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

Saranya Ravi,Traci Parry,Pamela Lockyer,Jonathan Schisler,Robert Stevens,Olga Ilkayeva,Monte Willis,James Bain,Christopher Newgard,Cam Patterson

doi:10.3390/jcdd5030043

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.

Highlights

Carboxyl terminus of Hsc70-interacting protein (CHIP, encoded by the gene STUB1) is a dual-function enzyme, which has both chaperone-related and ubiquitin ligase activities [1]
These data suggest that pressure overload in wild-type hearts results in specific changes to oxidative metabolic flux that are distinct from those found in CHIP−/− hearts
Pressure overload resulted in a compensatory increase in ATP production mostly from an increase in fatty acid oxidation (Figure 1c), which is consistent with the metabolite data (Figure 1b)

Summary

Introduction

Carboxyl terminus of Hsc70-interacting protein (CHIP, encoded by the gene STUB1) is a dual-function enzyme, which has both chaperone-related and ubiquitin ligase activities [1]. Studies suggest that the majority of CHIP coding mutations result in protein destabilization and loss-of-function [4,5]. The impact of CHIP mutations on cardiac function in SCAR16 patients has not been reported. The loss of CHIP decreased survival, compromised cardiac function, and reduced metabolic reserves [13]. Metabolic insufficiency in CHIP−/− mice following cardiac pressure overload occurred in part due to the inability to increase the activation of 5 AMP-activated protein kinase (AMPK) [13]. Increasing AMPK activity promotes fatty-acid and glucose oxidation. These data suggest that targeting other metabolic regulators besides AMPK could potentially blunt the metabolic dysfunction observed in CHIP−/− hearts

Methods

Results

Conclusion