title: Protein kinase-D1 overexpression prevents lipid-induced cardiac insulin resistance.
abstract: In the insulin resistant heart, energy fuel selection shifts away from glucose utilization towards almost complete dependence on long-chain fatty acids (LCFA). This shift results in excessive cardiac lipid accumulation and eventually heart failure. Lipid-induced cardiomyopathy may be averted by strategies that increase glucose uptake without elevating LCFA uptake. Protein kinase-D1 (PKD1) is involved in contraction-induced glucose, but not LCFA, uptake allowing to hypothesize that this kinase is an attractive target to treat lipid-induced cardiomyopathy. For this, cardiospecific constitutively active PKD1 overexpression (caPKD1)-mice were subjected to an insulin resistance-inducing high fat-diet for 20-weeks. Substrate utilization was assessed by microPET and cardiac function by echocardiography. Cardiomyocytes were isolated for measurement of substrate uptake, lipid accumulation and insulin sensitivity. Wild-type mice on a high fat-diet displayed increased basal myocellular LCFA uptake, increased lipid deposition, greatly impaired insulin signaling, and loss of insulin-stimulated glucose and LCFA uptake, which was associated with concentric hypertrophic remodeling. The caPKD1 mice on high-fat diet showed none of these characteristics, whereas on low-fat diet a shift towards cardiac glucose utilization in combination with hypertrophy and ventricular dilation was observed. In conclusion, these data suggest that PKD pathway activation may be an attractive therapeutic strategy to mitigate lipid accumulation, insulin resistance and maladaptive remodeling in the lipid-overloaded heart, but this requires further investigation.
authors.affiliation: Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.
authors.forename: Ellen
authors.initials: E
authors.lastname: Dirkx
authors.affiliation: Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.
authors.forename: Guillaume J J M
authors.initials: GJ
authors.lastname: van Eys
authors.affiliation: Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.
authors.forename: Robert W
authors.initials: RW
authors.lastname: Schwenk
authors.affiliation: Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.
authors.forename: Laura K M
authors.initials: LK
authors.lastname: Steinbusch
authors.affiliation: Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.
authors.forename: Nicole
authors.initials: N
authors.lastname: Hoebers
authors.affiliation: Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.
authors.forename: Will A
authors.initials: WA
authors.lastname: Coumans
authors.affiliation: Department of Experimental Cardiology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.
authors.forename: Tim
authors.initials: T
authors.lastname: Peters
authors.affiliation: Department of Pharmacology, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.
authors.forename: Ben J
authors.initials: BJ
authors.lastname: Janssen
authors.affiliation: Department of Nuclear Medicine, Maastricht University Medical Center, The Netherlands.
authors.forename: Boudewijn
authors.initials: B
authors.lastname: Brans
authors.affiliation: Department of Nuclear Medicine, University Hospital Aachen, Germany.
authors.forename: Andreas T
authors.initials: AT
authors.lastname: Vogg
authors.affiliation: Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.
authors.forename: Dietbert
authors.initials: D
authors.lastname: Neumann
authors.affiliation: Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands.
authors.forename: Jan F C
authors.initials: JF
authors.lastname: Glatz
authors.affiliation: Department of Molecular Genetics, Cardiovascular Research Institute Maastricht (CARIM), Maastricht University, The Netherlands. Electronic address: j.luiken@maastrichtuniversity.nl.
authors.forename: Joost J F P
authors.initials: JJ
authors.lastname: Luiken
mesh_terms: D000818:Animals; D002311:Cardiomyopathy, Dilated / Q000201:enzymology*; D059305:Diet, High-Fat / Q000009:adverse effects; D005260:Female; D015870:Gene Expression; D006352:Heart Ventricles / Q000378:metabolism / Q000473:pathology; D006655:Histone Deacetylases / Q000378:metabolism; D007333:Insulin Resistance; D050356:Lipid Metabolism; D008297:Male; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009206:Myocardium / Q000201:enzymology / Q000473:pathology; D032383:Myocytes, Cardiac / Q000201:enzymology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000235:genetics / Q000378:metabolism*; D011499:Protein Processing, Post-Translational
chemical_list: C089212:protein kinase D; D011493:Protein Kinase C; C498618:Hdac5 protein, mouse; D006655:Histone Deacetylases
keywords: Cardiomyopathy; Fatty acid transport; Glucose transport; Insulin resistance; Protein kinase D