For decades, textbooks taught that two enzymes are responsible for the complete hydrolysis of triacylglycerol, hormone-sensitive lipase and monoglyceride lipase, originally described by Steinberg and colleagues in 1964. Recently, lipolysis attracted renewed attention when the complexity and systemic physiological importance of this biochemical pathway became apparent.
Localization of ATGL on lipid droplets of cos-7 cells. Cellular localization of YFP-tagged ATGL (yellow) was determined by Nipkow®-based array confocal laser scanning microscopy. Neutral lipids in cells (red) were stained with Bodipy® 558/568 C12. (Courtesy of W. Graier, R. Malli and M. Schweiger.)
Fatty acids are essential in all organisms as precursors for lipids involved in the formation of biological membranes and in cell signaling processes. Additionally, FA are important energy substrates in animals, most insects and micro-organisms. However, increased cellular concentrations of FA are toxic. Due to their amphipatic nature, they form micelles, disrupt membrane architecture and affect the cellular acid/base homeostasis. To prevent increased cellular FA concentrations, essentially all cells “detoxify” FA by their esterification and storage as triacylglycerol in lipid droplets. In mammals, adipose tissue is the most efficient organ for fat storage. When needed, FA are released from TG by enzymatic hydrolysis mediated by lipases. This process commonly is called lipolysis.
For decades, textbooks taught that two enzymes are responsible for the complete hydrolysis of TG, hormone-sensitive lipase and monoglyceride lipase, originally described by Steinberg and colleagues in 1964. Recently, lipolysis attracted renewed attention when the complexity and systemic physiological importance of this biochemical pathway became apparent.
The lipolytic pathway required the first revision in 2004 when three laboratories reported the discovery of a previously overlooked TG hydrolase (1-3). Due to its enzymatic function and its high abundance in adipose tissue, the enzyme was named adipose triglyceride lipase (2). The critical role of ATGL in fat catabolism became evident when ATGL-deficient mice accumulated massive amounts of fat in many tissues, including adipose, cardiac and skeletal, muscle, liver, kidney and testis. Soon after it was shown that ATGL activity is controlled by a mandatory co-activator (CGI-58) and a potent co-repressor (G0/G1 switch gene 2) (4, 5). The relevance for human physiology was established when mutations in ATGL and CGI-58 were found to be causative for two variants of a rare, autosomal hereditary disease called “neutral lipid storage disease” (6, 7).
In an early, ground-breaking observation, Londos, Greenberg and colleagues demonstrated that perilipin, the “prototype” of structural lipid droplet proteins, regulates HSL access to the TG substrate. On the basis of this finding, numerous proteins recently have been shown to act in a “gate-keeping” role for both HSL and ATGL. The list includes additional members of the perilipin family, members of the CideN family of proteins such as Fsp27 or pigment epithelium-derived factor. Additionally, specific vesicle transport systems (such as Arf1-COP1) also regulate the access of ATGL to lipid droplets by mechanisms that are understood insufficiently (8, 9). Although the list of regulatory factors affecting lipolysis still is incomplete, it is safe to say that lipolysis requires the large regulatory network of a “lipolysome” to function appropriately in various cell types.
Another recently emerging field of interest is the role of lipolysis in lipid-mediated cell signaling. The systemic effects of ATGL deficiency in tissues with relatively low FA oxidation rates suggest that lipase-generated products and intermediates participate in the regulation of lipid and energy homeostasis. The crucial role of MGL in the inactivation of 2-arachidonylglycerol, the most abundant and potent endocannabinoid, became evident in MGL-deficient mice (10). Emerging evidence also indicates that FA or FA derivatives may regulate the activity of nuclear receptors. Similarly, it is conceivable that lipolytic diacylglycerols participate in protein kinase C activation. Future studies will need to address the question of whether the stereospecificity of ATGL supports the generation of bioactive 1,2-sn-DG and whether lipid droplet-derived DG can be translocated to the plasma membrane for PKC activation. Additionally, clarification is needed on whether the potent DG lipase activity of HSL contributes to the catabolism of signaling DG in the plasma membrane.
Taken together, (i) functional lipolysis is much more complex than originally anticipated and requires a regulatory network of a “lipolysome,” (ii) lipolysis is not only important for the mobilization of fat in adipose tissue but has a crucial cell-autonomous function in many tissues and non-adipose cell types of the body and (iii) although lipolysis is essential for the provision of FA as energy substrate, it additionally produces lipolytic products and intermediates involved in the generation of lipid mediators that affect lipotoxicity, inflammation and gene regulation. Thus, lipid droplets could be seen as a metabolic platform that requires the “lipolysome” to control cellular homeostasis.
