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Abstract: FR-OR39

The Transcription Factor ChREBP Links Mitochondrial Lipidomes to Mitochondrial Morphology and Progression of Diabetic Kidney Disease

Session Information

Category: Diabetic Kidney Disease

  • 701 Diabetic Kidney Disease: Basic

Authors

  • Long, Jianyin, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
  • Li, Li, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
  • Mise, Koki, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
  • Chang, Benny B., The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
  • Danesh, Farhad R., The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
Background

Recent studies have suggested that both mitochondrial dynamics and lipid metabolism contribute to the pathogenesis of diabetic kidney disease (DKD). However, the precise interplay between these two key metabolic regulators is not fully understood. We recently showed that the expression of carbohydrate-response element-binding protein (ChREBP), a glucose-responsive transcription factor and a master regulator of lipogenesis, is induced by high glucose in podocytes (J Long, et al, JBC 2020). Here we examine the role of ChREBP on progression of DKD in vivo and its role as a link between mitochondrial dynamics and lipid metabolism

Methods

An inducible podocyte-specific ChREBP knockout mouse model was generated by crossing floxed ChREBP mice with tamoxifen-inducible Cre transgenic mice controlled by human podocin promoter. These mice subsequently rendered diabetic by crossing with db/db mice. The triple transgenic mice were assessed for kidney function, morphometric analyses and mitochondrial morphology. To explore whether ChREBP-mediated lipidomes plays a role in mitochondrial remodeling, we generated a stable ChREBP-knockdown cell line in podocytes and carried out an untargeted mitochondrial lipidomic profiling. ChIP-qPCR, site-directed mutagenesis and luciferase assay were used to validate whether glyceronephosphate O-acyltransferase (GNPAT), an enzyme involved in the de novo biosynthesis of plasmalogens phospholipids, serve as a direct transcriptional target of ChREBP.

Results

We find that ChREBP deficiency in podocytes of diabetic mice improves key biochemical and histological features of DKD in addition to significantly reducing mitochondrial fission. Using mitochondrial lipidomic analysis, we find that the abundance of plasmalogen, but not that of diacyl or alkyl subclasses of PC or PE, is increased by high glucose and reversed with ChREBP knockdown, suggesting a modulatory role of ChREBP on plasmalogen phospholipids biosynthesis. Importantly, overexpression of GNPAT reverses the protective phenotype of ChREBP deficiency on mitochondrial fragmentation. Finally, our findings suggest that ChREBP bind to Gnpat promoter to activates its transcription.

Conclusion

Our results uncover a distinct plasmalogen phospholipids as the mechanistic link between ChREBP-mediated lipid metabolism and mitochondrial remodeling.

Funding

  • NIDDK Support