Inhibition of ATP-Citrate Lyase Improves CKD Through Multiple Mechanisms
Bibliographic record
Abstract
Background: ATP-citrate lyase (ACLY), upregulated in chronic kidney disease (CKD), catalyzes the synthesis of acetyl-coA from citrate. Acetyl-CoA is a vital precursor for lipid synthesis and histone acetylation that regulates gene expression. In kidney cells, ACLY regulates fibrogenic, lipogenic and inflammatory gene expression; its inhibition reduced fibrosis in the unilateral ureteral obstruction (UUO) model. The ACLY metabolic by-product malonyl-coA, however, is also an important inhibitor of fatty acid oxidation (FAO), and defective FAO in proximal tubular epithelial cells (PTEC) is now established as a major contributor to fibrosis. Here we tested the efficacy of a novel ACLY inhibitor (ACLYi) on reducing fibrosis and its potential role in improving FAO in UUO. Methods: 8-week-old male C57BL/6J mice underwent UUO surgery and were treated orally with an ACLY inhibitor (Espervita Therapeutics) for 10 days. Kidneys were assessed by immunohistochemistry, immunoblotting and RNAseq. Effects of ACLYi were tested on the HK2 PTEC cell line and primary renal fibroblast responses to TGFβ1 (5ng/ml, 48h), a cytokine known to promote fibrosis and reduce FAO. Lipid accumulation was assessed by Oil Red O staining and LC/MS analysis. Results: ACLYi significantly and dose-dependently decreased fibrosis in the UUO model determined by trichrome, PSR, fibronectin and α-smooth muscle actin (SMA) expression. ACLYi decreased macrophage (F4/80) infiltration including that of the profibrotic M2 phenoype marked by CD206. RNAseq analysis showed upregulation of FAO-related hallmark pathways and reduction in inflammation pathways with ACLYi. Defective FAO is known to result in PTEC apoptosis and lipid accumulation. ACLYi reduced both apoptosis, as assessed by the presence of cleaved caspase 3, as well as lipid accumulation, with a particular decrease in cholesteryl esters. In HK2 cells and renal fibroblasts, TGFβ1-induced fibrotic protein expression was inhibited by ACLYi, and lipid accumulation was reduced in PTEC. Conclusions: ACLYi reduced renal fibrosis, apoptosis and lipid accumulation in UUO mice. ACLYi also prevented profibrotic responses to TGFβ1 in PTEC and fibroblasts. Current studies are ongoing to confirm beneficial effects on restoring FAO. Funding: Commercial Support - Espervita Therapeutics, Government Support - Non-U.S.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".