TY - JOUR
T1 - PPARα agonist fenofibrate enhances fatty acid β-oxidation and attenuates polycystic kidney and liver disease in mice
AU - Lakhia, Ronak
AU - Yheskel, Matanel
AU - Flaten, Andrea
AU - Quittner-Strom, Ezekiel B.
AU - Holland, William L.
AU - Patel, Vishal
N1 - Funding Information:
We thank the University of Texas (UT) Southwestern O’Brien Kidney Research Core Center (P30DK-079328), the Touchstone Diabetes Center at UT Southwestern, and the Mayo Translation PKD center (DK-090728) for providing critical reagents and services. The work from the authors’ laboratory is supported by National Institutes of Health Grants R01-DK-102572 (to V. Patel).
Publisher Copyright:
© 2018 American Physiological Society. All rights reserved.
PY - 2018/1
Y1 - 2018/1
N2 - Peroxisome proliferator-activated receptor α (PPARα) is a nuclear hormone receptor that promotes fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS). We and others have recently shown that PPARα and its target genes are downregulated, and FAO and OXPHOS are impaired in autosomal dominant polycystic kidney disease (ADPKD). However, whether PPARα and FAO/OXPHOS are causally linked to ADPKD progression is not entirely clear. We report that expression of PPARα and FAO/OXPHOS genes is downregulated, and in vivo β-oxidation rate of3H-labeled triolein is reduced in Pkd1RC/RC mice, a slowly progressing orthologous model of ADPKD that closely mimics the human ADPKD phenotype. To evaluate the effects of upregulating PPARα, we conducted a 5-mo, randomized, preclinical trial by treating Pkd1RC/RC mice with fenofibrate, a clinically available PPARα agonist. Fenofibrate treatment resulted in increased expression of PPARα and FAO/OXPHOS genes, upregulation of peroxisomal and mitochondrial biogenesis markers, and higher β-oxidation rates in Pkd1RC/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 Pkd1RC/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 PPARα activity to enhance mitochondrial metabolism may be a useful therapeutic strategy for ADPKD.
AB - Peroxisome proliferator-activated receptor α (PPARα) is a nuclear hormone receptor that promotes fatty acid β-oxidation (FAO) and oxidative phosphorylation (OXPHOS). We and others have recently shown that PPARα and its target genes are downregulated, and FAO and OXPHOS are impaired in autosomal dominant polycystic kidney disease (ADPKD). However, whether PPARα and FAO/OXPHOS are causally linked to ADPKD progression is not entirely clear. We report that expression of PPARα and FAO/OXPHOS genes is downregulated, and in vivo β-oxidation rate of3H-labeled triolein is reduced in Pkd1RC/RC mice, a slowly progressing orthologous model of ADPKD that closely mimics the human ADPKD phenotype. To evaluate the effects of upregulating PPARα, we conducted a 5-mo, randomized, preclinical trial by treating Pkd1RC/RC mice with fenofibrate, a clinically available PPARα agonist. Fenofibrate treatment resulted in increased expression of PPARα and FAO/OXPHOS genes, upregulation of peroxisomal and mitochondrial biogenesis markers, and higher β-oxidation rates in Pkd1RC/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 Pkd1RC/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 PPARα activity to enhance mitochondrial metabolism may be a useful therapeutic strategy for ADPKD.
KW - Fatty acid oxidation
KW - Fenofibrate
KW - Peroxisome proliferator-activated receptor α
KW - Polycystic kidney disease
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U2 - 10.1152/ajprenal.00352.2017
DO - 10.1152/ajprenal.00352.2017
M3 - Article
C2 - 28903946
AN - SCOPUS:85043513291
SN - 1931-857X
VL - 314
SP - F122-F131
JO - American Journal of Physiology - Renal Physiology
JF - American Journal of Physiology - Renal Physiology
IS - 1
ER -