The increased risk of developing heart disease, strokes, and diabetes with excess adipose tissue is well known;obesity is generally caused by excess caloric intake. Less well appreciated are the devastating effects on health of the lipodystrophies. In the most severe forms, adipose tissue is virtually nonexistent, fat is abnormally stored in the liver and muscle, and there is a huge increase in circulating levels of triglycerides and free fatty acids. Metabolic diseases including diabetes, and frank organ failure, often are the results. Neutral fat is normally stored in lipid bodies, which are most apparent in adipocytes, yet the origin of these organelles is mysterious and no known factors that catalyze their assembly have been identified. We propose that defects in assembly and/or maintenance of lipid bodies are a cause of lipodystrophy. A yeast genomic screen for aberrant lipid bodies (observation of gene deletion strains) has revealed 62 genes involved in lipid body assembly or maintenance, three of which are known to cause lipodystrophy in humans or mice. We will study the function of the genes involved in lipodystrophy, particularly seipin, mutations in which cause severe human disease. We will determine if seipin is found at lipid body exit sites of the endoplasmic reticulum and whether it might organize these sites. We will study the murine lipodystrophy gene lipin and its activators, and determine if they are involved in packaging of lipid and protein for lipid bodies. Our screen also detected 17 genes involved in organelle trafficking, especially involving endosomes. We will study three groups of these as they relate to possible roles in retrograde transport of factors involved in lipid body assembly, or possible endosomal communication required for maintenance of lipid bodies. In summary, novel factors for lipid bodies have been identified by our screen and we shall study several of them, especially seipin, to begin to elucidate the steps of lipid body assembly and maintenance. This information should be useful in the lipodystrophies and obesity, and it may prove valuable in the design of novel forms of therapy for these devastating diseases.

Public Health Relevance

Both an absence of fat tissue and an overabundance of fat tissue are major risk factors for heart disease, strokes, diabetes, and organ failure. Fat is stored in cell organelles called lipid bodies, yet how they are formed is a mystery, and what goes wrong in lipodystrophy (absence of fat tissue) is often not clear. Experiments are proposed to understand how lipid bodies are formed and what goes wrong in two types of lipodystrophy.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM084210-03
Application #
7827986
Study Section
Membrane Biology and Protein Processing (MBPP)
Program Officer
Chin, Jean
Project Start
2008-05-01
Project End
2012-04-30
Budget Start
2010-05-01
Budget End
2011-04-30
Support Year
3
Fiscal Year
2010
Total Cost
$310,860
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Pharmacology
Type
Schools of Medicine
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Chen, Xiao; Goodman, Joel M (2017) The collaborative work of droplet assembly. Biochim Biophys Acta 1862:1205-1211
Cai, Yingqi; Goodman, Joel M; Pyc, Michal et al. (2015) Arabidopsis SEIPIN Proteins Modulate Triacylglycerol Accumulation and Influence Lipid Droplet Proliferation. Plant Cell 27:2616-36
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Han, Sungwon; Binns, Derk D; Chang, Yu-Fang et al. (2015) Dissecting seipin function: the localized accumulation of phosphatidic acid at ER/LD junctions in the absence of seipin is suppressed by Sei1p(?Nterm) only in combination with Ldb16p. BMC Cell Biol 16:29
Han, Sungwon; Bahmanyar, Shirin; Zhang, Peixiang et al. (2012) Nuclear envelope phosphatase 1-regulatory subunit 1 (formerly TMEM188) is the metazoan Spo7p ortholog and functions in the lipin activation pathway. J Biol Chem 287:3123-37
Cartwright, Bethany R; Goodman, Joel M (2012) Seipin: from human disease to molecular mechanism. J Lipid Res 53:1042-55
Adeyo, Oludotun; Horn, Patrick J; Lee, Sungkyung et al. (2011) The yeast lipin orthologue Pah1p is important for biogenesis of lipid droplets. J Cell Biol 192:1043-55

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