Drosophila Lipase 3 Mediates the Metabolic Response to Starvation and Aging

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.

The transcriptomic signature of responses to larval crowding in Drosophila melanogaster

“…This is in agreement with recent findings showing that Lip3 is upregulated under responses to extreme dietary stress (starvation) (Hänschke et al. , 2022). Interestingly Klepsatel et al.…”

“…For instance, we found that steroid metabolism was upregulated, including lipases Lip3 and Lip4. This is in agreement with recent findings showing that Lip3 is upregulated under responses to extreme dietary stress (starvation) (Hänschke et al, 2022). Interestingly Klepsatel et al (2018) reported that flies that had developed under high larval density had reduced protein content and were fatter than the flies from standard density.…”

The remoulding of dietary effects on the fecundity / longevity trade-off in a social insect

“…The effect on lifespan varies between different genes. A knockdown of the triglyceride lipase brummer leads to a shortened lifespan in D. melanogaster [ 52 ] while lipase 3 is upregulated in starved and aged flies and has been associated with a shortened lifespan [ 53 ]. Regarding fecundity, there are studies linking triglyceride lipase activity positively to fecundity in Drosophila [ 54 – 56 ].…”

Transcriptomic analysis of cave, surface, and hybrid samples of the isopod Asellus aquaticus and identification of chromosomal location of candidate genes for cave phenotype evolution

“…Another cave-biased gene Blasted to lipase 1 in Tribolium but lipase 3 in Homarus americanus . Lipase 3 was recently shown to be upregulated in starved D. melanogaster larvae and in aged adult males suggesting a role for lipase 3 in starvation resistance and aging [ 33 ]. Ten genes showed surface-biased expression in F 1 hybrids of A. aquaticus , including two paralogs of dopamine N-acetyltransferase , aanat2 by Blast search, which has many functions including pigmentation and melatonin production [ 34 ].…”