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 regulation of carnitine palmitoyltransferase 1 (CPT1) mRNA splicing by nutrient availability in Drosophila fat tissue

“…We focused on starvation as previous work in Drosophila has shown that lipid levels decrease during starvation ultimately leading to death of the flies starting from 48 to 72 h after the onset of starvation, depending on the genetic background and lipid storage [ 18 , 20 ]. Consistent with the decrease in lipids during starvation, the expression of the lipid breakdown gene Lipase 3 increases during starvation [ 21 ]; however, whether other lipid breakdown genes like CPT1 were regulated by starvation was not fully understood. We found that a 24-h starvation period induces the preferential inclusion of exon 6A in CPT1 transcripts.…”

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 ].…”