European Molecular Biology Laboratorium (EMBL), Structural and Computational Biology Unit, Heidelberg, Germany
Luigi R De La Motte
Section Nephrogenetics, Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany
Kelli Grand
Institute of Anatomy, University of Zurich, Zurich, Switzerland
Anis Mansouri
Institute for Computational Biomedicine, Faculty of Medicine, Heidelberg University, University Hospital Heidelberg, Heidelberg, Germany
Mélanie Parisot
Genomics Core Facility, Institut Imagine-Structure Fédérative de Recherche Necker, INSERM U1163, INSERM US24/CNRS UMS3633, Paris Descartes Sorbonne Paris Cite University, Paris, France
Soeren S Lienkamp
Institute of Anatomy, University of Zurich, Zurich, Switzerland
Julio Saez-Rodriguez
Institute 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, Germany
Section Nephrogenetics, Institute of Human Genetics, University Hospital Heidelberg, Heidelberg, Germany; Molecular Medicine Partnership Unit (MMPU), European Molecular Biology Laboratory (EMBL) and Heidelberg University, Heidelberg, Germany
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.
