Ectopic fat deposition, which is the accumulation of lipid droplets outside the adipose tissue, is well recognized as a strong prognostic factor for the development of insulin resistance and """"""""metabolic syndrome"""""""" in obesity and people with lipodystrophies. Therefore a key question has been raised as to whether ectopic fat is not simply a marker but in fact a mediator of disease. We now have preliminary results in a liver cell culture system where siRNA gene inhibitors of lipid droplet surface proteins induce insulin resistance, providing some of the first evidence suggesting that ectopic fat is indeed a mediator of disease. To continue this promising line of investigation to better understand the pathophysiology associated with ectopic fat deposition, we propose to investigate the function and mechanism of lipid droplet surface protein to control lipolysis in non-adipogenic cells and tissues as well as potential changes in lipid droplet composition and activity as the underlying cause of these pathophysiological consequences of obesity, and potentially as a new biochemical pathway for therapeutic intervention. In the healthy state, lipid droplets maintain cellular non-esterifed fatty acid (NEFA) homeostasis by storing any excess NEFA as triglyceride (TAG) and releasing it when needed. This ability to minimize excess NEFA is thought to provide protection from """"""""lipotoxicity"""""""", characterized by insulin resistance leading to inflammation, and in extreme cases cellular apoptosis. In addition, both of the pathways for storage and release of NEFA involve the intermediate production of diacylglyceride (DAG), which also has a signaling function. It is possible that an increase in DAG production by disregulated lipolysis may have a role in the adverse effects associated with ectopic fat. Therefore, regulation of lipid droplet storage AND release of NEFA is a strong candidate for a mechanism by which ectopic fat contributes to disease. Although lipid droplet regulation remains poorly understood, numerous studies have revealed that one or more members of the PAT protein family always seem to be associated with the lipid droplet surface and one, Perilipin, has been shown to help regulate adipocyte lipolysis. The PAT protein family is composed of lipid droplet coat proteins sharing high primary sequences, and similarity with apolipoproteins, and some are tissue specific. Therefore, the overall goal of this proposal is to understand the pathophysiological importance of three functionally uncharacterized PAT proteins, ADRP, TIP47 and PAT-1 (or MLDP) known to be expressed in non-adipogenic tissues. Given our preliminary results, these proteins are strong candidates for regulating lipid droplet lipolysis in non-adipogenic tissues and their disfunction is a likely cause of ectopic fat mediated insulin resistance. These proposed studies will test this hypothesis, and if correct provide an approach for prevention of disease or therapeutic intervention.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK075017-05
Application #
8090287
Study Section
Integrative Physiology of Obesity and Diabetes Study Section (IPOD)
Program Officer
Haft, Carol R
Project Start
2007-08-01
Project End
2013-06-30
Budget Start
2011-07-01
Budget End
2013-06-30
Support Year
5
Fiscal Year
2011
Total Cost
$266,538
Indirect Cost
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201
Sztalryd, Carole; Brasaemle, Dawn L (2017) The perilipin family of lipid droplet proteins: Gatekeepers of intracellular lipolysis. Biochim Biophys Acta 1862:1221-1232
Albert, Jessica S; Yerges-Armstrong, Laura M; Horenstein, Richard B et al. (2014) Null mutation in hormone-sensitive lipase gene and risk of type 2 diabetes. N Engl J Med 370:2307-2315
Kimmel, Alan R; Sztalryd, Carole (2014) Perilipin 5, a lipid droplet protein adapted to mitochondrial energy utilization. Curr Opin Lipidol 25:110-7
Konige, Manige; Wang, Hong; Sztalryd, Carole (2014) Role of adipose specific lipid droplet proteins in maintaining whole body energy homeostasis. Biochim Biophys Acta 1842:393-401
Sztalryd, Carole; Kimmel, Alan R (2014) Perilipins: lipid droplet coat proteins adapted for tissue-specific energy storage and utilization, and lipid cytoprotection. Biochimie 96:96-101
Wang, Hong; Lei, Ming; Hsia, Ru-ching et al. (2013) Analysis of lipid droplets in cardiac muscle. Methods Cell Biol 116:129-49
Wang, Hong; Sreenivasan, Urmila; Gong, Da-Wei et al. (2013) Cardiomyocyte-specific perilipin 5 overexpression leads to myocardial steatosis and modest cardiac dysfunction. J Lipid Res 54:953-65
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Drager, Luciano F; Li, Jianguo; Shin, Mi-Kyung et al. (2012) Intermittent hypoxia inhibits clearance of triglyceride-rich lipoproteins and inactivates adipose lipoprotein lipase in a mouse model of sleep apnoea. Eur Heart J 33:783-90
Wang, Hong; Sreenivasan, Urmilla; Sreenevasan, Urmilla et al. (2011) Perilipin 5, a lipid droplet-associated protein, provides physical and metabolic linkage to mitochondria. J Lipid Res 52:2159-68

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