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Abstract: TH-PO611

Monounsaturated Fatty Acids Protect Proximal Tubules from Lipotoxicity

Session Information

Category: Health Maintenance, Nutrition, and Metabolism

  • 1301 Health Maintenance, Nutrition, and Metabolism: Basic

Authors

  • Perez-Marti, Albert, Institut Imagine, Paris, France
  • Mollet, Geraldine, Institut Imagine, Paris, France
  • Antignac, Corinne, Institut Imagine, Paris, France
  • Simons, Matias, Institut Imagine, Paris, France
Background

A disrupted glomerular filtration barrier, such as in nephrotic syndrome, causes loss of serum albumin into the urine. As albumin is an important carrier of fatty acids (FAs), the increased exposure of the tubular nephron to FAs may contribute to disease progression. This is particularly the case for FAs such as palmitic acid (PA) as their saturated acyl chains are known to damage the endoplasmic reticulum (ER) and mitochondria. To cope with excess lipids, FAs can be esterified with glycerol and deposited as triglycerides in cytoplasmic lipid droplets (LD). Here, we addressed the question in how far lipid unsaturation promotes lipid storage and thereby prevents lipotoxicity in proximal tubular cells.

Methods

In vitro experiments with PA and oleic acid (OA) were performed on iREC (induced renal tubular epithelial cells) and HK-2 cells. The inducible conditional knockout mouse of Nphs2 was used as an in vivo model of nephrotic syndrome. Mice were maintained on MUFA (monounsaturated fatty acids) or SFA (saturated fatty acids) diets two weeks before Cre induction until death.

Results

To mimic the overexposure of proximal tubules to albumin that takes place during nephrotic syndrome, iRECs were treated with different doses of albumin-FAs. While the treatment with PA-BSA resulted in the upregulation of ER stress markers and decreased cell survival, the additional treatment with OA-BSA completely rescued the phenotypes. To assess the capacity of OA to sequester saturated FAs into LDs, we analyzed lipid droplet formation. In contrast to PA, OA increased LD formation, which occurred in a DGAT1/2 dependent manner. Moreover, lipid trafficking studies with the fluorescent analog of a saturated fatty acid BODIPY-C12 showed that co-treatment with OA shifted BODIPY-C12 from the ER into LDs. Finally, our preliminary in vivo data suggest that Nphs2 KO mice live longer with MUFA diet compared to SFA diet.

Conclusion

Collectively, our work shows that OA protects renal tubular cells from lipotoxicity by channeling PA into LDs. Our findings suggest that promotion of unsaturation and, thereby, lipid storage can improve the homeostasis of PTs during nephrotic syndrome and, thus, ameliorate the progression of the disease.

Funding

  • Private Foundation Support