Abstract: TH-PO1150
High Citrate-Dependent Overactivation of Acetyl CoA Carboxylase Leads to Ectopic Kidney Lipid Accumulation and Mitochondrial Dysfunction in a CKD Model
Session Information
- CKD: Mechanisms, AKI, and Beyond - 1
November 06, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2303 CKD (Non-Dialysis): Mechanisms
Authors
- Sanz-Gómez, Marta, Universidad Complutense de Madrid, Madrid, Community of Madrid, Spain
- Bragado García, Elvira, Universidad Complutense de Madrid, Madrid, Community of Madrid, Spain
- Guzman Aguayo, Ana Karen, Universidad Complutense de Madrid, Madrid, Community of Madrid, Spain
- Palma Guzmán, Paloma, Universidad Complutense de Madrid, Madrid, Community of Madrid, Spain
- Kreutz, Reinhold, Charite - Universitatsmedizin Berlin, Berlin, BE, Germany
- Plaza de la Fuente, Adrián, Universidad CEU San Pablo, Madrid, Community of Madrid, Spain
- Fernandez-Alfonso, Maria S., Universidad Complutense de Madrid, Madrid, Community of Madrid, Spain
Group or Team Name
- Group for the Study of Cardiometabolic Health (GESCAMET).
Background
Kidney ectopic lipid deposition is a pathological hallmark of chronic kidney disease (CKD) in which renal lipid metabolism regulation becomes impaired, contributing to disease (lipo-toxicity, inflammation, fibrosis...). Acetyl-CoA carboxylase (ACC), a rate-limiting enzyme in fatty acid synthesis, is inhibited by AMP-activated protein kinase (AMPK) via phosphorylation. CKD is associated with increased bone resorption and plasma citrate, that induces allosteric ACC activation by polymerization. We hypothesize that in CKD, high citrate levels lead to ectopic lipid accumulation by ACC overactivation independently of AMPK.
Methods
Munich Wistar Frömter (MWF) rats, a CKD model, and control Wistar (W) rats' kidneys were collected for RTqPCR, Western Blot and histology. Vitamin D (VitD) and citrate plasmatic levels were measured, and femurs were fixated in 4% PFA and the bone density was assessed by micro CT. HEK293 cells were used to corroborate the in vivo findings.
Results
Kidney p-Thr-172 AMPK was significantly higher at 45 weeks of age in both W and MWF compared to younger ages (10,16 and 22 weeks). However, p-Thr-172 AMPK was lower in MWF compared to age-matched W rats. Whereas p-Ser-79-ACC level correlated with p-Thr-172 AMPK in W, this was not observed in MWF. This impaired AMPK-dependent ACC inhibition was associated to renal parenchyma lipid depositions, higher plasma citrate levels (1.5-fold vs. W), and both lower VitD plasma levels and femur bone density in MWF. Mitochondrial oxidative respiratory chain complexes I, II and III were lower in MWF kidneys, suggesting mitochondrial dysfunction and increased oxidative stress. HEK293 cells exposure to citrate 1.5mM reduced mitochondrial function with no effects in cell viability. Citrate 1.5mM promoted decreased p-Thr172-AMPK and p-Ser79-ACC levels and higher ectopic lipid deposition, as well as ACC oligomerization in both kidney and HEK293 cells.
Conclusion
CKD-related VitD deficiency may lincrease bone resorption that redistributes citrate from bone to plasma. This high-citrate activates renal ACC by polymerization, making it inaccessible for AMPK-dependent inhibition, causing higher lipid synthesis and reduced mitochondrial activity.
Funding
- Government Support – Non-U.S.