Fenofibrate Induces Cardiac Fibrosis in Mice Lacking the Co‐chaperone and E3‐ubiquitin Ligase CHIP

Objective To determine if stimulation of PPARα with fenofibrate can rescue cardiac hypertrophy induced by energy starvation in CHIP −/− mice. Carboxyl Terminus of HSP70 (CHIP) is a co‐chaperone and E3 ubiquitin ligase involved in protein quality control. The genetic depletion of CHIP in mice is associated with cardiac hypertrophy and decreased survival following myocardial infarction. We previously demonstrated that pressure overload‐induced cardiac hypertrophy is a result of energy starvation and lack of AMPK activation. We found that while the rate of fatty acid uptake in isolated adult mouse cardiomyocytes lacking CHIP expression (CHIP −/− ) was similar to WT cardiomyocytes, there was a 33% decrease in fatty acid oxidation accompanied by a 98% increase in fatty acid incorporation into cellular lipids in CHIP −/− versus wild‐type cardiomyocytes. This suggested that a decrease in fatty acid oxidation may contribute to the cardiac disease seen in CHIP −/− mice, and activation of fatty acid oxidation may ameliorate the cardiac pathophysiology associated with the loss of CHIP function. To test our hypothesis, we treated mice with 65 mg/g body weight of fenofibrate, a PPARα agonist that increases lipid uptake and oxidation, for six weeks and observed changes in cardiac function via conscious cardiac echocardiography and histological characterization. Much to our surprise, we found that fenofibrate increased cardiac fibrosis in the CHIP −/− mice by 60%, without a change in total heart size or cardiomyocyte cross‐sectional area compared to wild‐type mice. We determined the effectiveness of fenofibrate as a PPARα agonist by measuring PPARα target genes in the liver of mice and observed similar activation of fatty acid gene expression in both CHIP −/− and wild‐type mice. Likewise, candidate PPAR‐responsive genes in whole heart did not reveal any genotype‐specific differences. We suspect that the fibrotic response is due to pathophysiological stimulation of cardiac fibroblasts lacking CHIP expression. We are now studying isolated primary cardiac fibroblasts from wild‐type and CHIP −/− mice in combination with PPAR isoform specific agonists to measure the fibrotic response to PPAR activation. Our findings have important implications for understanding how the loss of CHIP function (CHIPopathy) recently identified as the causal gene in spinocerebellar ataxia autosomal recessive 16, affects cardiac function given the large population of patients taking fibrates to treat hyperlipidemia.