Figure 1. CGI-58 and ATGL functions in adipocytes (A) and hepatocytes (B). (A) Within the adipocyte, triacylglycerol (TAG) hydrolysis is dynamically regulated by hormones to ensure appropriate metabolic adaptation to nutritional and physiologic cues. In the basal state, CGI-58 is primarily sequestered by perilipin-1(Plin-1) at the lipid droplet, ATGL is localized at the lipid droplet, and hormone sensitive lipase (HSL) resides in the cytoplasm. Downstream of catecholamine stimulation through β-adrenergic receptors (βAR), cAMP-activated protein kinase A (PKA) phosphorylates Plin-1 and HSL. Plin-1 phosphorylation results in the release of CGI-58. CGI-58 reversibly disperses to the cytoplasm, while a small amount remains at the lipid droplet, interacting with ATGL to co-activate TAG hydrolysis. Meanwhile, phosphorylated HSL translocates to the lipid droplet and interacts closely with Plin-1, preferentially hydrolyzing diacylglycerol (DAG) to monoacylglycerol (MAG). In the final step of lipolysis, MAG is hydrolyzed by MAG lipase (MAGL), leading to glycerol release from the adipocyte. Based on the localization of CGI-58 in the cytoplasm during stimulated lipolysis, CGI-58 may have a physiological function distinct from the co-activation of ATGL-mediated lipolysis. The role of CGI-58 LPA acyltransferase (LPAAT) activity in adipocytes is not known, but CGI-58-derived PA and downstream products might participate in signal transduction. (B) Within the hepatocyte, CGI-58 generates signaling lipids to activate inflammatory kinases and dampen insulin signaling. Downstream of nutrient oversupply or systemic inflammation, CGI-58-derived PA could serve as a precursor to pro-inflammatory signaling lipids that lead to the activation of stress kinases such as IκB kinase (IKK), c-jun N-terminal kinase (JNK) and mammalian target of rapamycin (mTOR). CGI-58-derived PA might directly activate mTOR complex 1(mTORC1), similar to PA generated by phospholipase D (PLD). mTORC1 activates S6 kinase 1 (S6K1) which phosphorylates insulin receptor substrate-1 (IRS-1) at Ser1101 and other residues to inhibit insulin signaling through the insulin receptor (IR). mTOR complex 2 (mTORC2) mediates insulin action by phosphorylating Akt at Ser473. PA generated within the glycerolipid synthesis pathway can impair insulin signaling through mTORC2. CGI-58-derived PA might also inactivate mTORC2 to prevent Akt phosphorylation. Phosphorylated Akt inactivates forkhead box protein O1 (FoxO1), a transcription factor that drives expression of genes involved in gluconeogenesis and very low density lipoprotein (VLDL) secretion. In addition to signaling lipids derived through CGI-58 LPAAT activity, it is possible that ATGL-mediated lipolysis could produce precursors to signaling lipids. Products of ATGL-mediated lipolysis can serve as signaling lipids to activate PPARα, a transcription factor that drives oxidative gene expression. CGI-58’s role in hepatic TAG mobilization and PPARα target gene expression is likely ATGL-dependent (blue lines). Unlike CGI-58, ATGL does not significantly affect hepatic insulin signaling. Thus, CGI-58’s role in the regulation of insulin signaling is proposed to be independent of ATGL (red lines). Direct effects are denoted by solid lines. Potential pathway effects are indicated by dotted lines. CGI-58, comparative gene identification-58; ATGL, adipose triglyceride lipase; LPA, lysophosphatidic acid; PA, phosphatidic acid; PI3Ks, phosphoinositide 3 kinases; PDPK1, phosphoinositide dependent protein kinase 1; GPAT, glycerol-3-phosphate acyltransferases; AGPAT, sn-1-acylglycerol-3-phosphate acyltransferase; PAP, phosphatidic acid phosphatase; DGAT, diglyceride acyltransferase.