Abstract 18236: Perilipin 5 Links Lipid Droplets with Mitochondria
Maintaining cellular lipid homeostasis is crucial to heart function, and is compromised in obesity-induced cardiomyopathy. Lipid droplets (LDs) play a central role in lipid homeostasis by mediating fatty acids (FA) storage in the form of triglyceride (TAG), lowering intracellular lipid levels that mediate cellular lipotoxicity. LD and mitochondrial function are intimately related but mechanisms of interaction have not been uncovered. Perilipin 5 (Plin5) is the newest perilipin protein coating LD surfaces and is highly expressed in heart. We investigated Plin5's role in interactions between mitochondria and LDs using a combination of cell culture and transgenic model studies. We have studied cardiomyocytes using live confocal imaging and electron microscopy analysis and found that Plin5 expression recruits mitochondria to the LD surface thru a C-terminal region. At the molecular level, Plin5 interacts with the key lipolytic proteins adipocyte triglyceride lipase and its co-lipase CGI-58, as determined by FRET and co-immunoprecipitation studies. At the metabolic level, we found that Plin5 regulates LD hydrolysis by limiting basal lipolysis but not after protein kinase a (pka) activation and that plin5 is a phoshorylated protein and a putative pka downstream target. Compared to control cells, plin5 expressing cells show (p<0.05) decreased palmitate (PA) β-oxidation detected by cell respirometry and increased PA incorporation into TAG. These in vitro results suggest that Plin5 regulates cardiac LD hydrolysis and controls local FA flux to protect mitochondria against FA surge in physiological conditions. To investigate plin5 function in vivo, we obtained transgenic mice with heart-specific plin5 over-expression (αMHC-plin5). Preliminary results suggest that these mice have a strong cardiac lipid droplet phenotype. Hearts from αMHC-plin5 mice expressed at least 20-fold higher levels of plin5 and exhibit a 3.5- fold increase in TAG content versus non-transgenic littermate. These studies support a conclusion that Plin5 is a promising key gene in the pathways that efficiently couple the LD storage compartment to the mitochondria FA utilization compartment and will help unravel the underpinnings of cardiac cellular lipid homeostasis.
- © 2011 by American Heart Association, Inc.