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Cardiovasc Pathol. 2016 Mar-Apr;25(2):127-140. doi: 10.1016/j.carpath.2015.09.008. Epub 2015 Oct 29.

Fenofibrate unexpectedly induces cardiac hypertrophy in mice lacking MuRF1.

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McAllister Heart Institute, University of North Carolina, Chapel Hill, NC, USA.
Department of Biology, University of North Carolina, Chapel Hill, NC, USA.
Department of Pharmacology, University of North Carolina, Chapel Hill, NC, USA.
Department of Pathology & Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
Department of Surgery, University of North Carolina, Chapel Hill, NC, USA.
Department of Bioinformatics and Computational Biology, University of North Carolina, Chapel Hill, NC, USA.
Presbyterian Hospital/Weill-Cornell Medical Center, New York, NY, USA.
Contributed equally


The muscle-specific ubiquitin ligase muscle ring finger-1 (MuRF1) is critical in regulating both pathological and physiological cardiac hypertrophy in vivo. Previous work from our group has identified MuRF1's ability to inhibit serum response factor and insulin-like growth factor-1 signaling pathways (via targeted inhibition of cJun as underlying mechanisms). More recently, we have identified that MuRF1 inhibits fatty acid metabolism by targeting peroxisome proliferator-activated receptor alpha (PPARα) for nuclear export via mono-ubiquitination. Since MuRF1-/- mice have an estimated fivefold increase in PPARα activity, we sought to determine how challenge with the PPARα agonist fenofibrate, a PPARα ligand, would affect the heart physiologically. In as little as 3 weeks, feeding with fenofibrate/chow (0.05% wt/wt) induced unexpected pathological cardiac hypertrophy not present in age-matched sibling wild-type (MuRF1+/+) mice, identified by echocardiography, cardiomyocyte cross-sectional area, and increased beta-myosin heavy chain, brain natriuretic peptide, and skeletal muscle α-actin mRNA. In addition to pathological hypertrophy, MuRF1-/- mice had an unexpected differential expression in genes associated with the pleiotropic effects of fenofibrate involved in the extracellular matrix, protease inhibition, hemostasis, and the sarcomere. At both 3 and 8 weeks of fenofibrate treatment, the differentially expressed MuRF1-/- genes most commonly had SREBP-1 and E2F1/E2F promoter regions by TRANSFAC analysis (54 and 50 genes, respectively, of the 111 of the genes >4 and <-4 log fold change; P ≤ .0004). These studies identify MuRF1's unexpected regulation of fenofibrate's pleiotropic effects and bridges, for the first time, MuRF1's regulation of PPARα, cardiac hypertrophy, and hemostasis.


Cardiac hypertrophy; Fenofibrate; Mitochondria; MuRF1; Myocyte; PPARα; Ubiquitin ligase

[Available on 2017-03-01]
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