There has been an explosion of interest in the biology of intracellular lipid droplets (LDs) over the past several years that has been fueled by the realization that LDs are not simply static repositories for lipid storage, but are dynamic intracellular "organelles" that participate in interactions and interplay with much of the cell's machinery. Advances in our understanding of LD metabolism have been made through a variety of approaches, including microscopy, proteomics, and genome-wide screens. LDs are most prominently associated with adipose cells, where triacylglycerol (TAG) is stored. The major contribution of adipose tissue to whole body metabolism is the storage of energy in the form of TAG and the mobilization of this stored energy leading to the release of free fatty acids, the process known as lipolysis. However, LDs do not occur exclusively in adipose cells, but can be found in many, if not most, tissues and cells, including liver, skeletal muscle, cardiac muscle, enterocytes, and leukocytes, under certain physiological and pathophysiological conditions where the LDs generally serve as an energy repository. In addition, LDs that are primarily composed of cholesteryl esters (CEs) are prominently found in adrenals and ovaries under physiological conditions and in macrophage foam cells in atherosclerotic lesions under pathophysiological conditions. The CE-rich LDs in the adrenal and ovary serve as important sources of cholesterol substrate for steroid hormone production. The overall goal of this proposal is to advance our understanding of the cell biology of LDs, which is likely to have broad implications for health in light of the biological importance of LD cholesterol utilization for steroid hormone production and the fact that excessive accumulation of lipids in droplets is a hallmark of obesity, type 2 diabetes, hepatic steatosis, atherosclerosis, and other metabolic diseases that are prevalent worldwide and particularly prevalent among the population of veterans. The overall goal will be accomplished by testing 2 major hypotheses. First, we hypothesize that the physical properties of LDs are distinctively altered in quantifiably defined ways by specific droplet-associated proteins and these physical properties contribute to LD size (growth and fusion) and metabolism. This hypothesis will be tested using specialized equipment to measure the viscoelastic properties (viscosity, surface tension, etc.) of LDs within normal adipocytes and within adipocytes in which specific LD-associated proteins have been manipulated by gene targeting. Second, we hypothesize that the formation of CE-rich LDs differs in important and identifiable ways from TAG-rich LDs and that CE-rich LDs have a complement of droplet-associated proteins that specifically facilitates their utilization for steroidogenesis. This hypothesis will be tested through the exploration of the function of specific LD-associated proteins on LD homeostasis and cholesterol transport for steroidogenesis. The results from these studies should identify pathways and functions of key molecules in LD biology, some of which are expected to emerge as therapeutic targets that should help curb the morbidities associated with excessive LD accumulation.

Public Health Relevance

When fats (lipids) collect within cells of the body, they form droplets, which are called lipid droplets. Lipid droplets form under normal conditions and in diseases. Under normal, healthy conditions, lipid droplets are mainly found in fat (adipose) cells, where the lipid droplets are usd for energy when people are not eating. Lipid droplets are also found under normal conditions in the adrenal gland, ovaries and testes, where lipid droplets are used to produce the hormones (cortisol, estrogen, testosterone) that these glands secrete and that are needed for normal function. When too many lipid droplets form or when they form in different cells than they are meant to, you see diseases such as obesity, diabetes mellitus (high blood sugar), fatty liver disease and problems such as heart attacks and strokes. All of these diseases are extremely common among the Veteran population. The current proposal is designed to develop a basic understanding of lipid droplets with a goal of identifying new treatments that will help control diseases associated with lipid droplets.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
2I01BX000398-05
Application #
8538217
Study Section
Endocriniology A (ENDA)
Project Start
2009-04-01
Project End
2017-03-31
Budget Start
2013-04-01
Budget End
2014-03-31
Support Year
5
Fiscal Year
2013
Total Cost
Indirect Cost
Name
Veterans Admin Palo Alto Health Care Sys
Department
Type
DUNS #
046017455
City
Palo Alto
State
CA
Country
United States
Zip Code
94304