A potent PPAR{alpha} agonist stimulates mitochondrial fatty acid {beta}-oxidation in liver and skeletal muscle

• Published in: American journal of physiology: endocrinology and metabolism 2001-02, Vol.280 (2), p.E270
• Main Authors: Minnich, Anne, Tian, Nian, Byan, Lisa, Bilder, Glenda
• Format: Article
• Language: English
• ISSN: 0193-1849; 1522-1555

Department of Cardiovascular Biology, Aventis Pharmaceuticals Research and Development, Collegeville, Pennsylvania 19426-0994 The proposed mechanism for the triglyceride (TG) lowering by fibrate drugs is via activation of the peroxisome proliferator-activated receptor- (PPAR ). Here we show that a PPAR 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 [ 3 H]palmitate -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) -oxidation, PPAR agonists stimulate mitochondrial FA -oxidation in vivo in both liver and muscle. These observations suggest an important mechanism for the biological effects of PPAR agonists. fibrates; carnitine palmitoyltransferase I; nuclear receptors; gene expression; peroxisome proliferator-activated receptor