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agonist stimulates mitochondrial
fatty acid 
-oxidation in liver and skeletal muscle
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
[3H]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
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