Premium
Protein kinase‐D1 overexpression in mice prevents lipid‐induced insulin resistance and cardiomyopathy by upregulation of glucose uptake
Author(s) -
Dirkx Ellen,
Schwenk Robert W.,
Steinbusch Laura KM,
Hoebers Nicole,
Janssen Ben J,
Brans Boudewijn,
BaselDuby Rhonda,
Olson Eric N,
Bonen Arend,
Eys Guillaume JJM,
Glatz Jan FC,
Luiken Joost JFP
Publication year - 2011
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.25.1_supplement.914.3
Subject(s) - insulin resistance , medicine , downregulation and upregulation , glucose uptake , endocrinology , glut4 , muscle hypertrophy , heart failure , lipid metabolism , diabetic cardiomyopathy , insulin , myocyte , cardiomyopathy , biology , biochemistry , gene
Disturbances in metabolic substrate uptake promote the development of cardiomyopathy and eventually lead to heart failure. Understanding the pathways that control substrate uptake could enable therapeutic approaches to prevent maladaptive cardiac remodeling. We identified protein kinase‐D1 (PKD1) as a contraction‐activated kinase, which promotes GLUT4‐mediated glucose uptake, without affecting long chain fatty acids (LCFA) uptake. This corroborated with in‐vitro experimentation using PKD1 siRNA in HL‐1 cells and in‐vivo by microPET scan results showing a higher glucose uptake in the hearts of mice overexpressing constitutively active PKD1 (caPKD1). The increased glucose uptake in the heart of caPKD1 mice results in dilated cardiac hypertrophy and heart failure. In contrast, mice on a high fat diet with lipid‐overloaded hearts displayed concentric cardiac hypertrophy, accompanied by insulin resistance. However, hearts of caPKD1 mice on a high fat diet displayed neither dilated nor concentric hypertrophy. Further, these hearts did not show increased glucose uptake nor increased LCFA uptake, demonstrating the role of PKD1 to balance cardiac substrate utilization, which is crucial in preventing pathological cardiomyopathy. In conclusion, in the lipid‐overloaded heart, upregulation of PKD1 offers protection against the development of insulin resistance and hypertrophic remodeling. Grant Funding Source : NWO (Dutch Organisation for scientific research)