The laboratory conducts pioneering research investigating the biochemistry and cell biology of lipid droplets. Lipid droplets are dynamic organelles that are found in nearly all mammalian cells, and serve a particularly vital function in adipocytes where they hold the body's major energy reserves as triacylglycerols. Obesity is characterized by the excessive storage of triacylglycerols in adipocytes, and is a growing global health problem leading to increased prevalence of diabetes and cardiovascular disease in the human population. Despite a need for therapeutic options to control obesity, little is known about the intracellular mechanisms that regulate fat storage and release in adipocytes.
We are particularly interested in the role that structural lipid droplet-associated proteins within the PAT (perilipin, adipophilin, TIP47) family of proteins play in forming an organizing scaffold that regulates the access of lipid metabolic enzymes to stored neutral lipids. Perilipins are a family of polyphosphorylated proteins coating the surfaces of lipid droplets in adipocytes and steroidogenic cells of the adrenal gland, testes, and ovaries. In adipocytes, perilipins are required to maintain fat stores by controlling the rates of triacylglycerol turnover and release. Adipophilin (also called ADRP) and TIP47 are structurally related to perilipins, but are found on lipid droplets in many cell types throughout the body. A major project in the laboratory uses approaches of biochemistry and molecular and cellular biology to investigate the structural basis for perilipin function in controlling lipid droplet morphology and triacylglycerol storage and hydrolysis.
Recent studies from our laboratory and others have shown that lipid droplets have a unique and dynamic protein composition (Figure 1). The identification of novel lipid droplet-associated proteins using proteomics technologies suggests that lipid droplets comprise a metabolically active pool of lipids that is used as a source of substrates for the production of energy, signaling molecules, and structural materials for membrane synthesis and repair.
Using proteomics, we have identified CGI-58 as a major component of adipocyte lipid droplets (Figure 2). Mutations in CGI-58 are responsible for a rare inherited neutral lipid storage disorder in humans, suggesting that CGI-58 plays a critical role in triacylglycerol metabolism. A second major project in the laboratory uses a variety of technologies including in vitro studies of recombinant proteins, RNAi approaches in cultured mammalian cells, and the characterization of transgenic mice to investigate the function of CGI-58 in triacylglycerol metabolism.
Finally, we are interested in further identification of novel lipid droplet-associated proteins and in studying the functions of these proteins.
Selected Recent Publications
- Garcia, A., Subramanian, V., Sekowski, A., Love, M., and Brasaemle, D. L. 2004. The amino and carboxyl termini of perilipin A facilitate the storage of triacylglycerol. J. Biol. Chem. 279, 8409-8416.
- Cohen, A. W., Razani, B., Schubert, W., Williams, T. M., Wang, X. B., Iyengar, P., Brasaemle, D. L., Scherer, P. E., and Lisanti, M. P. 2004. Role of Caveolin-1 in the Regulation of Lipolysis and Lipid Droplet Formation. Diabetes 53, 1261-1270.
- Subramanian, V., Rothenberg, A., Gomez, C., Cohen, A. W., Garcia, A., Bhattacharyya, S., Shapiro, L., Dolios, G., Wang, R., Lisanti, M. P., and Brasaemle, D. L. 2004. Perilipin A mediates the reversible binding of CGI-58 to lipid droplets in 3T3-L1 adipocytes. J. Biol. Chem. 279, 42062-42071.
- Subramanian, V., Garcia, A., Sekowski, A., and Brasaemle, D. L. 2004. Hydrophobic sequences target and anchor perilipin A to lipid droplets. J. Lipid Res. 45, 1983-1991.
- Brasaemle, D. L., Dolios, G., Shapiro, L., and Wang, R. 2004. Proteomic analysis of proteins associated with lipid droplets in basal and lipolytically-stimulated 3T3-L1 adipocytes. J. Biol. Chem., 279 , 46835-46842.
