PPARα agonist fenofibrate enhances fatty acid β-oxidation and attenuates polycystic kidney and liver disease in mice
Open accessAbstract
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 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 PPARα, we conducted a 5-mo, randomized, preclinical trial by treating Pkd1 RC/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 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 PPARα activity to enhance mitochondrial metabolism may be a useful therapeutic strategy for ADPKD.
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Improved mitochondrial function, including enhanced oxidative phosphorylation and mitochondrial biogenesis, is consistently associated with macrophage reprogramming and fibrosis resolution.
“Conversely, improved mitochondrial function -including enhanced oxidative phosphorylation and mitochondrial biogenesis- has been consistently associated with macrophage reprogramming and fibrosis resolution (28–31).”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [30]
Pharmacological activation of PPARα increases restorative macrophage populations.
“Pharmacological activation of PPARα increases restorative macrophage populations (30), and its upregulation, together with PPARγ, may depend on AMPK activation, linking transcriptional control with metabolic reprogramming (35).”
From Strategies to promote liver fibrosis amelioration with involvement of restorative macrophages (2026) · cites this paper as [30]
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- Authors
- Lakhia, R., Yheskel, M., Flaten, A., Quittner-Strom, E. B., Holland, W. L., & Patel, V.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Corresponding author
- Patel, Vishal
- ORCID
- Venue
- American Journal of Physiology-Renal Physiology
- Publisher
- American Physiological Society
- Published
- 2018-01-01
- Volume
- 314
- Issue
- 1
- Pages
- F122-F131
- ISSN
- 1522-1466 (ISSN-L)
- 1931-857X
- PMC
- PMC5866355
- OpenAlex
- W2754464449
- Cited by
- 140
- References
- 38
- Citations by year
- 2026: 19 · 2025: 19 · 2024: 21 · 2023: 15 · 2022: 20 · 2021: 15 · 2020: 17 · 2019: 11 · 2018: 3
- FWCI
- 5.63
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- American Journal of Physiology-Renal Physiology (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- HHS | NIH | National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (DK102572)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Peroxisome Proliferator-Activated Receptors
- Health Sciences › Medicine › Physiology › Tuberous Sclerosis Complex Research
- Keywords
- PPARα, fenofibrate, fatty acid beta-oxidation, oxidative phosphorylation, autosomal dominant polycystic kidney disease, mitochondrial biogenesis, peroxisome biogenesis, renal cysts, bile duct cyst, liver fibrosis, M2 macrophages, liver inflammation, mitochondrial metabolism
- MeSH terms
- Animals, Cysts, Fatty Acids, Fatty Liver, Polycystic Kidney Diseases, Liver Diseases, Mice, Transgenic, Oxidation-Reduction, Transcription Factors, PPAR alpha
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