Abstract
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.
Highlights
Caloric restriction and intermittent fasting induce transcriptional programs that lead to break-down of storage fat and glycogen and induce autophagy
This is in contrast to other lipases like Brummer, Lip1, Lip4 and Magro, that are transcriptionally regulated by Foxo (Grönke et al, 2005; Vihervaara and Puig, 2008; Karpac et al, 2013; Molaei et al, 2019): Magro is downregulated in old flies (Karpac et al, 2013), and downregulation of Brummer extends lifespan (Nazario-Yepiz et al, 2021)
We propose that signaling pathways with different effectors than Foxo mediate the response to prolonged starvation, and that regulation of these pathways is affected in aging
Summary
Caloric restriction and intermittent fasting induce transcriptional programs that lead to break-down of storage fat and glycogen and induce autophagy. The latter functions as a self-renewal program to the cell and is accepted as one of the drivers of lifespan extension and the health-promoting effects of dietary restriction (Madeo et al, 2015). Lipases are important effectors of the response to starvation by mobilizing lipid stores such as triacylglycerides. Lipid mobilization takes place already after short periods of nutrient restriction to maintain the supply of the brain when glucose is limiting (Izumida et al, 2013). Lipases that regulate phospholipids in the brain increase in age-related neurodegenerative diseases (Oliveira and Di Paolo, 2010)
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