2024
1571-P: CIDEB and CGI-58 Regulate Liver Lipid Droplet Size with Cholesterol Content, Linking to Inflammation and Fibrosis in Metabolic Dysfunction–Associated Steatohepatitis
SAKUMA I, GASPAR R, NASIRI A, KAHN M, ZHENG J, GUERRA M, YIMLAMAI D, MURRAY S, PERELIS M, BARNES W, VATNER D, PETERSEN K, SAMUEL V, SHULMAN G. 1571-P: CIDEB and CGI-58 Regulate Liver Lipid Droplet Size with Cholesterol Content, Linking to Inflammation and Fibrosis in Metabolic Dysfunction–Associated Steatohepatitis. Diabetes 2024, 73 DOI: 10.2337/db24-1571-p.Peer-Reviewed Original ResearchLipid droplet sizeCGI-58Choline-deficient l-amino acid-defined high-fat dietGlycerol-3-phosphate acyltransferaseAntisense oligonucleotidesComparative gene identification-58Glycerol-3-phosphateLoss of function mutationsLipid droplet morphologyExpression of CGI-58Liver inflammationCidebCholesterol contentFunction mutationsL-amino acid-defined high-fat dietComplications of type 2 diabetesMolecular mechanismsDevelopment of liver inflammationMacrophage crown-like structuresType 2 diabetesHigh-fat dietCrown-like structuresASO treatmentGPAMKnockdown
2020
A 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
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
2016
Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance
Petersen MC, Madiraju AK, Gassaway BM, Marcel M, Nasiri AR, Butrico G, Marcucci MJ, Zhang D, Abulizi A, Zhang XM, Philbrick W, Hubbard SR, Jurczak MJ, Samuel VT, Rinehart J, Shulman GI. Insulin receptor Thr1160 phosphorylation mediates lipid-induced hepatic insulin resistance. Journal Of Clinical Investigation 2016, 126: 4361-4371. PMID: 27760050, PMCID: PMC5096902, DOI: 10.1172/jci86013.Peer-Reviewed Original ResearchConceptsInsulin receptorKinase activityHigh-fat diet-induced hepatic insulin resistanceKinase activation loopNonalcoholic fatty liver diseaseLipid-induced hepatic insulin resistanceProtein kinase CHepatic insulin resistanceDiet-induced hepatic insulin resistanceDiacylglycerol-mediated activationActivation loopPKCε inhibitionAlanine mutationsInsulin resistanceMolecular mechanismsKinase CCritical pathophysiological rolePathogenesis of T2DMechanistic linkMutantsGlycogen synthesisConsequent inhibitionPhosphorylationActive configurationPKCε