1. Villena, J. A., Roy, S., Sarkadi-Nagy, E., Kim, K. H. and Sul, H. S. (2004) Desnutrin, an Adipocyte Gene Encoding a Novel Patatin Domain-containing Protein, Is Induced by Fasting and Glucocorticoids: Ectopic Expression of Desnutrin Increases Triglyceride Hydrolysis. J. Biol. Chem. 279, 47066 – 47075.
2. Zimmermann, R., Strauss, J. G., Haemmerle, G., Schoiswohl, G., Birner-Gruenberger, R., Riederer, M., Lass, A., Neuberger, G., Eisenhaber, F., Hermetter, A. and Zechner, R. (2004) Fat Mobilization in Adipose Tissue Is Promoted by Adipose Triglyceride Lipase. Science 306, 1383 – 1386.
3. Jenkins, C. M., Mancuso, D. J., Yan, W., Sims, H. F., Gibson, B. and Gross, R. W. (2004) Identification, Cloning, Expression and Purification of Three Novel Human Calcium-independent Phospholipase A2 Family Members Possessing Triacylglycerol Lipase and Acylglycerol Transacylase Activities. J. Biol. Chem. 279, 48968 – 48975.
4. Yang, X., Lu, X., Lombès, M., Rha, G. B., Chi, Y. I., Guerin, T. M., Smart, E. J. and Liu, J. (2010) The G(0)/G(1) Switch Gene 2 Regulates Adipose Lipolysis through Association with Adipose Triglyceride Lipase. Cell. Metab. 11, 194 – 205.
5. Lass, A., Zimmermann, R., Haemmerle, G., Riederer, M., Schoiswohl, G., Schweiger, M., Kienesberger, P., Strauss, J. G., Gorkiewicz, G. and Zechner, R. (2006) Adipose Triglyceride Lipase-mediated Lipolysis of Cellular Fat Stores Is Activated by CGI-58 and Defective in Chanarin-Dorfman Syndrome. Cell Metab. 3, 309 – 319.
6. Fischer, J., Lefèvre, C., Morava, E., Mussini, J. M., Laforêt, P., Negre-Salvayre, A., Lathrop, M. and Salvayre, R. (2007) The Gene Encoding Adipose Triglyceride Lipase (PNPLA2) Is Mutated in Neutral Lipid Storage Disease with Myopathy. Nat. Genet. 39, 28 – 30.
7. Lefevre, C., Jobard, F., Caux, F., Bouadjar, B., Karaduman, A., Heilig, R., Lakhdar, H., Wollenberg, A., Verret, J. L., Weissenbach, J., Ozgüc, M., Lathrop, M., Prud’homme, J. F. and Fischer, J. (2001) Mutations in CGI-58, the Gene Encoding a New Protein of the Esterase/Lipase/Thioesterase Subfamily, in Chanarin-Dorfman Syndrome. Am. J. Hum. Genet. 69, 1002 – 1012.
8. Beller, M., Sztalryd, C., Southall, N., Bell, M., Jäckle, H., Auld, D. S. and Oliver, B. (2008) COPI Complex Is a Regulator of Lipid Homeostasis. PLoS Biol. 6, e292.
9. Guo, Y., Walther, T. C., Rao, M., Stuurman, N., Goshima, G., Terayama, K., Wong, J. S., Vale, R. D., Walter, P. and Farese, R. V. (2008) Functional Genomic Screen Reveals Genes Involved in Lipid-droplet Formation and Utilization. Nature 453, 657 – 661.
10. Schlosburg, J. E., Blankman, J. L., Long, J. Z., Nomura, D. K., Pan, B., Kinsey, S. G., Nguyen, P. T., Ramesh, D., Booker, L., Burston, J. J., Thomas, E. A., Selley, D. E., Sim-Selley, L. J., Liu, Q. S., Lichtman, A. H. and Cravatt, B. F. (2010) Chronic Monoacylglycerol Lipase Blockade Causes Functional Antagonism of the Endocannabinoid System. Nat. Neurosci. 13, 1113 – 1119.
Rudolf Zechner (email@example.com) is a professor of biochemistry in the Institute of Molecular Biosciences at the University of Graz, Austria.