Cargando…

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

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 pa...

Descripción completa

Detalles Bibliográficos
Autores principales: Lubojemska, Aleksandra, Stefana, M. Irina, Sorge, Sebastian, Bailey, Andrew P., Lampe, Lena, Yoshimura, Azumi, Burrell, Alana, Collinson, Lucy, Gould, Alex P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121332/
https://www.ncbi.nlm.nih.gov/pubmed/33945525
http://dx.doi.org/10.1371/journal.pbio.3001230
_version_ 1783692319950635008
author Lubojemska, Aleksandra
Stefana, M. Irina
Sorge, Sebastian
Bailey, Andrew P.
Lampe, Lena
Yoshimura, Azumi
Burrell, Alana
Collinson, Lucy
Gould, Alex P.
author_facet Lubojemska, Aleksandra
Stefana, M. Irina
Sorge, Sebastian
Bailey, Andrew P.
Lampe, Lena
Yoshimura, Azumi
Burrell, Alana
Collinson, Lucy
Gould, Alex P.
author_sort Lubojemska, Aleksandra
collection PubMed
description 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.
format Online
Article
Text
id pubmed-8121332
institution National Center for Biotechnology Information
language English
publishDate 2021
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-81213322021-05-24 Adipose triglyceride lipase protects renal cell endocytosis in a Drosophila dietary model of chronic kidney disease Lubojemska, Aleksandra Stefana, M. Irina Sorge, Sebastian Bailey, Andrew P. Lampe, Lena Yoshimura, Azumi Burrell, Alana Collinson, Lucy Gould, Alex P. PLoS Biol Research Article 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. Public Library of Science 2021-05-04 /pmc/articles/PMC8121332/ /pubmed/33945525 http://dx.doi.org/10.1371/journal.pbio.3001230 Text en © 2021 Lubojemska et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Lubojemska, Aleksandra
Stefana, M. Irina
Sorge, Sebastian
Bailey, Andrew P.
Lampe, Lena
Yoshimura, Azumi
Burrell, Alana
Collinson, Lucy
Gould, Alex P.
Adipose triglyceride lipase protects renal cell endocytosis in a Drosophila dietary model of chronic kidney disease
title Adipose triglyceride lipase protects renal cell endocytosis in a Drosophila dietary model of chronic kidney disease
title_full Adipose triglyceride lipase protects renal cell endocytosis in a Drosophila dietary model of chronic kidney disease
title_fullStr Adipose triglyceride lipase protects renal cell endocytosis in a Drosophila dietary model of chronic kidney disease
title_full_unstemmed Adipose triglyceride lipase protects renal cell endocytosis in a Drosophila dietary model of chronic kidney disease
title_short Adipose triglyceride lipase protects renal cell endocytosis in a Drosophila dietary model of chronic kidney disease
title_sort adipose triglyceride lipase protects renal cell endocytosis in a drosophila dietary model of chronic kidney disease
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121332/
https://www.ncbi.nlm.nih.gov/pubmed/33945525
http://dx.doi.org/10.1371/journal.pbio.3001230
work_keys_str_mv AT lubojemskaaleksandra adiposetriglyceridelipaseprotectsrenalcellendocytosisinadrosophiladietarymodelofchronickidneydisease
AT stefanamirina adiposetriglyceridelipaseprotectsrenalcellendocytosisinadrosophiladietarymodelofchronickidneydisease
AT sorgesebastian adiposetriglyceridelipaseprotectsrenalcellendocytosisinadrosophiladietarymodelofchronickidneydisease
AT baileyandrewp adiposetriglyceridelipaseprotectsrenalcellendocytosisinadrosophiladietarymodelofchronickidneydisease
AT lampelena adiposetriglyceridelipaseprotectsrenalcellendocytosisinadrosophiladietarymodelofchronickidneydisease
AT yoshimuraazumi adiposetriglyceridelipaseprotectsrenalcellendocytosisinadrosophiladietarymodelofchronickidneydisease
AT burrellalana adiposetriglyceridelipaseprotectsrenalcellendocytosisinadrosophiladietarymodelofchronickidneydisease
AT collinsonlucy adiposetriglyceridelipaseprotectsrenalcellendocytosisinadrosophiladietarymodelofchronickidneydisease
AT gouldalexp adiposetriglyceridelipaseprotectsrenalcellendocytosisinadrosophiladietarymodelofchronickidneydisease