Adipose triglyceride lipase protects renal cell endocytosis in a Drosophila dietary model of chronic kidney disease

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.

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

“…It will be interesting to determine whether in these instances ATGL also acts via AA release to drive PG production. Finally, ectopic ATGL expression has beneficial roles in two Drosophila disease models: neurodegeneration due to mitochondrial dysfunction (Liu et al ., 2015) and impairment of nephrocytes, components of the renal system, due to high fat diet (Lubojemska et al ., 2021). Here, tissue-specific overexpression of ATGL in glia or nephrocytes, respectively, reverts disease-induced LD accumulation as well as disease phenotypes.…”

“…In males, ATGL function in neurons and testes regulates whole-body energy storage by an as-yet uncharacterized mechanism thought to involve systemic signaling. And ectopic ATGL expression has beneficial roles in two Drosophila disease models, neurodegeneration due to mitochondrial dysfunction [79] and impairment of nephrocytes, components of the renal system, due to high fat diet [80]. Here, tissue-specific overexpression of ATGL in glia or nephrocytes, respectively, reverts disease-induced LD accumulation as well as disease phenotypes.…”

High-Fat Diet-Induced Renal Proximal Tubular Inflammatory Injury: Emerging Risk Factor of Chronic Kidney Disease

“…As known, mitochondria mainly provide ATP and energy to maintain cellular homeostasis and regulate the communication between cells and tissues. Recent studies showed that mitochondria play an important role in HFD-induced renal inflammatory injury ( Sun et al, 2020 ; Han et al, 2021 ; Lubojemska et al, 2021 ). Mitochondrial dysfunction-induced by HFD is related to mitochondrial fatty acid oxidative (FAO) impairment, dynamic change (e.g., mitochondrial fission and fusion) and mitophagy deficiency.…”

Metabolic decisions in development and disease

“…Many other speakers turned to Drosophila as a model to study the impact of diet on development and disease. Alex Gould (Francis Crick Institute, London, UK) presented a high-fat diet (HFD) model of chronic kidney disease in Drosophila (Lubojemska et al, 2021). He showed that lipid droplet (LD) accumulation in HFD decreases mitochondrial volume in nephrocytes and compromises endocytosis.…”