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

Nature Communications · 5 authors, 3 centres

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TL;DR

In Drosophila, the endoribonuclease Arlr degrades mRNAs of lipolytic genes to maintain lipid droplet storage in adipose tissues during aging. Knockdown of lipolytic genes rescues the lipid defects of arlr mutants, and human ENDOU can compensate for loss of arlr.

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This preclinical study in Drosophila melanogaster characterized the endoribonuclease Arlr (CG2145), an ortholog of mammalian EndoU, as a regulator of lipid homeostasis during aging. Using RNA-seq, RIP-seq, and genetic knockdown/rescue experiments in adult adipose tissues, the authors demonstrated that Arlr is necessary for maintenance of lipid storage in lipid droplets as flies age. Arlr binds to and promotes degradation of mRNAs encoding lipolytic genes. Knockdown of four lipolytic genes—Lsd-1, CG5162, yip2, and regucalcin—rescued the lipid droplet defects of arlr mutants. Loss of arlr led to accelerated lipid consumption and reduced lifespan under both standard food and starvation conditions, which could be rescued by high-fat or high-glucose diet. Human ENDOU expression also rescued arlr mutants, indicating conserved function.

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other

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preclinical research

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ORIGINAL PAPER

PMC10558556

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

Nature Communications

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ABSTRACT

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.

CITATION EXPORT

Xiaowei Sun, Jie Shen, Norbert Perrimon et al.. The endoribonuclease Arlr is required to maintain lipid homeostasis by downregulating lipolytic genes during aging. Nature Communications. (2023). https://doi.org/10.1038/s41467-023-42042-7

AUTHORS

5 · 3 CENTRES

Xiaowei Sun, Jie Shen, Norbert Perrimon, Xue Kong, Dan Wang

1https://ror.org/04v3ywz14grid.22935.3f0000 0004 0530 8290Department of Plant Biosecurity and MARA Key Laboratory of Surveillance and Management for Plant Quarantine Pests, College of Plant Protection, China Agricultural University, Beijing, China
2grid.38142.3c000000041936754XDepartment of Genetics, Blavatnik Institute, Harvard Medical School, Boston, MA USA
3https://ror.org/006w34k90grid.413575.10000 0001 2167 1581Howard Hughes Medical Institute, Boston, MA USA