2024
292-OR: Coenzyme A Synthase Knockdown Alleviates Metabolic Dysfunction–Associated Steatohepatitis via Decreasing Cholesterol in Liver Lipid Droplets
SAKUMA I, GASPAR R, NASIRI A, KAHN M, GUERRA M, YIMLAMAI D, MURRAY S, PERELIS M, BARNES W, VATNER D, PETERSEN K, SAMUEL V, SHULMAN G. 292-OR: Coenzyme A Synthase Knockdown Alleviates Metabolic Dysfunction–Associated Steatohepatitis via Decreasing Cholesterol in Liver Lipid Droplets. Diabetes 2024, 73 DOI: 10.2337/db24-292-or.Peer-Reviewed Original ResearchCholine-deficient l-amino acid-defined high-fat dietAccumulation of cholesterolMRNA expressionPlasma ALTL-amino acid-defined high-fat dietProtective effectLiver lipid dropletsType 2 diabetesPotential therapeutic approachHigh-fat dietDecreased plasma ALTFibrosis markersFree cholesterol accumulationLipid dropletsLiver inflammationDay 1Macrophage markersHepatic inflammationMouse modelMarker expressionTherapeutic approachesDay 2Day 3Day 7Fibrosis
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 phenotypingA Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance
Lyu K, Zhang Y, Zhang D, Kahn M, Ter Horst KW, Rodrigues MRS, Gaspar RC, Hirabara SM, Luukkonen PK, Lee S, Bhanot S, Rinehart J, Blume N, Rasch MG, Serlie MJ, Bogan JS, Cline GW, Samuel VT, Shulman GI. A Membrane-Bound Diacylglycerol Species Induces PKCϵ-Mediated Hepatic Insulin Resistance. Cell Metabolism 2020, 32: 654-664.e5. PMID: 32882164, PMCID: PMC7544641, DOI: 10.1016/j.cmet.2020.08.001.Peer-Reviewed Original ResearchConceptsPlasma membraneEndoplasmic reticulumHigh-fat diet-induced hepatic insulin resistanceSubcellular fractionation methodInsulin receptor kinaseKey lipid speciesHepatic insulin resistanceDiet-induced hepatic insulin resistanceReceptor kinaseDiacylglycerol acyltransferase 2Molecular mechanismsAcute knockdownPhosphorylationLipid dropletsLipid speciesAcyltransferase 2KnockdownLiver-specific overexpressionDAG accumulationPKCϵDAG contentMembraneFractionation methodKinaseMitochondria
2019
266-OR: Plasma Membrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance
LYU K, ZHANG Y, ZHANG D, KAHN M, NOZAKI Y, BHANOT S, BOGAN J, CLINE G, SAMUEL V, SHULMAN G. 266-OR: Plasma Membrane sn-1,2 Diacylglycerol Mediates Lipid-Induced Hepatic Insulin Resistance. Diabetes 2019, 68 DOI: 10.2337/db19-266-or.Peer-Reviewed Original ResearchHepatic insulin resistanceInsulin resistanceExogenous fatty acidsInsulin actionLipid dropletsHepatic ceramide contentHyperinsulinemic-euglycemic clampHepatic insulin actionBioactive lipid speciesHepatic glucose productionChow-fed ratsHepatic diacylglycerol contentAdvisory PanelFatty acidsHepatic steatosisImpaired suppressionSingle doseSpouse/partnerGlucose productionPKCε activationJanssen ResearchAcute knockdownCeramide contentNational InstituteReceptor kinase activation
2011
Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease
Kumashiro N, Erion DM, Zhang D, Kahn M, Beddow SA, Chu X, Still CD, Gerhard GS, Han X, Dziura J, Petersen KF, Samuel VT, Shulman GI. Cellular mechanism of insulin resistance in nonalcoholic fatty liver disease. Proceedings Of The National Academy Of Sciences Of The United States Of America 2011, 108: 16381-16385. PMID: 21930939, PMCID: PMC3182681, DOI: 10.1073/pnas.1113359108.Peer-Reviewed Original ResearchConceptsNonalcoholic fatty liver diseaseFatty liver diseaseHepatic DAG contentInsulin resistanceHepatic insulin resistanceLiver diseaseHepatic steatosisCellular mechanismsHomeostatic model assessmentInsulin resistance indexMarkers of inflammationType 2 diabetesER stress markersLipid dropletsHepatic diacylglycerol contentEndoplasmic reticulum stressActivation of PKCεLiver biopsyNondiabetic individualsHepatocellular lipidsInsulin sensitivityCytoplasmic lipid dropletsDAG contentResistance indexAnimal models