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

Published online

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Ravi, S; Parry, TL; Willis, MS; Lockyer, P; Patterson, C; Bain, JR; Stevens, RD; Ilkayeva, OR; Newgard, CB; Schisler, JC

Published Date

  • August 15, 2018

Published In

Volume / Issue

  • 5 / 3

PubMed ID

  • 30111698

Pubmed Central ID

  • 30111698

Electronic International Standard Serial Number (EISSN)

  • 2308-3425

Digital Object Identifier (DOI)

  • 10.3390/jcdd5030043

Language

  • eng

Conference Location

  • Switzerland