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Abstract: TH-PO728

A Unique Mutation in the MODY1 Gene HNF4A Causes Fanconi Syndrome by Shifting Lipid Catabolism to Anabolism

Session Information

Category: Genetic Diseases of the Kidney

  • 1002 Genetic Diseases of the Kidney: Non-Cystic

Authors

  • Marchesin, Valentina, Institut Imagine, Paris, France
  • Perez-Marti, Albert, Institut Imagine, Paris, France
  • Simons, Matias, Institut Imagine, Paris, France
Background

Renal proximal tubular cells (PTCs) have the task to reabsorb most of water, solutes and proteins filtered by the glomerulus. To cope with their high energy demand, PTCs exclusively rely on fatty acid oxidation. However, lipid metabolism needs to be finely regulated in this tissue as recent evidence has suggested that renal lipid accumulation and lipotoxicity may lead to kidney dysfunction. Here, we focus on the function of the nuclear hormone receptor HNF4A whose mutations cause MODY1, a monogenic type of diabetes in humans. Only one mutation (p.R85W) in the DNA binding domain leads to additional PTC dysfunction (also known as Fanconi syndrome), but the reason for this is unclear.

Methods

To address the role of HNF4A in lipid metabolism and to illuminate the pathogenetic mechanisms underlying the R85W mutation, we made use of the Drosophila model. In particular, we utilized fly nephrocytes as a simplified cell model for PTCs.

Results

We show that HNF4A controls a genetic program that regulates lipid metabolism in nephrocytes. Silencing HNF4A causes an increase in lipid droplet size and number, while the overexpression of HNF4A causes depletion of lipid stores through brummer/ATGL-mediated neutral lipolysis. Interestingly, very high expression levels of HNF4A or the expression of the R85W mutation behave in a dominant-negative fashion by triggering a shift from lipid catabolism to lipid anabolism. In addition to a lipolysis block, this involves the increased DGAT1-dependent formation of lipid droplets. In both conditions, the lack of lipolysis leads to mitochondrial depolarization, possibly due to the decreased availability of free fatty acids and lack of ATP production. The mitochondrial damage is accompanied by the accumulation of ER fragmentation, p62- and PDI-positive protein aggregates and a strong induction of autophagy. Collectively, these organellar injuries eventually lead to nephrocyte loss and shorten the life span of flies.

Conclusion

Altogether, our data describe a novel pathogenetic mechanism for Fanconi syndrome with important implications for the general understanding of lipid metabolism in PTCs. Moreover, targeting HNF4A or one of its downstream partners could represent a very useful therapeutic strategy in situations with lipid overload in the PTCs.

Funding

  • Government Support - Non-U.S.