Reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetes
In diabetic patients, dyslipidemia frequently contributes to organ damage such as diabetic kidney disease (DKD). Dyslipidemia is associated with both excessive deposition of triacylglycerol (TAG) in lipid droplets (LDs) and lipotoxicity. Yet, it is unclear how these two effects correlate with each o...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2022-05-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/74391 |
| _version_ | 1811252172100206592 |
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| author | Albert Pérez-Martí Suresh Ramakrishnan Jiayi Li Aurelien Dugourd Martijn R Molenaar Luigi R De La Motte Kelli Grand Anis Mansouri Mélanie Parisot Soeren S Lienkamp Julio Saez-Rodriguez Matias Simons |
| author_facet | Albert Pérez-Martí Suresh Ramakrishnan Jiayi Li Aurelien Dugourd Martijn R Molenaar Luigi R De La Motte Kelli Grand Anis Mansouri Mélanie Parisot Soeren S Lienkamp Julio Saez-Rodriguez Matias Simons |
| author_sort | Albert Pérez-Martí |
| collection | DOAJ |
| description | In diabetic patients, dyslipidemia frequently contributes to organ damage such as diabetic kidney disease (DKD). Dyslipidemia is associated with both excessive deposition of triacylglycerol (TAG) in lipid droplets (LDs) and lipotoxicity. Yet, it is unclear how these two effects correlate with each other in the kidney and how they are influenced by dietary patterns. By using a diabetes mouse model, we find here that high-fat diet enriched in the monounsaturated oleic acid (OA) caused more lipid storage in LDs in renal proximal tubular cells (PTCs) but less tubular damage than a corresponding butter diet with the saturated palmitic acid (PA). This effect was particularly evident in S2/S3 but not S1 segments of the proximal tubule. Combining transcriptomics, lipidomics, and functional studies, we identify endoplasmic reticulum (ER) stress as the main cause of PA-induced PTC injury. Mechanistically, ER stress is caused by elevated levels of saturated TAG precursors, reduced LD formation, and, consequently, higher membrane order in the ER. Simultaneous addition of OA rescues the cytotoxic effects by normalizing membrane order and increasing both TAG and LD formation. Our study thus emphasizes the importance of monounsaturated fatty acids for the dietary management of DKD by preventing lipid bilayer stress in the ER and promoting TAG and LD formation in PTCs. |
| first_indexed | 2024-04-12T16:30:52Z |
| format | Article |
| id | doaj.art-377e2b91e28b44ed87a64cd0b82e2ce3 |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T16:30:52Z |
| publishDate | 2022-05-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-377e2b91e28b44ed87a64cd0b82e2ce32022-12-22T03:25:08ZengeLife Sciences Publications LtdeLife2050-084X2022-05-011110.7554/eLife.74391Reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetesAlbert Pérez-Martí0https://orcid.org/0000-0003-3234-3756Suresh Ramakrishnan1Jiayi Li2Aurelien Dugourd3https://orcid.org/0000-0002-0714-028XMartijn R Molenaar4https://orcid.org/0000-0001-5221-608XLuigi R De La Motte5Kelli Grand6Anis Mansouri7Mélanie Parisot8Soeren S Lienkamp9Julio Saez-Rodriguez10Matias Simons11https://orcid.org/0000-0003-3959-6350Section Nephrogenetics, Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, GermanySection Nephrogenetics, Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, GermanySection Nephrogenetics, Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, GermanyInstitute for Computational Biomedicine, Faculty of Medicine, Heidelberg University, University Hospital Heidelberg, Heidelberg, GermanyEuropean Molecular Biology Laboratorium (EMBL), Structural and Computational Biology Unit, Heidelberg, GermanySection Nephrogenetics, Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, GermanyInstitute of Anatomy, University of Zurich, Zurich, SwitzerlandInstitute for Computational Biomedicine, Faculty of Medicine, Heidelberg University, University Hospital Heidelberg, Heidelberg, GermanyGenomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163, INSERM US24/CNRS UMS3633, Paris Descartes Sorbonne Paris Cite University, Paris, FranceInstitute of Anatomy, University of Zurich, Zurich, SwitzerlandInstitute for Computational Biomedicine, Faculty of Medicine, Heidelberg University, University Hospital Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit (MMPU), European Molecular Biology Laboratory (EMBL) and Heidelberg University, Heidelberg, GermanySection Nephrogenetics, Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit (MMPU), European Molecular Biology Laboratory (EMBL) and Heidelberg University, Heidelberg, GermanyIn diabetic patients, dyslipidemia frequently contributes to organ damage such as diabetic kidney disease (DKD). Dyslipidemia is associated with both excessive deposition of triacylglycerol (TAG) in lipid droplets (LDs) and lipotoxicity. Yet, it is unclear how these two effects correlate with each other in the kidney and how they are influenced by dietary patterns. By using a diabetes mouse model, we find here that high-fat diet enriched in the monounsaturated oleic acid (OA) caused more lipid storage in LDs in renal proximal tubular cells (PTCs) but less tubular damage than a corresponding butter diet with the saturated palmitic acid (PA). This effect was particularly evident in S2/S3 but not S1 segments of the proximal tubule. Combining transcriptomics, lipidomics, and functional studies, we identify endoplasmic reticulum (ER) stress as the main cause of PA-induced PTC injury. Mechanistically, ER stress is caused by elevated levels of saturated TAG precursors, reduced LD formation, and, consequently, higher membrane order in the ER. Simultaneous addition of OA rescues the cytotoxic effects by normalizing membrane order and increasing both TAG and LD formation. Our study thus emphasizes the importance of monounsaturated fatty acids for the dietary management of DKD by preventing lipid bilayer stress in the ER and promoting TAG and LD formation in PTCs.https://elifesciences.org/articles/74391diabetic nephropathyproximal tubuleslipotoxicityER stressmembrane orderlipid bilayer stress |
| spellingShingle | Albert Pérez-Martí Suresh Ramakrishnan Jiayi Li Aurelien Dugourd Martijn R Molenaar Luigi R De La Motte Kelli Grand Anis Mansouri Mélanie Parisot Soeren S Lienkamp Julio Saez-Rodriguez Matias Simons Reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetes eLife diabetic nephropathy proximal tubules lipotoxicity ER stress membrane order lipid bilayer stress |
| title | Reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetes |
| title_full | Reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetes |
| title_fullStr | Reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetes |
| title_full_unstemmed | Reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetes |
| title_short | Reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetes |
| title_sort | reducing lipid bilayer stress by monounsaturated fatty acids protects renal proximal tubules in diabetes |
| topic | diabetic nephropathy proximal tubules lipotoxicity ER stress membrane order lipid bilayer stress |
| url | https://elifesciences.org/articles/74391 |
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