Regulation of mammalian skeletal muscle lipid metabolism: the role of perilipin proteins

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The long-term objective of my ongoing NSERC-funded research program is to understand the underlying mechanisms and the regulation of mammalian enzymes/proteins that regulate triglyceride (fat or lipid) metabolism in muscle. We know that dysregulation of skeletal muscle lipid metabolism results in deterioration of cell signaling and disruptions in cellular energy homeostasis, and therefore understanding the underlying mechanisms of regulation of these processes would be a first step to identifying therapeutic targets and alternate therapies (e.g., exercise). The current proposal focuses on the potential role(s) that the perilipin family of lipid droplet proteins plays in these processes. Perilipin (PLIN) proteins were first discovered in adipose or fat tissue. The first one discovered (PLIN1) is the only one that has a well-described function. In adipose tissue, PLIN1 is very important in regulating the breakdown and accumulation of the stored fat in lipid droplets. Although PLIN1 content is very low, PLIN2, PLIN3, and PLIN5 are abundant in skeletal muscle. Therefore, the current proposal outlines experiments that will explore the potential role(s) that these three skeletal muscle proteins play in lipid metabolism. We recently demonstrated that two of these PLIN proteins increased in the mitochondrial fraction in response to acute contraction (PLIN5) or endurance training (PLIN3). This intriguingly suggests that they have disparate functions in the mitochondria that are responsible for oxidizing the fatty acids that are released from the intramuscular lipid droplets. Several of the proposed experiments are focused on exploring this important new function further. In addition, our previous work indicates that PLIN2 does not interact with other important metabolic regulators of fat breakdown (e.g., lipase and lipase activators) and that PLIN3 might be involved in intracellular trafficking, which would be important in both fat breakdown and synthesis. Therefore we propose to begin exploration of a potential role for PLIN2 and PLIN3 in fat accumulation/synthesis. Together these studies will be expected to make an impact on our understanding of skeletal muscle lipid metabolism and pave the way for pharmaceutical and/or alternate therapy research.