Administration of Fenofibrate Markedly Elevates Fabp3 in Rat Liver and Plasma and Confounds Its Use as a Preclinical Biomarker of Cardiac and Muscle Toxicity

Proteins involved in lipid homeostasis are often regulated through the nuclear peroxisome proliferator‐activated receptors (PPAR). PPARα is the target for the fibrate‐class of drugs. Fenofibrate has been approved for its lipid‐lowering effects in patients with hypercholesterolemia and hypertriglyceridemia. We were interested in understanding the expression of the energy transporters in energy‐utilizing tissues like liver, heart, muscle, and adipose tissues in rat with the hypothesis that the change in transporter expression would align with the known lipid‐lowering effects of PPARα agonists like fenofibrate. We found that several fatty‐acid transporter proteins had significantly altered levels following 8 days of fenofibrate dosing. The mRNA levels of the highly abundant Fatp2 and Fatp5 in rat liver increased approximately twofold and decreased fourfold, respectively. Several fatty‐acid‐binding proteins and acyl‐CoA‐binding proteins had a significant increase in mRNA abundance but not the major liver fatty‐acid‐binding protein, Fabp1. Of particular interest was the increased liver expression of Fabp3 also known as heart‐fatty acid binding protein (H‐FABP or FABP3). FABP3 has been proposed as a circulating clinical biomarker for cardiomyopathy and muscle toxicity, as well as a preclinical marker for PPARα‐induced muscle toxicity. Here, we show that fenofibrate induces liver mRNA levels of Fabp3 ~5000‐fold resulting in an approximately 50‐fold increase in FABP3 protein levels in the whole liver. This increased liver expression complicates the interpretation and potential use of FABP3 as a specific biomarker for PPARα‐induced muscle toxicities.