Lipid Droplet Associated Proteins and Control of Triacylglycerol Metabolism

Abstract

Perilipin A controls lipolysis in adipocytes and is phosphorylated by protein kinase A (PKA) on six serine residues, promoting hormone‐sensitive lipase activity, and triggering remodeling of lipid droplets, whereby large droplets fragment into myriad micro‐droplets. Phosphorylation of perilipin Ser492 initiates this process and is required for maximal lipolysis. We hypothesize that perilipin A forms a dynamic scaffold on lipid droplets that organizes lipid metabolic enzymes; perilipin conformation responds to the metabolic status of the adipocyte. CGI‐58 binds to the carboxyl terminus of perilipin A in adipocytes under basal conditions. Humans with neutral lipid storage disorder (NLSD) have mutations in CGI‐58 and store excessive triacylglycerol (TAG) in many cells and tissues; hence, CGI‐58 plays a role in cellular TAG homeostasis. Recombinant CGI‐58 shows Coenzyme A‐dependent lysophosphatidic acid acyltransferase activity, and is important for channeling fatty acids released from triacylglycerol hydrolysis to phospholipid synthesis. CGI‐58 is a substrate for PKA and is phosphorylated on Ser239, yet mutation of Ser239 to Ala does not alter the function of CGI‐58 in reducing TAG levels of NLSD fibroblasts. This PKA‐mediated phosphorylation facilitates release of CGI‐58 from the perilipin scaffold. Supported by DK54797 from NIH and an American Heart Association Established Investigator Award.