Our primary research interests in the field of Diabetes and Obesity are directed to the study and characterization of lipid droplet surface proteins and their role in regulating the fat storage compartment in adipose tissues as well as in non-adipose tissues (liver, muscle and heart). Clear and convincing evidence links type 2 diabetes mellitus (T2D) with obesity. Elevated non-esterified free fatty acids (NEFA) levels, caused by a dysregulation of adipose tissue lipolysis, may serve the link between obesity and risk for T2D. Lipolysis is needed to release stored NEFA during increased energy demand but excessive release contributes to insulin resistance, excess NEFA are now being stored by non adipose tissues, ill equipped to handle surplus fat. The role of ectopic fat deposition, the accumulation of lipid droplets in non-adipose tissues, is recognized as a strong prognostic factor for the development of insulin resistance. Formation of lipid droplets maintains cellular NEFA homeostasis by storing excess NEFA as triglyceride and releasing it when needed. The ability to store excess NEFA provides protection from â?olipotoxicityâ? leading to inflammation, insulin resistance and in extreme cases cellular apoptosis. Thus the mechanisms regulating cellular lipid droplet formation and turnover are clearly important yet poorly understood. This regulation appears to be mediated by the protein coat surrounding all lipid droplets, which include at least one member of the PAT protein family originally named for a triad of Perilipin, ADRP and Tip47 with high primary sequence homology and conservation across species and now including S3-12, and PAT-1. Perilipin (Peri) and S3-12 are confined to adipose, while ADRP, Tip47, LSPD-5 are ubiquitously distributed. To date, a functional role regulating lipolysis in adipocytes has been shown only for Peri. Mylaboratory goals are to understand the functional importance of three functionally uncharacterized PAT proteins, ADRP, TIP47 and LSPD-5 in lipid droplet metabolism in non-adipogenic tissues using loss of function with RNAI techniques and this work is supported by an RO1. Another important goal of my laboratory is to develop methodologies to study in situ the interactions between lipid droplet surface proteins and proteins involved in lipid metabolism (lipogenesis and lipolysis). More specifically, I received an American Diabetes Carrier Award to characterize the molecular events underlying the critical role of Perilipin as a gatekeeper to lipases in adipose tissue by adapting novel fluorescent techniques (FRAP, FRET and FLIP) to the study of Perilipin and lipases interactions at the surface of the lipid droplet. Most recently, I have been collaborating with scientists at the Max Planck institute and at NIDDK to identify genes involved in the lipid droplet biogenesis and metabolism using RNAi technology.
Grants and Contracts:
"Role of PAT Proteins in Ectopic Fat"
NIH/NIDDK 1RO1 DK 075017-01A2
"Perilipin Regulation of Hormone Sensitive Lipase"
ADA Career Development Award 1-05
CD-17 US Patent Application Number: 12/061,773
Carole Sztalryd, Ming Bell, Hong Wang Title: "Method of Measuring Lipid Droplets and Applications of Using the Same"
UMB Ref: CS-2007-055
VA Ref: 07-163
- Bell M., Wang H., Chen H, McLenithan J., Yang R, Yu D., Fried S.K., Quon M.J., Londos C. and Sztalryd C. Consequences of lipid droplet coat proteins down –regulation in liver cells: Abnormal lipid droplet metabolism and induction of insulin resistance. Diabetes 2008 57(8):2037-45.
- Beller M, Sztalryd C, Southall N, Bell M, Jäckle H, Auld DS, Oliver B. COPI complex is a regulator of lipid homeostasis. PLoS Biol. 2008 6(11) e29]
- Wang H., Hu L., Dalen K., Dorward H., Marcinkiewicz A., Russel D., Gong D., Londos C.,Yamaguchi T., Holm C., Rizzo M.A., Brasaemle D., Sztalryd C. 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. 2009 284 (46):32116-321125
- Wang H. and Sztalryd C. Oxidative tissue: perilipin 5 links storage with the furnace. Trends in Endocrinology. 2011. 22(6):197-203.
- Wang H, Sreenevasan U, Hu H, Saladino A, Polster BM, Lund LM, Gong DW, Stanley WC, Sztalryd C. Perilipin 5, lipid droplet associated protein provides physical and metabolic linkage to mitochondria. J Lipid Res. 2011. 52(12):2159-2168.
- Wang X, Yang R, Jadhao SB, Yu D, Hu H, Glynn-Cunningham N, Sztalryd C, Silver KD, Gong DW.Transmembrane emp24 protein transport domain 6 is selectively expressed in pancreatic islets and implicated in insulin secretion and diabetes.. Pancreas. 2012.41(1):10-14.
- Wang H, Sreenivasan U, Gong DW, O'Connell KA, Dabkowski ER, Hecker PA, Ionica N, Konig M, Mahurkar A, Sun Y, Stanley WC, Sztalryd C. Cardiomyocyte-specific perilipin 5 overexpression leads to myocardial steatosis and modest cardiac dysfunction. J Lipid Res. 2013 Apr;54(4):953-65.
- Albert, JS, Yerges-Armstrong, LM, Horenstein, RB, Pollin, TI, Sreenivasan, UT, Chai S, Blaner, WS, Snitker, S, O'Connell, JR, Gong D-W, Breyer III, RJ, Ryan, AS, McLenithan, JC, Shuldiner, AR, Sztalryd, C*, Damcott, CM*.. Null Mutation in Hormone-Sensitive Lipase Gene and Risk of Type 2 Diabetes. New England Journal of Medicine, N Engl J Med. 2014 Jun 12;370(24):2307-15. * Authors have equally contributed to the work.
Links of Interest:Lipofly Website
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