Perilipin 5, a lipid droplet protein adapted to mitochondrial energy utilization

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We summarize recent mechanistic and physiological studies related to the role of perilipin 5 (Plin5) in regulating lipid droplet accumulation and protection to fatty acids in tissues with high lipid oxidative metabolism. Plin5 is a lipid droplet targeting protein that promotes association of lipid droplets with mitochondria and is most highly expressed in oxidative tissues, including cardiac and skeletal muscle. Recent in-vivo and in-vitro data indicate an important role for Plin5 in the regulation of cardiac lipid storage and function. Targeted overexpression of Plin5 in heart causes steatosis, mild mitochondria dysfunction, and hypertrophy in cardiac tissue, but without affecting cardiac function. In contrast, whole body ablation of Plin5 (Plin5 mice) reduces cardiac lipid droplet formation, increases cardiac fatty acid oxidation, and promotes cardiac dysfunction; cardiac defects can be prevented with antioxidative therapy. These data suggest a cytoprotective role for Plin5 to promote lipid storage but to limit fatty acid toxicity, parameters critical for tissues with high lipid oxidative metabolism. In-vivo and in-vitro data suggest that Plin5 is part of a cell-adaptive response to high lipid oxidative metabolism to protect lipid droplet storage against neutral lipases and, so, limit fatty acid accumulation. Although the specific mechanisms that underlie Plin5 lipid droplet storage protection in oxidative tissues remain to be fully elucidated, Plin5 provides a basis for the novel cytoprotective nature of lipid droplets.