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

Abstract

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.

Disrupted structure and aberrant function of CHIP mediates the loss of motor and cognitive function in preclinical models of SCAR16

“…For example, mutant CHIP may be unable to either ubiquitinate chaperone-engaged proteins or promote the refolding of proteins that are usually degraded by the proteasome. Similarly, mutant CHIP may promote the activation of compensatory pathways involved in proteins degradation or clearing protein aggregates such as autophagy [ 29 , 49 ] that could sensitize the cells to additional proteotoxic stress. Moreover, the formation of soluble CHIP oligomers that alter the chaperone or co-chaperone functions of CHIP may also contribute to the pathophysiology.…”

CHIP mutations affect the heat shock response differently in human fibroblasts and iPSC-derived neurons

“…More recently, CHIP was identified as a regulator of many other processes, such as TFEB activity and thereby macroautophagy regulation ( Guo et al, 2015 ; Sha et al, 2017 ), necroptosis ( Seo et al, 2016 ; Tang et al, 2018 ), cAMP and AMPK signaling ( Schisler et al, 2013 ; Rinaldi et al, 2019 ), oxidative metabolism ( Ravi et al, 2018 ), chaperone-mediated autophagy ( Ferreira et al, 2015 ) and neuronal preconditioning ( Lizama et al, 2018 ). In addition to this, CHIP was shown to be cytoprotective in many forms of neurodegeneration by degrading inter alia α-synuclein ( Shin et al, 2005 ; Tetzlaff et al, 2008 ), LRRK2 ( Ding and Goldberg, 2009 ), APP and BACE1 ( Kumar et al, 2007 ; Singh and Pati, 2015 ), as well as huntingtin ( Jana et al, 2005 ; Miller et al, 2005 ).…”

Changes in protein function underlie the disease spectrum in patients with CHIP mutations

“…In contrast, SCAR16 patients with cognitive dysfunction and Ubox mutations may benefit from the use of molecular chaperones to prevent the oligomerization of these mutant CHIP proteins. CHIP impacts several cellular pathways, and identifying the CHIP-dependent pathways that may contribute to the specific pathologies in SCAR16, such as necroptosis (23), IGF1 (24), mitophagy (25), autophagy (26, 27), or water balance (28), may also uncover therapeutically relevant targets. Additionally, gene therapy approaches might be applicable to SCAR16.…”