PPARα agonist fenofibrate enhances fatty acid β-oxidation and attenuates polycystic kidney and liver disease in mice

Peroxisome proliferator-activated receptor alpha (PPAR alpha) is a nuclear hormone receptor that promotes fatty acid beta-oxidation (FAO) and oxidative phosphorylation (OXPHOS). We and others have recently shown that PPAR alpha and its target genes are downregulated. and FAO and OXPHOS are impaired in autosomal dominant polycystic kidney disease (ADPKD). however, whether PPAR alpha and FAO/OXPIIOS are causally linked to ADPKD progression is not entirely clear. We report that expression of PPAR alpha and FAO/OXPHOS genes is downregulated, and in vivo beta-oxidation rate of H-3-labeled triolein is reduced in Pkd1(RC/RC) mice, a slowly progressing orthologous model of ADPKD that closely mimics the human ADPKD phenotype. To evaluate the effects of upregulating PPAR alpha, we conducted a 5-mo, randomized, preclinical trial by treating Pkd1(RC/RC) mice with fenofibrate, a clinically available PPAR alpha agonist. Fenotibrate treatment resulted in increased expression of PPARa and FAO/OXPIIOS genes, upregulation of peroxisomal and mitochondrial biogenesis markers, and higher beta-oxidation rates in Pkd1(RC/RC) kidneys. MRI-assessed total kidney volume and total cyst volume, kidney-weight-to-body-weight ratio, cyst index, and serum creatinine levels were significantly reduced in fenofibrate-treated compared with untreated littermate Pkd1(RC/RC) mice. Moreover, fenofibrate treatment was associated with reduced kidney cyst proliferation and infiltration by inflammatory cells, including M2-like macrophages. Finally. fenofibrate treatment also reduced bile duct cyst number, cyst proliferation, and liver inflammation and fibrosis. In conclusion, our studies suggest that promoting PPAR alpha activity to enhance mitochondria] metabolism may be a useful therapeutic strategy for ADPKD.