHyperglycemic clampAcid oxidationAwake ratsBasal concentrations