Location, location: protein trafficking and lipolysis in adipocytes

doi:10.1016/j.tem.2007.10.006

Trends in Endocrinology & Metabolism

Volume 19, Issue 1, January 2008, Pages 3-9

https://doi.org/10.1016/j.tem.2007.10.006 Get rights and content

The storage and mobilization of lipid are central functions of fat cells. Recent proteomic studies suggest that intracellular triglyceride storage droplets are dynamic organelles, and that the signaling events underlying lipid mobilization alter protein trafficking to a specialized subset of these droplets. Here we review recent research that has identified new players in hormone-stimulated lipolysis, and the role of perilipin A, a lipid droplet scaffold protein, in organizing and directing lipolytic protein trafficking.

Section snippets

Importance of fat cell lipolysis

The storage and mobilization of lipid are fundamental cellular processes, and multicellular organisms, from insects to mammals, have evolved specialized cells that store lipid energy in times of excess for mobilization in times of need. In mammals, adipose tissue functions as a specialized lipid energy buffer that stores excess energy as triglyceride (TG) for systemic mobilization as free fatty acids (FFA). Because adipocytes are a key source of fatty acids during fasting and exercise and in

Key players in adipocyte lipolysis

Adipocyte lipolysis is a multifaceted phenomenon that is subject to distinct temporal controls, many of which are poorly understood. This review focuses on protein trafficking during rapid, hormone-stimulated lipolysis (for recent reviews on the general regulation of lipolysis see Refs 1, 2). Interest in lipolytic protein trafficking stems from the seminal work of Londos and colleagues (reviewed in Refs 3, 4). These investigators demonstrated that hormone-stimulated lipolysis is directly

CGI-58

CGI-58 (UniGene name, A/B hydrolase domain-containing protein 5, ABHD5) belongs to the esterase-lipase subfamily of proteins containing α/β hydrolase folds. However, unlike bona fide lipases, the predicted catalytic serine within the consensus GxSxG motif is asparagine instead [49], and thus ABHD5 exhibits no lipase activity 43, 50. Rare homozygous mutations of CGI-58 (ABHD5) result in Chanarin–Dorfman syndrome (MIM 27630), which is characterized by ectopic lipid accumulation in numerous

Other lipases and the biological significance of HSL versus ATGL

A recent proteomic survey using novel activity-based probes concluded that ATGL, HSL and monoglyceride lipase are the major lipases in mouse adipose tissue [55], and combined pharmacological, immunological and genetic approaches strongly indicate that ATGL and HSL constitute more than 90% of TG hydrolase activity in fat cell extracts 56, 57, 58. It is important to remember, however, that TG hydrolase activities against artificial TG emulsions probably do not reflect activity against biological

PLIN subcellular targeting

As mentioned above, there is strong evidence that lipolysis occurs at LDs that have a unique protein composition, and that PLIN is indispensable in regulating the access and activity of lipases at these LD surfaces. Immunoelectron microscopic analysis of adipocytes demonstrated that PLIN is targeted to the surface of LDs [20]. Immunofluorescence staining of cultured adipocytes typically shows strong ‘rimming’ of PLIN-labeled fluorescence at the equator of most [28] if not all LDs [59]. However,

Working model and unresolved issues

A model of PKA-induced lipolytic protein trafficking is depicted in Figure 3, and focuses on the central role of PLIN. In the basal state, PLIN and CGI-58 are tightly bound. Some ATGL is localized to LDs containing PLIN; however, ATGL is likely to be inactive, because its coactivator (CGI-58) is sequestered by PLIN. PKA activation leads to PLIN phosphorylation, which has two parallel effects. First, PLIN phosphorylation frees CGI-58 to activate ATGL on LD surfaces with or without PLIN. Second,

Acknowledgements

The authors wish to thank E. Mottillo and T. Leff for comments and R. Granneman for illustrations. Supported by NIH grant DK062292 and ADA grant RA50.

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Trends in Endocrinology & Metabolism

OpinionLocation, location: protein trafficking and lipolysis in adipocytes

Section snippets

Importance of fat cell lipolysis

Key players in adipocyte lipolysis

CGI-58

Other lipases and the biological significance of HSL versus ATGL

PLIN subcellular targeting

Working model and unresolved issues

Acknowledgements

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Opinion
Location, location: protein trafficking and lipolysis in adipocytes