Phosphatidate Phosphatase Activity Plays Key Role in Protection against Fatty Acid-induced Toxicity in Yeast
Phosphatidate Phosphatase Activity Plays Key Role in Protection against Fatty Acid-induced Toxicity in Yeast
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DOI：
10.1074/jbc.m111.258798
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发表时间：
2011-08-19
影响因子：
4.8
通讯作者：
Carman, George M.
中科院分区：
文献类型：
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作者：
Fakas, Stylianos;Qiu, Yixuan;Carman, George M.
酿酒酵母中的PAH 1编码的磷脂酸（PA）磷酸酶是一种关键酶，其产生用于合成三酰甘油（TAG）的二酰甘油，同时控制用于磷脂合成的PA水平。定量脂质分析表明，pah1 Delta突变导致TAG质量减少，磷脂和游离脂肪酸质量升高，这些变化在稳定期更为明显。不饱和脂肪酸在pah1三角洲突变体的水平没有改变，虽然棕榈油酸的比例增加了类似的变化，在磷脂的脂肪酸组成。pah1 Delta突变体在稳定期表现出典型的凋亡特征，细胞质脂滴数量显著减少。缺乏PA磷酸酶的细胞对外源脂肪酸的敏感性顺序为棕榈油酸>油酸>棕榈酸。相反，野生型细胞的生长不受脂肪酸补充的抑制。此外，补充棕榈油酸的野生型细胞表现出PA磷酸酶活性的诱导和TAG合成的增加。DGK1编码的甘油二酯激酶（其在控制PA含量中抵消PA磷酸酶）的缺失抑制了pah1 Delta突变体中脂滴形成的缺陷。然而，pah1 Delta突变体对棕榈油酸的敏感性并没有被dgk1 Delta突变所挽救。总体而言，这些发现表明PA磷酸酶在TAG合成中的关键作用，以保护免受脂肪酸诱导的毒性。
The PAH1-encoded phosphatidate (PA) phosphatase in Saccharomyces cerevisiae is a pivotal enzyme that produces diacylglycerol for the synthesis of triacylglycerol (TAG) and simultaneously controls the level of PA used for phospholipid synthesis. Quantitative lipid analysis showed that the pah1 Delta mutation caused a reduction in TAG mass and an elevation in the mass of phospholipids and free fatty acids, changes that were more pronounced in the stationary phase. The levels of unsaturated fatty acids in the pah1 Delta mutant were unaltered, although the ratio of palmitoleic acid to oleic acid was increased with a similar change in the fatty acid composition of phospholipids. The pah1 Delta mutant exhibited classic hallmarks of apoptosis in stationary phase and a marked reduction in the quantity of cytoplasmic lipid droplets. Cells lacking PA phosphatase were sensitive to exogenous fatty acids in the order of toxicity palmitoleic acid > oleic acid > palmitic acid. In contrast, the growth of wild type cells was not inhibited by fatty acid supplementation. In addition, wild type cells supplemented with palmitoleic acid exhibited an induction in PA phosphatase activity and an increase in TAG synthesis. Deletion of the DGK1-encoded diacylglycerol kinase, which counteracts PA phosphatase in controlling PA content, suppressed the defect in lipid droplet formation in the pah1 Delta mutant. However, the sensitivity of the pah1 Delta mutant to palmitoleic acid was not rescued by the dgk1 Delta mutation. Overall, these findings indicate a key role of PA phosphatase in TAG synthesis for protection against fatty acid-induced toxicity.