Hormone-sensitive lipase couples intergenerational sterol metabolism to reproductive success

Abstract

Triacylglycerol (TG) and steryl ester (SE) lipid storage is a universal strategy to maintain organismal energy and membrane homeostasis. Cycles of building and mobilizing storage fat are fundamental in (re)distributing lipid substrates between tissues or to progress ontogenetic transitions. In this study we show that Hormone-sensitive lipase (Hsl) specifically controls SE mobilization to initiate intergenerational sterol transfer in Drosophila melanogaster. Tissue-autonomous Hsl functions in the maternal fat body and germline coordinately prevent adult SE overstorage and maximize sterol allocation to embryos. While Hsl-deficiency is largely dispensable for normal development on sterol-rich diets, animals depend on adipocyte Hsl for optimal fecundity when dietary sterol becomes limiting. Notably, accumulation of SE but not of TG is a characteristic of Hsl-deficient cells across phyla including murine white adipocytes. In summary, we identified Hsl as an ancestral regulator of SE degradation, which improves intergenerational sterol transfer and reproductive success in flies.

The sugar-responsive enteroendocrine neuropeptide F regulates lipid metabolism through glucagon-like and insulin-like hormones in Drosophila melanogaster

“…In the fat body of D. melanogaster, two major lipases, Bmm and Drosophila hormone sensitive lipase (dHSL), homologues of human adipose triglyceride lipase (ATGL), are involved in regulating TAG amount 19,44,45 . The activities of both Bmm and dHSL are regulated by AKH-AKHR signalling, while their regulatory mechanisms are substantially different 19,20,[45][46][47] . We observed an increase in Bmm mRNA expression in loss of NPF function animals (Fig.…”

Adipose triglyceride lipase promotes prostaglandin-dependent actin remodeling by regulating substrate release from lipid droplets

“…Jabba recruits numerous proteins to LDs [32, 33], which might include lipases or their regulators, such as the ATGL paralog Dob [42] or a cPLA2 ortholog. Another intriguing candidate is Hsl, an enzyme involved in the breakdown of sterol esters in Drosophila [83]. Hsl is among the most abundant proteins on maternally inherited LDs of early embryos [32], and its substrates, sterol esters, are present in ovary LDs (Fig 1K and 8E-8F).…”

Drosophila melanogaster females prioritise dietary sterols for producing high quality eggs

“…Our data support this concept since they indicate that female flies prioritise their supply of sterols to sustain high-quality reproduction whatever the cost to maternal lifespan. Flies likely maintain this level of optimal fecundity by first utilising as many resources from the diet as possible and secondly, by supplementing it from sterols stored in body tissues (Heier et al, 2021). Such a concept is curious as it suggests that DR may alter lifespan by stalling a program of tissue repurposing, which is in stark contrast to traditional models of ageing that envisage death as a side effect of random molecular damage (Kirkwood, 2005).…”

“…In contrast, when dietary yeast is low, the fall in P:C ratio would lower reproduction to a level such that the damage it inflicts could be met by the small amounts of sterols that are provided in the food. Under this scenario, because limiting sterols are prioritised for somatic maintenance over reproduction, the higher P:C diets that elevate egg laying and shorten lifespan should be accompanied by the production of sterol depleted eggs, which compromises their viability (Heier et al, 2021).…”