ADPKD has few therapeutic options.
Tolvaptan slows disease but has side effects limiting its tolerability.
Bempedoic acid (BA), an
ATP citrate-lyase (ACLY) inhibitor FDA-approved for
hypercholesterolemia, catalyzes a key step in
fatty acid/
sterol synthesis important for cell proliferation. BA is activated by
very long-chain acyl-CoA synthetase (FATP2) expressed primarily in kidney and liver. BA also activates AMPK. We hypothesized that BA could be a novel
ADPKD therapy by inhibiting
cyst growth, proliferation, injury, and metabolic dysregulation via ACLY inhibition and AMPK activation. Pkd1-null kidney cell lines derived from mouse proximal tubule (PT) and collecting duct (IMCD) were grown in 2D or 3D
Matrigel cultures and treated ± BA, ± SB-204990 (another ACLY inhibitor) or with Acly
shRNA before
cyst analysis, immunoblotting or mitochondrial assays using
MitoSox and MitoTracker staining. Pkd1 fl/fl ; Pax8-rtTA; Tet-O-Cre C57BL/6J mice were induced with
doxycycline injection on postnatal days 10 and 11 (P10-P11) and then treated ± BA (30 mg/kg/d) ±
tolvaptan (30-100 mg/kg/d) by gavage from P12-21. Disease severity was determined by % total-kidney-weight-to-bodyweight (%TKW/BW) and BUN levels at
euthanasia (P22). Kidney and liver homogenates were immunoblotted for expression of key
biomarkers. ACLY expression and activity were upregulated in Pkd1-null PT and IMCD-derived cells vs. controls. Relative to controls, both BA and SB-204990 inhibited cystic growth in Pkd1-null kidney cells, as did Acly knockdown. BA inhibited mitochondrial
superoxide production and promoted mitochondrial elongation, suggesting improved mitochondrial function. In
ADPKD mice, BA reduced %TKW/BW and BUN to a similar extent as
tolvaptan vs. untreated controls. Addition of BA to
tolvaptan caused a further reduction in %TKW/BW and BUN vs.
tolvaptan alone. BA generally reduced ACLY and stimulated AMPK activity in kidneys and livers vs. controls. BA also inhibited mTOR and ERK signaling and reduced kidney injury markers. In liver, BA treatment, both alone and together with
tolvaptan, increased mitochondrial biogenesis while inhibiting apoptosis. We conclude that BA and ACLY inhibition inhibited
cyst growth in vitro, and BA decreased
ADPKD severity in vivo. Combining BA with
tolvaptan further improved various
ADPKD disease parameters. Repurposing BA may be a promising new
ADPKD therapy, having beneficial effects alone and along with
tolvaptan.