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.