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J. Cardiovasc. Dev. Dis. 2018, 5(3), 43;

Adverse Effects of Fenofibrate in Mice Deficient in the Protein Quality Control Regulator, CHIP

McAllister Heart Institute at The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Indiana Center for Musculoskeletal Health, University of Indiana School of Medicine, Indianapolis, IN 46202, USA
The Office of the Chancellor, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA
Sarah W. Stedman Nutrition and Metabolism Center and Duke Molecular Physiology Institute, Departments of Pharmacology and Cancer Biology and Medicine, Duke University Medical Center, Durham, NC 27701, USA
Department of Pharmacology and Department of Pathology and Lab Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
Current affiliation, University of North Carolina at Greensboro:
Author to whom correspondence should be addressed.
Received: 6 July 2018 / Revised: 8 August 2018 / Accepted: 9 August 2018 / Published: 15 August 2018
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We previously reported how the loss of CHIP expression (Carboxyl terminus of Hsc70-Interacting Protein) during pressure overload resulted in robust cardiac dysfunction, which was accompanied by a failure to maintain ATP levels in the face of increased energy demand. In this study, we analyzed the cardiac metabolome after seven days of pressure overload and found an increase in long-chain and medium-chain fatty acid metabolites in wild-type hearts. This response was attenuated in mice that lack expression of CHIP (CHIP−/−). These findings suggest that CHIP may play an essential role in regulating oxidative metabolism pathways that are regulated, in part, by the nuclear receptor PPARα (Peroxisome Proliferator-Activated Receptor alpha). Next, we challenged CHIP−/− mice with the PPARα agonist called fenofibrate. We found that treating CHIP−/− mice with fenofibrate for five weeks under non-pressure overload conditions resulted in decreased skeletal muscle mass, compared to wild-type mice, and a marked increase in cardiac fibrosis accompanied by a decrease in cardiac function. Fenofibrate resulted in decreased mitochondrial cristae density in CHIP−/− hearts as well as decreased expression of genes involved in the initiation of autophagy and mitophagy, which suggests that a metabolic challenge, in the absence of CHIP expression, impacts pathways that contribute to mitochondrial quality control. In conclusion, in the absence of functional CHIP expression, fenofibrate results in unexpected skeletal muscle and cardiac pathologies. These findings are particularly relevant to patients harboring loss-of-function mutations in CHIP and are consistent with a prominent role for CHIP in regulating cardiac metabolism. View Full-Text
Keywords: metabolism; fibrates; fibrosis; metabolomics; pressure overload; autophagy; mitophagy metabolism; fibrates; fibrosis; metabolomics; pressure overload; autophagy; mitophagy

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material

  • Externally hosted supplementary file 1
    Doi: 10.17615/C6WM1F
    Description: Raw, processed, and normalized metabolite concentrations (nmol metabolite/µg of heart protein) from homogenates prepared from either wild-type (WT) or CHIP-/- (KO) hearts after one week of either Sham or Trans Aortic Banding (TAB) surgery. Results from 2-way ANOVA and metabolite abbreviations are also provided.

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Ravi, S.; Parry, T.L.; Willis, M.S.; Lockyer, P.; Patterson, C.; Bain, J.R.; Stevens, R.D.; Ilkayeva, O.R.; Newgard, C.B.; Schisler, J.C. Adverse Effects of Fenofibrate in Mice Deficient in the Protein Quality Control Regulator, CHIP. J. Cardiovasc. Dev. Dis. 2018, 5, 43.

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