The endoribonuclease Arlr is required to maintain lipid homeostasis by downregulating lipolytic genes during aging

While disorders in lipid metabolism have been associated with aging and age-related diseases, how lipid metabolism is regulated during aging is poorly understood. Here, we characterize the Drosophila endoribonuclease CG2145, an ortholog of mammalian EndoU that we named Age-related lipid regulator (Arlr), as a regulator of lipid homeostasis during aging. In adult adipose tissues, Arlr is necessary for maintenance of lipid storage in lipid droplets (LDs) as flies age, a phenotype that can be rescued by either high-fat or high-glucose diet. Interestingly, RNA-seq of arlr mutant adipose tissues and RIP-seq suggest that Arlr affects lipid metabolism through the degradation of the mRNAs of lipolysis genes - a model further supported by the observation that knockdown of Lsd-1, regucalcin, yip2 or CG5162, which encode genes involved in lipolysis, rescue the LD defects of arlr mutants. In addition, we characterize DendoU as a functional paralog of Arlr and show that human ENDOU can rescue arlr mutants. Altogether, our study reveals a role of ENDOU-like endonucleases as negative regulator of lipolysis. Fat is generally considered to have a negative effect on longevity but lipids can be beneficial for longevity. Here the authors show that fly Arlr endoribonuclease affects lipid metabolism by degrading the mRNAs of lipolysis genes.

Automated summary

This study demonstrates the role of the Drosophila endoribonuclease CG2145 (Arlr) in regulating lipid metabolism. Arlr affects lipid homeostasis by degrading the mRNAs of lipolysis genes and this phenotype can be rescued by high-fat or high-glucose diet.