RRC ID 70800
Author Lubojemska A, Stefana MI, Sorge S, Bailey AP, Lampe L, Yoshimura A, Burrell A, Collinson L, Gould AP.
Title Adipose triglyceride lipase protects renal cell endocytosis in a Drosophila dietary model of chronic kidney disease.
Journal PLoS Biol
Abstract Obesity-related renal lipotoxicity and chronic kidney disease (CKD) are prevalent pathologies with complex aetiologies. One hallmark of renal lipotoxicity is the ectopic accumulation of lipid droplets in kidney podocytes and in proximal tubule cells. Renal lipid droplets are observed in human CKD patients and in high-fat diet (HFD) rodent models, but their precise role remains unclear. Here, we establish a HFD model in Drosophila that recapitulates renal lipid droplets and several other aspects of mammalian CKD. Cell type-specific genetic manipulations show that lipid can overflow from adipose tissue and is taken up by renal cells called nephrocytes. A HFD drives nephrocyte lipid uptake via the multiligand receptor Cubilin (Cubn), leading to the ectopic accumulation of lipid droplets. These nephrocyte lipid droplets correlate with endoplasmic reticulum (ER) and mitochondrial deficits, as well as with impaired macromolecular endocytosis, a key conserved function of renal cells. Nephrocyte knockdown of diglyceride acyltransferase 1 (DGAT1), overexpression of adipose triglyceride lipase (ATGL), and epistasis tests together reveal that fatty acid flux through the lipid droplet triglyceride compartment protects the ER, mitochondria, and endocytosis of renal cells. Strikingly, boosting nephrocyte expression of the lipid droplet resident enzyme ATGL is sufficient to rescue HFD-induced defects in renal endocytosis. Moreover, endocytic rescue requires a conserved mitochondrial regulator, peroxisome proliferator-activated receptor-gamma coactivator 1α (PGC1α). This study demonstrates that lipid droplet lipolysis counteracts the harmful effects of a HFD via a mitochondrial pathway that protects renal endocytosis. It also provides a genetic strategy for determining whether lipid droplets in different biological contexts function primarily to release beneficial or to sequester toxic lipids.
Volume 19(5)
Pages e3001230
Published 2021-5-1
DOI 10.1371/journal.pbio.3001230
PMID 33945525
PMC PMC8121332
MeSH Adipose Tissue / metabolism Animals Diet, High-Fat / adverse effects Disease Models, Animal Drosophila Proteins / metabolism Drosophila melanogaster / metabolism Endocytosis / physiology Epithelial Cells / metabolism Fatty Acids / metabolism Humans Kidney / pathology Lipase / metabolism* Lipase / physiology Lipid Droplets / metabolism* Lipid Droplets / physiology Lipid Metabolism / physiology Lipids / physiology Mitochondria / metabolism Obesity / complications Renal Insufficiency, Chronic / metabolism* Renal Insufficiency, Chronic / physiopathology Triglycerides / metabolism
IF 7.076