Phosphatidic acid phosphatase (PAP) catalyzes the dephosphorylation of phosphatidic acid (PA) to yield diacylglycerol (DAG) and Pi. The DAG generated in the reaction is used for the synthesis of triacylglycerol (TAG), and for the synthesis of phosphatidylethanolamine and phosphatidylcholine via the Kennedy pathway. By the nature of its reaction, PAP also controls the cellular content of PA, which is the precursor of phospholipids synthesized via the CDP-DAG pathway. PA is also a signaling molecule that triggers phospholipid synthesis gene expression, membrane expansion, vesicular trafficking, secretion, and endocytosis. Biochemical and genetic studies to establish the roles of PAP in lipid metabolism became possible by our discoveries of the PAP-encoding genes from the yeast Saccharomyces cerevisiae (e.g., PAH1) and mammals (e.g., LPIN1). The importance PAP in lipid metabolism is exemplified by its mutant phenotypes. In yeast, pah1 mutants exhibit defects in the transcriptional regulation of phospholipid synthesis genes, the anomalous expansion of the nuclear/ER membrane, and a 90 % reduction in TAG content in stationary phase cells. Studies with mice and humans have shown that genetic defects in lipin 1 and lipin 2 are manifested in several metabolic diseases that include lipodystrophy, obesity, peripheral neuropathy, myoglobinuria, and inflammation. In the next grant period, we will focus on the regulated expression of the yeast PAH1-encoded PAP enzyme during growth and its role in lipid metabolism (specific aim 1). In addition, we will expand our studies on PAP to include the enzymology and biochemical regulation of the human LPIN1-, LPIN2-, and LPIN3-encoded PAP isoforms (specific aim 2). We also discovered a novel CTP-dependent DGK1-encoded DAG kinase in yeast that counterbalanced the activity of PAP to control the cellular contents of PA and DAG. The dgk1 mutation suppresses phenotypes caused by the pah1 mutation, whereas the overexpression of DAG kinase blunts phenotypes caused by the overexpression of PAP. In yeast, TAG hydrolysis (e.g., lipolysis) to DAG and fatty acids is a prerequisite for membrane phospholipid synthesis and resumption of growth from the stationary phase. We will examine the role and regulation of the DGK1-encoded DAG kinase enzyme in this metabolism (specific aim 3).
The activities of phosphatidic acid phosphatase and diacylglycerol kinase control the cellular balance of phosphatidic acid and diacylglycerol, which are lipid precursors used for the synthesis of membrane phospholipids and triacylglycerol. Phosphatidic acid is also a signaling molecule that triggers phospholipid synthesis gene expression, membrane expansion, secretion, and endocytosis. Genetic defects of phosphatidic acid phosphatase in yeast, mice, and humans are manifested in metabolic disorders that include lipodystrophy, obesity, peripheral neuropathy, myoglobinuria, and inflammation.
|Qiu, Yixuan; Hassaninasab, Azam; Han, Gil-Soo et al. (2016) Phosphorylation of Dgk1 Diacylglycerol Kinase by Casein Kinase II Regulates Phosphatidic Acid Production in Saccharomyces cerevisiae. J Biol Chem 291:26455-26467|
|Merrill Jr, Alfred H; Carman, George M (2015) Introduction to Thematic Minireview Series: Novel Bioactive Sphingolipids. J Biol Chem 290:15362-4|
|Park, Yeonhee; Han, Gil-Soo; Mileykovskaya, Eugenia et al. (2015) Altered Lipid Synthesis by Lack of Yeast Pah1 Phosphatidate Phosphatase Reduces Chronological Life Span. J Biol Chem 290:25382-94|
|Hsieh, Lu-Sheng; Su, Wen-Min; Han, Gil-Soo et al. (2015) Phosphorylation regulates the ubiquitin-independent degradation of yeast Pah1 phosphatidate phosphatase by the 20S proteasome. J Biol Chem 290:11467-78|
|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|
|McMahon, Derek; Dinh, Anna; Kurz, Daniel et al. (2014) Comparative gene identification 58/Î±/Î² hydrolase domain 5 lacks lysophosphatidic acid acyltransferase activity. J Lipid Res 55:1750-61|
|Pascual, Florencia; Hsieh, Lu-Sheng; Soto-Cardalda, AnÃbal et al. (2014) Yeast Pah1p phosphatidate phosphatase is regulated by proteasome-mediated degradation. J Biol Chem 289:9811-22|
|Chae, Minjung; Carman, George M (2013) Characterization of the yeast actin patch protein App1p phosphatidate phosphatase. J Biol Chem 288:6427-37|
|Michot, Caroline; Mamoune, Asmaa; Vamecq, Joseph et al. (2013) Combination of lipid metabolism alterations and their sensitivity to inflammatory cytokines in human lipin-1-deficient myoblasts. Biochim Biophys Acta 1832:2103-14|
|Gallo-Ebert, Christina; Donigan, Melissa; Liu, Hsing-Yin et al. (2013) The yeast anaerobic response element AR1b regulates aerobic antifungal drug-dependent sterol gene expression. J Biol Chem 288:35466-77|
Showing the most recent 10 out of 31 publications