Abstract: FR-PO616
Lipid Metabolism Reprogramming in ADPKD
Session Information
- Cystic Kidney Diseases: Mechanisms and Models
October 25, 2024 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Cystic
Authors
- Stefanoni, Davide, IRCCS Ospedale San Raffaele, Milano, Italy
- Clerici, Sara, IRCCS Ospedale San Raffaele, Milano, Italy
- Spies, Daniel, IRCCS Ospedale San Raffaele, Milano, Italy
- D'Alessandro, Angelo, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
- Boletta, Alessandra, IRCCS Ospedale San Raffaele, Milano, Italy
Background
ADPKD, caused by either loss of PKD1 or PKD2, is characterized by metabolic changes such as increased glycolysis, glutaminolysis, and fatty acid synthesis (FAS). Recently, our group assessed the critical role of asparagine synthase (ASNS) to fuel the TCA cycle through glutamine. We reported that antisense oligonucleotides (ASO) therapy against Asns results in reduced disease progression. We also showed that central carbon metabolism alterations are improved upon silencing of Asns. Moreover, we previously stated an upregulation of reductive carboxylation in PKD, which generates great levels of citrate broken into acetyl-CoA required to fuel FAS. Here, we asked to which extent lipids are altered in PKD kidneys and whether they can be rescued by inhibition of Asns.
Methods
To assess the impact of Asns knockdown on FAS we performed untargeted lipidomics analysis by mass spectrometry (LC-MS) using kidney tissue samples of a TamCre;Pkd1ΔC/flox mouse model in which tamoxifen was injected at P45 and mice followed up for 160 days, and treated with either scramble or Asns-ASO.
Results
Lipidomics profiling identified over 900 lipids, with many altered in PKD murine tissues. Specifically, KO samples exhibited 347 significant lipid changes to untreated controls. Among those only 120 lipids preserved significance following Asns-ASO treatment, whereas the majority were rescued. In line with this, PCA analysis revealed a clear separation between controls and KO, which Asns-ASO treatment largely rescued. A disease-characteristic signature emerged in KO samples as exhibited by lipid class composition analysis, which shows steryl esters, and fatty acids (FA) as the most upregulated, whereas triglycerides (TG) as the most down-regulated lipids. Volcano plot and enrichment analyses of the lipid classes confirmed these data. Of note, changes in TG were significantly rescued upon Asns silencing, while sterols and FA only partially, revealing a connection between ASNS and lipid dysregulation in ADPKD.
Conclusion
We previously identified Asns as a key player in multiple metabolic pathways in PKD including FAS. Our data show that along with central carbon metabolism, major changes in lipid composition can be observed in PKD kidneys. Unexpectedly our data seem to suggest a potential mechanistic link between ASNS and FAS and confirm the therapeutic significance of targeting Asns in ADPKD.