Adverse Effects of Fenofibrate in Mice Deficient in the Protein Quality Control Regulator, CHIP
AbstractWe 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
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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.
Ravi S, Parry TL, Willis MS, Lockyer P, Patterson C, Bain JR, Stevens RD, Ilkayeva OR, Newgard CB, Schisler JC. Adverse Effects of Fenofibrate in Mice Deficient in the Protein Quality Control Regulator, CHIP. Journal of Cardiovascular Development and Disease. 2018; 5(3):43.Chicago/Turabian Style
Ravi, Saranya; Parry, Traci L.; Willis, Monte S.; Lockyer, Pamela; Patterson, Cam; Bain, James R.; Stevens, Robert D.; Ilkayeva, Olga R.; Newgard, Christopher B.; Schisler, Jonathan C. 2018. "Adverse Effects of Fenofibrate in Mice Deficient in the Protein Quality Control Regulator, CHIP." J. Cardiovasc. Dev. Dis. 5, no. 3: 43.
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