- Cohen, A. W., Schubert, W., Brasaemle, D. L., Scherer, P. E., and Lisanti, M. P. 2005. Caveolin-1 expression is essential for proper non-shivering thermogenesis in brown adipose tissue. Diabetes, 54, 679-686.
- Brasaemle, D. L., and Wolins, N. E. 2005. Isolation of Lipid Droplets. Methods Chapter for Current
Protocols in Cell Biology. Editors Juan S. Bonifacino, Mary Dasso, Joe B. Harford, Jennifer Lippincott-Schwartz, and Kenneth M. Yamada, Publisher John Wiley & Sons, Inc. Supplement 29, Unit 3.15; pages 3.15.1-3.15.12.
- Marcinkiewicz, A., Gauthier, D., Garcia, A., and Brasaemle, D. L. 2006. Phosphorylation of serine 492
of perilipin A directs lipid droplet fragmentation and dispersion. J. Biol. Chem., 281, 11901-11909.
- Wolins, N. E., Brasaemle, D. L., Bickel, P. E. 2006. A proposed model of fat packaging by exchangeable lipid droplet proteins. FEBS Lett. 580, 5484-5491.
- Brasaemle, D. L. 2006. A Metabolic Push to Proliferate. Science, 313, 1581-1582.
- Brasaemle, D. L., and Hansen, J. C. 2006. Holding Pattern for Histones. Current Biology,16:R918-R920.
- Brasaemle, D. L., and Wolins, N. E. 2006. Isolation of Lipid Droplets. Methods Chapter for Current Protocols in Cell Biology. Editors Juan S. Bonifacino, Mary Dasso, Joe B. Harford, Jennifer Lippincott-Schwartz, and Kenneth M. Yamada, Publisher John Wiley & Sons, Inc. Supplement 29, Unit 3.15; pages 3.15.1-3.15.12.
- Brasaemle, D. L. 2007. The perilipin family of structural lipid droplet proteins: Stabilization of lipid droplets and control of lipolysis. J. Lipid Res. 48:2547-2559.
- Caviglia, J. M., Sparks, J., Toraskar, N., Brinker, A., Yin, T. C., Dixon, J., and Brasaemle, D. L. 2009. ABHD5/CGI58 facilitates the assembly and secretion of apolipoprotein B-lipoproteins by McA RH7777 rat hepatoma cells. Biochim. Biophys. Acta-Molec. and Cell Biol. Lipids 1791:198-205.
- Brasaemle, D. L., Subramanian, V., Garcia, A., Marcinkiewicz, A., and Rothenberg, A. 2009. Perilipin A and the Control of Lipolysis. Molecular and Cell. Biochem. 326:15-21.
- Wang, H., Hu, L., Dalen, K., Dorward, H., Marcinkiewicz, A., Russell, D., Gong, D., Londos, C., Holm, C., Yamaguchi, T., Rizzo, M., Brasaemle, D. L., and Sztalryd, C. 2009. Activation of hormone-sensitive lipase requires two steps: protein phosphorylation and binding to the PAT-1 domain of lipid droplet coat proteins. J. Biol. Chem. 284, 32116-32125.
- Kimmel, A. R., Brasaemle, D. L., McAndrews-Hill, M., Sztalryd, C., and Londos, C. 2010. Adoption of PERILIPIN as a unifying nomenclature for the mammalian PAT-family of intracellular lipid storage droplet proteins. J. Lipid Res.51:468-471.
- Brasaemle, D. L. 2010. Lipolysis control: The plot thickens. Cell Metab. 11:173-174.
- Montero-Moran, G., Caviglia, J. M., McMahon, D., Subramanian, V., Rothenberg, A., Xu, Z., Lara-Gonzalez, S., Storch, J., Carman, G. M., and Brasaemle, D. L. 2010. CGI-58/ABHD5 is a Coenzyme A-dependent lysophosphatidic acid acyltransferase. J. Lipid Res.51, 709-719.