A potent PPARa agonist stimulates mitochondrial fatty acid b-oxidation in liver and skeletal muscle

Minnich, Anne, Nian Tian, Lisa Byan, and Glenda Bilder. A potent PPARa agonist stimulates mitochondrial fatty acid b-oxidation in liver and skeletal muscle. Am J Physiol Endocrinol Metab 280: E270–E279, 2001.—The proposed mechanism for the triglyceride (TG) lowering by fibrate drugs is via activation of the peroxisome proliferator-activated receptor-a (PPARa). Here we show that a PPARa 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 [H]palmitate b-oxidation in vitro in human hepatic and skeletal muscle cells 2.7and 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) b-oxidation, PPARa agonists stimulate mitochondrial FA b-oxidation in vivo in both liver and muscle. These observations suggest an important mechanism for the biological effects of PPARa agonists.