DataSheet1_Drosophila Lipase 3 Mediates the Metabolic Response to Starvation and Aging.pdf

The human LIPA gene encodes for the enzyme lysosomal acid lipase, which hydrolyzes cholesteryl ester and triacylglycerol. Lysosomal acid lipase deficiency results in Wolman disease and cholesteryl ester storage disease. The Drosophila genome encodes for two LIPA orthologs, Magro and Lipase 3. Magro is a gut lipase that hydrolyzes triacylglycerides, while Lipase 3 lacks characterization based on mutant phenotypes. We found previously that Lipase 3 transcription is highly induced in mutants with defects in peroxisome biogenesis, but the conditions that allow a similar induction in wildtypic flies are not known. Here we show that Lipase 3 is drastically upregulated in starved larvae and starved female flies, as well as in aged male flies. We generated a lipase 3 mutant that shows sex-specific starvation resistance and a trend to lifespan extension. Using lipidomics, we demonstrate that Lipase 3 mutants accumulate phosphatidylinositol, but neither triacylglycerol nor diacylglycerol. Our study suggests that, in contrast to its mammalian homolog LIPA, Lipase 3 is a putative phospholipase that is upregulated under extreme conditions like prolonged nutrient deprivation and aging.

人类LIPA基因编码溶酶体酸性脂肪酶（lysosomal acid lipase），该酶可水解胆固醇酯与三酰甘油。溶酶体酸性脂肪酶缺乏症会导致沃尔曼病（Wolman disease）与胆固醇酯贮积病（cholesteryl ester storage disease）。果蝇基因组编码两个LIPA同源基因：Magro与脂肪酶3（Lipase 3）。其中Magro为肠道脂肪酶，可水解三酰甘油；而目前尚无基于突变表型的脂肪酶3功能表征。我们此前的研究发现，过氧化物酶体生物发生缺陷的突变体中，脂肪酶3的转录会被显著诱导，但在野生型果蝇中实现类似诱导的条件仍不明确。本研究发现，脂肪酶3在饥饿幼虫、饥饿雌性果蝇以及老年雄性果蝇中均被显著上调。我们构建了脂肪酶3突变体，该突变体表现出性别特异性的饥饿抗性，且呈现出寿命延长的趋势。利用脂质组学（lipidomics）技术，我们证实脂肪酶3突变体会积累磷脂酰肌醇（phosphatidylinositol），但不会积累三酰甘油与二酰甘油。本研究表明，与哺乳动物同源基因LIPA不同，脂肪酶3是一种推定的磷脂酶，会在长期营养剥夺与衰老等极端条件下被上调。