A potent PPARα agonist stimulates mitochondrial fatty acid β-oxidation in liver and skeletal muscle

Abstract

The proposed mechanism for the triglyceride (TG) lowering by fibrate drugs is via activation of the peroxisome proliferator-activated receptor-α (PPARα). Here we show that a PPARα agonist, ureido-fibrate-5 (UF-5), ∼200-fold more potent than fenofibric acid, exerts TG-lowering effects (37%) in fat-fed hamsters after 3 days at 30 mg/kg. In addition to lowering hepatic apolipoprotein C-III (apoC-III) gene expression by ∼60%, UF-5 induces hepatic mitochondrial carnitine palmitoyltransferase I (CPT I) expression. A 3-wk rising-dose treatment results in a greater TG-lowering effect (70%) at 15 mg/kg and a 2.3-fold elevation of muscle CPT I mRNA levels, as well as effects on hepatic gene expression. UF-5 also stimulated mitochondrial [3H]palmitate β-oxidation in vitro in human hepatic and skeletal muscle cells 2.7- and 1.6-fold, respectively, in a dose-related manner. These results suggest that, in addition to previously described effects of fibrates on apoC-III expression and on peroxisomal fatty acid (FA) β-oxidation, PPARα agonists stimulate mitochondrial FA β-oxidation in vivo in both liver and muscle. These observations suggest an important mechanism for the biological effects of PPARα agonists.