A potent PPARalpha agonist stimulates mitochondrial fatty acid beta-oxidation in liver and skeletal muscle.
The proposed mechanism for the triglyceride (TG) lowering by fibrate drugs is via activation of the peroxisome proliferator-activated receptor-alpha (PPARalpha). Here we show that a PPARalpha agonist, ureido-fibrate-5 (UF-5), approximately 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 approximately 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 beta-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) beta-oxidation, PPARalpha agonists stimulate mitochondrial FA beta-oxidation in vivo in both liver and muscle. These observations suggest an important mechanism for the biological effects of PPARalpha agonists.
Minnich
A
A
Department of Cardiovascular Biology, Aventis Pharmaceuticals Research and Development, Collegeville, Pennsylvania 19426-0994, USA. anne.minnich@aventis.com
Tian
N
N
Byan
L
L
Bilder
G
G
D000818:Animals; D006224:Cricetinae; D004041:Dietary Fats / Q000008:administration & dosage / Q000494:pharmacology; D005227:Fatty Acids / Q000378:metabolism; D011345:Fenofibrate / Q000031:analogs & derivatives* / Q000494:pharmacology; D050356:Lipid Metabolism; D008297:Male; D008647:Mesocricetus; D008930:Mitochondria, Liver / Q000187:drug effects / Q000378:metabolism*; D008931:Mitochondria, Muscle / Q000187:drug effects / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D010084:Oxidation-Reduction / Q000187:drug effects; D010671:Phenylurea Compounds / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D013997:Time Factors; D014157:Transcription Factors / Q000819:agonists*; D014280:Triglycerides / Q000378:metabolism
D004041:Dietary Fats; D005227:Fatty Acids; D010671:Phenylurea Compounds; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D014280:Triglycerides; C006012:fenofibric acid; D011345:Fenofibrate