Adipose Triglyceride Lipase Regulation: An Overview

Abstract

Adipose triglyceride lipase (ATGL) is the key-enzyme for the release of fatty acids (FAs) from triacylglycerol (TG) stores during intracellular lipolysis producing FAs used for energy production. There is growing evidence that the products and intermediates from lipolytic breakdown during the FA mobilization process also have fundamental regulatory functions affecting cell signaling, gene expression, metabolism, cell growth, cell death, and lipotoxicity. Regulation of ATGL is therefore vital for maintaining a defined balance between lipid storage and mobilization. This review addresses the regulation of ATGL activity at the post-translational level with special emphasis on protein-mediated interaction at the site of hydrolytic action, namely to the lipid droplet.

Keywords: ABHD5; ATGL; Atglistatin; CGI-58; CIDEC; FSP27; G0/G1 switch gene 2; G0S2; HILPDA; Lipolysis; PEDF; PNPLA2; Plin; SERPINF1; adipose triglyceride lipase; cell death activator CIDE-3; comparative gene identification 58; fat-specific protein 27; hypoxia-inducible lipid dropleT-associated; oleoyl-CoA; patatin-like phospholipase domain-containing protein 2; perilipin; pigment epithelium derived factor; serpin family F member 1; α/β hydrolase domain containing protein 5.

Figure 1

Schematic overview of intracellular lipolysis, the sequential breakdown of TG to glycerol and three molecules of FAs. ATGL catalyzes the hydrolysis of TG stored in LDs to DG and FA, which is the first step of lipolysis. The next step of lipolysis is catalyzed by HSL to degrade DGs to MGs and FAs. The last step of lipolysis is catalyzed by MGL, which hydrolyzes MG to glycerol and FA.

Figure 2

Schematic overview of the regulation of ATGL on the LD. In basal condition of lipolysis, the LD is decorated with perilipins (Plins) and cell death activator CIDE-3 (CIDEC) to restrict the access of ATGL to the TG stores of the LD. The additional role of Plin1 is to sequester the co-activator protein comparative gene identification 58 (CGI-58) preventing its stimulating interaction with ATGL. ATGL hydrolyzes TG to DG and FA which also takes place to a small extent in basal conditions. Upon hormonal stimulation, the phosphorylation of Plin1, Plin2, CGI-58 and ATGL leads to a change on the surface of the LD: The chaperone heat shock protein HSPA8/hsc70 (HSPA8) shuttles Plin2 and Plin3 to the proteasome for degradation. The dissociation of CGI-58 from Plin1 enables its interaction with ATGL, which activates ATGL’s TG hydrolyzing activity. In both, basal and stimulated state of lipolysis, ATGL can be inhibited by the protein G0/G1 switch gene 2 (G0S2), acyl-CoA and synthetic inhibitor Atglistatin (which is effective in murine ATGL only).

Figure 3. Overview of patatin-like domain containing proteins.

(A) Graphical representation of Pat17 and nine members of the human PNPLA family and the location of their patatin-like domains, which are depicted in magenta. Crystal structures of (B) Pat17, (C) cytosolic phospholipase A2, (D) ExoU and (E) VipD. Patatin-like domains of Pat17, ExoU and VipD and the catalytic phospholipase A2 (PLA2c) domain in cytosolic phospholipase A2 are depicted in magenta.