Acyl-CoA Synthetase Short-Chain Family 2 Is a Renal Disease Risk Gene: Controlling De Novo Lipogenesis in Kidney Tubules
- Genetic Diseases: Tubulopathies
November 03, 2023 | Location: Exhibit Hall, Pennsylvania Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1202 Genetic Diseases of the Kidneys: Non-Cystic
- Mukhi, Dhanunjay, University of Pennsylvania, Philadelphia, Pennsylvania, United States
- Susztak, Katalin, University of Pennsylvania, Philadelphia, Pennsylvania, United States
Group or Team Name
- Susztak Lab.
Worldwide, over 800 million people are affected by kidney disease, yet its pathogenesis remains elusive, hindering the development of novel therapeutics.
In this study, we employed kidney-specific expression of quantitative traits and single-nuclear open chromatin analysis to show that genetic variants linked to kidney dysfunction on chromosome 20 target the acyl-CoA synthetase short-chain family 2 (ACSS2). By generating ACSS2 knock-out mice, we demonstrated their protection from kidney fibrosis.
Our analysis of primary tubular cells revealed that ACSS2 regulates de novo lipogenesis (DNL), causing NADPH depletion and increasing ROS levels, ultimately leading to NLRP3-dependent pyroptosis. Additionally, we discovered that pharmacological inhibition or genetic ablation of fatty acid synthase safeguarded kidney cells against profibrotic gene expression and prevented kidney disease in mice. Lipid accumulation and the expression of genes related to DNL were elevated in the kidneys of patients with fibrosis.
Our findings pinpoint ACSS2 as a critical kidney disease gene and reveal the role of DNL in kidney disease.
- NIDDK Support