2024
High-fat-diet-induced hepatic insulin resistance per se attenuates murine de novo lipogenesis
Goedeke L, Strober J, Suh R, Paolella L, Li X, Rogers J, Petersen M, Nasiri A, Casals G, Kahn M, Cline G, Samuel V, Shulman G, Vatner D. High-fat-diet-induced hepatic insulin resistance per se attenuates murine de novo lipogenesis. IScience 2024, 27: 111175. PMCID: PMC11550620, DOI: 10.1016/j.isci.2024.111175.Peer-Reviewed Original ResearchDuration of high-fat dietAttenuated insulin signalingHigh-fat dietHepatic insulin resistanceInsulin signalingInsulin stimulationLipogenic substrateStimulation of de novo lipogenesisReduced lipogenesisHFD feedingReduce DNLInsulin resistanceResistance per seLipogenesisInsulin resistance per sePathway selectionGlucose metabolismHepatic IRMiceFat dietSREBP1cINSR
2023
Inhibition 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
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
2012
Fatty acid amide hydrolase ablation promotes ectopic lipid storage and insulin resistance due to centrally mediated hypothyroidism
Brown WH, Gillum MP, Lee HY, Camporez JP, Zhang XM, Jeong JK, Alves TC, Erion DM, Guigni BA, Kahn M, Samuel VT, Cravatt BF, Diano S, Shulman GI. Fatty acid amide hydrolase ablation promotes ectopic lipid storage and insulin resistance due to centrally mediated hypothyroidism. Proceedings Of The National Academy Of Sciences Of The United States Of America 2012, 109: 14966-14971. PMID: 22912404, PMCID: PMC3443187, DOI: 10.1073/pnas.1212887109.Peer-Reviewed Original ResearchMeSH KeywordsAmidesAmidohydrolasesAnalysis of VarianceAnimalsArachidonic AcidsChromatography, LiquidEndocannabinoidsEnergy MetabolismEthanolaminesHypothyroidismImmunoblottingInsulin ResistanceMiceMice, KnockoutPalmitic AcidsPolymerase Chain ReactionPolyunsaturated AlkamidesPPAR gammaTandem Mass SpectrometryThyrotropinThyrotropin-Releasing HormoneThyroxineTriiodothyronineConceptsEctopic lipid storageHepatic insulin resistanceInsulin resistanceEnergy expenditureDiet-induced hepatic insulin resistanceHypothalamic thyrotropin-releasing hormoneFatty acid amide hydrolase knockout miceThyroid-stimulating hormoneThyrotropin-releasing hormoneLipid storageDeiodinase 2 expressionReduced mRNA expressionProtein kinase Cε activationHepatic diacylglycerol contentPituitary thyroid-stimulating hormoneExcess energy storageFAAH deletionKnockout miceReceptor γThyroid axisThyroxine concentrationsMRNA expressionMiceHypothyroidismFAAH