| First Author | Lakhia R | Year | 2018 |
| Journal | Am J Physiol Renal Physiol | Volume | 314 |
| Issue | 1 | Pages | F122-F131 |
| PubMed ID | 28903946 | Mgi Jnum | J:283117 |
| Mgi Id | MGI:6367877 | Doi | 10.1152/ajprenal.00352.2017 |
| Citation | Lakhia R, et al. (2018) PPARalpha agonist fenofibrate enhances fatty acid beta-oxidation and attenuates polycystic kidney and liver disease in mice. Am J Physiol Renal Physiol 314(1):F122-F131 |
| abstractText | Peroxisome proliferator-activated receptor alpha (PPARalpha) is a nuclear hormone receptor that promotes fatty acid beta-oxidation (FAO) and oxidative phosphorylation (OXPHOS). We and others have recently shown that PPARalpha and its target genes are downregulated, and FAO and OXPHOS are impaired in autosomal dominant polycystic kidney disease (ADPKD). However, whether PPARalpha and FAO/OXPHOS are causally linked to ADPKD progression is not entirely clear. We report that expression of PPARalpha and FAO/OXPHOS genes is downregulated, and in vivo beta-oxidation rate of (3)H-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 PPARalpha, we conducted a 5-mo, randomized, preclinical trial by treating Pkd1(RC/RC) mice with fenofibrate, a clinically available PPARalpha agonist. Fenofibrate treatment resulted in increased expression of PPARalpha and FAO/OXPHOS 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 PPARalpha activity to enhance mitochondrial metabolism may be a useful therapeutic strategy for ADPKD. |
