Dramatic Accumulation of Triglycerides and Precipitation of Cardiac Hemodynamic Dysfunction during Brief Caloric Restriction in Transgenic Myocardium Expressing Human Calcium-independent Phospholipase A sub(2) gamma

• Published in: The Journal of biological chemistry Vol. 282; no. 12; pp. 9216 - 9227
• Main Authors: Mancuso, David J, Han, Xianlin, Jenkins, Christopher M, Lehman, John J, Sambandam, Nandakumar, Sims, Harold F, Yang, Jingyue, Yan, Wei, Yang, Kui, Green, Karen, Abendschein, Dana R, Saffitz, Jeffrey E, Gross, Richard W
• Format: Journal Article
• Language: English
• Published: 01-03-2007
• ISSN: 0021-9258; 1083-351X

Previously, we identified calcium-independent phospholipase A sub(2) gamma (iPLA sub(2) gamma ) with multiple translation initiation sites and dual mitochondrial and peroxisomal localization motifs. To determine the role of iPLA sub(2) gamma in integrating lipid and energy metabolism, we generated transgenic mice containing the alpha -myosin heavy chain promoter ( alpha MHC) placed proximally to the human iPLA sub(2) gamma coding sequence that resulted in cardiac myocyte-restricted expression of iPLA sub(2) gamma (TGiPLA sub(2) gamma ). TGiPLA sub(2) gamma mice possessed multiple phenotypes including: 1) a dramatic similar to 35% reduction in myocardial phospholipid mass in both the fed and mildly fasted states; 2) a marked accumulation of triglycerides during brief caloric restriction that represented 50% of total myocardial lipid mass; and 3) acute fasting-induced hemodynamic dysfunction. Biochemical characterization of the TGiPLA sub(2) gamma protein expressed in cardiac myocytes demonstrated over 25 distinct isoforms by two-dimensional SDS-PAGE Western analysis. Immunohistochemistry identified iPLA sub(2) gamma in the peroxisomal and mitochondrial compartments in both wild type and transgenic myocardium. Electron microscopy revealed the presence of loosely packed and disorganized mitochondrial cristae in TGiPLA sub(2) gamma mice that were accompanied by defects in mitochondrial function. Moreover, markedly elevated levels of 1-hydroxyl-2-arachidonoyl-sn-glycero-3-phosphocholine and 1-hydroxyl-2-docosahexaenoyl-sn-glycero-3-phosphocholine were prominent in the TGiPLA sub(2) gamma myocardium identifying the production of signaling metabolites by this enzyme in vivo. Collectively, these results identified the participation of iPLA sub(2) gamma in the remarkable lipid plasticity of myocardium, its role in generating signaling metabolites, and its prominent effects in modulating energy storage and utilization in myocardium in different metabolic contexts.