title: Impaired stimulation of glucose transport in cardiac myocytes exposed to very low-density lipoproteins.
abstract: We recently observed that free fatty acids impair the stimulation of glucose transport into cardiomyocytes in response to either insulin or metabolic stress. In vivo, fatty acids for the myocardium are mostly obtained from triglyceride-rich lipoproteins (chylomicrons and Very Low-Density Lipoproteins). We therefore determined whether exposure of cardiac myocytes to VLDL resulted in impaired basal and stimulated glucose transport. Primary adult rat cardiac myocytes were chronically exposed to VLDL before glucose uptake was measured in response to insulin or metabolic stress, provoked by the mitochondrial ATP synthase inhibitor oligomycin. Exposure of cardiac myocytes to VLDL reduced both insulin-and oligomycin-stimulated glucose uptake. The reduction of glucose uptake was associated with a moderately reduced tyrosine phosphorylation of the insulin receptor. No reduction of the phosphorylation of the downstream effectors of insulin signaling Akt and AS160 was however observed. Similarly only a modest reduction of the activating phosphorylation of the AMP-activated kinase (AMPK) was observed in response to oligomycin. Similar to our previous observations with free fatty acids, inhibition of fatty acid oxidation restored oligomycin-stimulated glucose uptake. In conclusions, VLDL-derived fatty acids impair stimulated glucose transport in cardiac myocytes by a mechanism that seems to be mediated by a fatty acid oxidation intermediate. Thus, in the clinical context of the metabolic syndrome high VLDL may contribute to enhancement of ischemic injury by reduction of metabolic stress-stimulated glucose uptake.
authors.affiliation: Division of Cardiology, Department of Medical Specialties, Geneva University Hospitals, Switzerland; Foundation for Medical Researches, University of Geneva School of Medicine, Switzerland.
authors.forename: I
authors.initials: I
authors.lastname: Papageorgiou
authors.affiliation: Foundation for Medical Researches, University of Geneva School of Medicine, Switzerland.
authors.forename: C
authors.initials: C
authors.lastname: Viglino
authors.affiliation: Division of Endocrinology and Diabetology, Department of Medical Specialties, Geneva University Hospitals, Switzerland.
authors.forename: M-C
authors.initials: MC
authors.lastname: Brulhart-Meynet
authors.affiliation: Division of Endocrinology and Diabetology, Department of Medical Specialties, Geneva University Hospitals, Switzerland.
authors.forename: R W
authors.initials: RW
authors.lastname: James
authors.affiliation: Division of Cardiology, Department of Medical Specialties, Geneva University Hospitals, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Lerch
authors.affiliation: Division of Cardiology, Department of Medical Specialties, Geneva University Hospitals, Switzerland; Foundation for Medical Researches, University of Geneva School of Medicine, Switzerland. Electronic address: christophe.montessuit@unige.ch.
authors.forename: C
authors.initials: C
authors.lastname: Montessuit
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D000818:Animals; D001692:Biological Transport; D002478:Cells, Cultured; D002784:Cholesterol / Q000378:metabolism; D003847:Deoxyglucose / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D005230:Fatty Acids, Nonesterified / Q000378:metabolism; D020690:GTPase-Activating Proteins / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D008079:Lipoproteins, VLDL / Q000494:pharmacology*; D008297:Male; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism; D009840:Oligomycins / Q000494:pharmacology; D010084:Oxidation-Reduction; D010766:Phosphorylation; D061251:Primary Cell Culture; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D011972:Receptor, Insulin / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013312:Stress, Physiological / Q000187:drug effects*; D014443:Tyrosine; D014475:Uncoupling Agents / Q000494:pharmacology
chemical_list: D005230:Fatty Acids, Nonesterified; D020690:GTPase-Activating Proteins; D007328:Insulin; D008079:Lipoproteins, VLDL; D009840:Oligomycins; C533101:TBC1D4 protein, rat; D014475:Uncoupling Agents; D014443:Tyrosine; D002784:Cholesterol; D003847:Deoxyglucose; D011972:Receptor, Insulin; C066542:insulin receptor-related receptor; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases
keywords: Cardiac myocytes; Fatty acids; Glucose transport; Insulin; Metabolic stress; VLDL