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, 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.
We previously reported how the loss of CHIP expression (Carboxyl terminus of Hsc70-Interacting Protein) during pressure overload resulted in robust cardiac dysfunction, 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- and medium-chain fatty acid metabolites in wild-type hearts, a response that 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, fenofibrate. Surprisingly, treating CHIP-/- mice with fenofibrate for five weeks under non-pressure overload conditions resulted in a loss of skeletal muscle mass and a marked increase in cardiac fibrosis, accompanied by a decrease in cardiac function. Isolated CHIP-/- cardiac fibroblasts treated with fenofibrate did not increase synthesis of collagen or TGFβ, suggesting that the fibrosis observed in CHIP-/- hearts likely depends on signaling from other cell types or circulating factors. In conclusion, in the absence of functional CHIP expression, fenofibrate results in unexpected 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.
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