Analysis of Lipolytic Protein Trafficking and Interactions in Adipocytes

Abstract

A central function of adipocytes is the storage and mobilization of energy in the form of triglyceride. A considerable amount is known about the enzymatic basis for lipogenesis and lipolysis; however, our understanding of how these processes are organized and regulated within cells is incomplete. Until recently, cellular triglyceride was considered to be stored in droplets lacking biological structure or organization. Growing evidence, however, suggests that lipid droplets are specialized, heterogeneous organelles that perform distinct roles in lipid biosynthesis, transport, and mobilization (1-3). A large number of proteins have been found to change their associations with lipid droplets in response to lipolytic stimulation. How these proteins are coordinated to control lipid storage and utilization remains largely unknown.It is well established that activation of cAMP-dependent kinase (PKA) 3 is the major signaling mechanism by which hormones and neurotransmitters stimulate lipolysis in adipocytes (4, 5). Most work regarding hormone stimulated lipolysis has focused on perilipin (Plin), a protein that binds to the surface of certain lipid droplets (LDs), and hormone-sensitive lipase (HSL), which translocates to lipid during lipolytic activation.Plin is the major target for PKA-mediated phosphorylation in adipocytes (6, 7), appears to be essential for hormone-stimulated lipolysis (8) and exerts both positive and negative effects on lipolytic rate (9 -11). Plin was originally viewed as a physical barrier that passively regulated access of lipases to store triglyceride; however, more recent data indicates that Plin may function more as a LD scaffold that directs the trafficking of lipolytic proteins to a specialized subcellular domain (11). Nonetheless, the temporal and spatial relationships between Plin and other proteins in the lipolytic pathway during PKA activation remain ill-defined.PKA activation promotes the translocation of HSL to lipid, which correlates with the magnitude of stimulated lipolysis (7,12). Work from several laboratories indicates that Plin and HSL synergize to trigger PKA-mediated lipolysis (11, 13), and our recent work indicates that HSL specifically translocates to a subset of LDs containing Plin (11). It is presently unclear whether Plin and HSL interact directly, whether the interaction takes place on certain LDs and not others, or whether the interaction occurs on a timescale that is compatible with the initiation of lipolysis.The complexity of regulated lipolysis has recently expanded with the identification of adipose triglyceride lipase (Atgl) (14, * This work was supported in part by grants from the National Institutes of Health (DK 62292), the American Diabetes Association, the Fund for Medical Research and Education at WSU, and the Joseph Young Research Fund. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fac...

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