Yeast cells synthesize a typically eukaryotic mixture of phospholipids, using pathways and enzymes that are largely similar to those in higher eukaryotes, ensuring that insights generated using this model system will be relevant to human metabolism and health. Experiments are proposed that exploit the rapid and dramatic changes that occur in the synthesis and turnover of phospholipids, sphingolipids and storage lipids when inositol, a precursor of phospholipids in eukaryotes, is added or removed from the growth medium of actively dividing yeast cells. Many of the lipids that respond to inositol availability i yeast are implicated in stress response signaling in eukaryotic cells. Rapid changes occurring in such lipids in response to abrupt changes in inositol availability will be correlated to changes in signaling and gene expression. This strategy will be used to define the specific signaling roles of the lipids;phosphatidic acid, diacylglycerol, and phosphatidylinositol 4- phosphate and sphingolipids in the endoplasmic reticulum and the plasma membrane. Phosphatidic acid not only serves as a signaling lipid but is also a key precursor of phospholipids essential for membrane biogenesis. Alternatively, phosphatidic acid serves as precursor via dephosphorylation for the production of diacylgycerol, which in turn serves as a precursor in the synthesis of both phospholipids and triacylglycerol, a major component of lipid droplets. The metabolic regulation controlling the synthesis of triacylglycerol is highly relevant to understanding factors underlying human health related conditions, such as chronic obesity. In yeast cells starved for inositol, phospholipid synthesis decreases and triacylglycerol levels increase, mimicking metabolic changes leading to obesity. Experiments designed to probe the mechanism of this important regulation are proposed. Lipids and metabolites derived from them have been implicated in many of the complex signaling pathways that regulate membrane biogenesis, cell growth and proliferation in higher eukaryotes, including humans. However, the specific roles of individual lipids and related metabolites in these complex cellular processes are often obscured by the complexity of the metabolism involved and by the fact that many potential signaling lipids serve as precursors to other such lipids. Moreover, many of the signals generated during ongoing lipid metabolism are transient and the correct identification of the specific signaling molecule may depend on being able to measure it accurately and observe its flux in the context of active metabolism. The experiments described in this proposal exploit the advantages of the yeast model system and the rapidity of changes in correlated lipid metabolism and signaling to overcome such barriers.

Public Health Relevance

An understanding of the regulation of lipid metabolism is critical in dealing with chronic conditions such as obesity, diabetes, and atherosclerosis. Yeast is an excellent model system for such studies since the relevant pathways are common to yeast and mammals and the major enzymes are homologous, ensuring that insights derived from yeast will generate knowledge relevant to human health.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
2R01GM019629-39A1
Application #
8295227
Study Section
Special Emphasis Panel (ZRG1-BCMB-B (02))
Program Officer
Chin, Jean
Project Start
1987-09-01
Project End
2016-01-31
Budget Start
2012-04-01
Budget End
2013-01-31
Support Year
39
Fiscal Year
2012
Total Cost
$530,105
Indirect Cost
$176,104
Name
Cornell University
Department
Biochemistry
Type
Schools of Earth Sciences/Natur
DUNS #
872612445
City
Ithaca
State
NY
Country
United States
Zip Code
14850
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(ΔNterm) only in combination with Ldb16p. BMC Cell Biol 16:29
Barneda, David; Planas-Iglesias, Joan; Gaspar, Maria L et al. (2015) The brown adipocyte protein CIDEA promotes lipid droplet fusion via a phosphatidic acid-binding amphipathic helix. Elife 4:e07485
Henry, Susan A; Gaspar, Maria L; Jesch, Stephen A (2014) The response to inositol: regulation of glycerolipid metabolism and stress response signaling in yeast. Chem Phys Lipids 180:23-43
Lee, Sojin; Gaspar, Maria L; Aregullin, Manuel A et al. (2013) Activation of protein kinase C-mitogen-activated protein kinase signaling in response to inositol starvation triggers Sir2p-dependent telomeric silencing in yeast. J Biol Chem 288:27861-71
Aung, Hnin W; Henry, Susan A; Walker, Larry P (2013) Revising the Representation of Fatty Acid, Glycerolipid, and Glycerophospholipid Metabolism in the Consensus Model of Yeast Metabolism. Ind Biotechnol (New Rochelle N Y) 9:215-228
Henry, Susan A; Kohlwein, Sepp D; Carman, George M (2012) Metabolism and regulation of glycerolipids in the yeast Saccharomyces cerevisiae. Genetics 190:317-49
Villa-García, Manuel J; Choi, Myung Sun; Hinz, Flora I et al. (2011) Genome-wide screen for inositol auxotrophy in Saccharomyces cerevisiae implicates lipid metabolism in stress response signaling. Mol Genet Genomics 285:125-49
Gaspar, Maria L; Hofbauer, Harald F; Kohlwein, Sepp D et al. (2011) Coordination of storage lipid synthesis and membrane biogenesis: evidence for cross-talk between triacylglycerol metabolism and phosphatidylinositol synthesis. J Biol Chem 286:1696-708
Jesch, Stephen A; Gaspar, Maria L; Stefan, Christopher J et al. (2010) Interruption of inositol sphingolipid synthesis triggers Stt4p-dependent protein kinase C signaling. J Biol Chem 285:41947-60
Fernandez-Murray, J Pedro; Gaspard, Gerard J; Jesch, Stephen A et al. (2009) NTE1-encoded phosphatidylcholine phospholipase b regulates transcription of phospholipid biosynthetic genes. J Biol Chem 284:36034-46

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