November 2010

From Lipolysis to the Lipolysome

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.

References

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 (rudolf.zechner@uni-graz.at) is a professor of biochemistry in the Institute of Molecular Biosciences at the University of Graz, Austria.

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COMMENTS:

Great article that summarizes lipolysis and its importance, and emphasizes the complex nature of the process.

 

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