Polyunsaturated fatty acids stimulate hepatic UCP-2 expression via a PPAR alpha-mediated pathway

The discovery of homologs of the brown fat uncoupling protein(s) (UCP) UCP- 2 and UCP-3 revived the hypothesis of uncoupling protein involvement in the regulation of energy metabolism. Thus we hypothesized that UCP-2 would be regulated in the hepatocyte by fatty acids, which are known to control othe r energy-related metabolic processes. Treatment with 250 muM palmitic acid was without effect on UCP-2 expression, whereas 250 muM oleic acid exhibite d a modest eightfold increase. Eicosapentaenoic acid (EPA), a polyunsaturat ed fatty acid, exerted a 50-fold upregulation of UCP-2 that was concentrati on dependent. This effect was seen within 12 h and was maximal by 36 h. Asp irin blocked the induction of UCP-2 by EPA, indicating involvement of the p rostaglandin pathway. Hepatocytes treated with arachidonic acid, the immedi ate precursor to the prostaglandins, also exhibited an aspirin-inhibitable increase in UCP-2 levels, further supporting the involvement of prostagland ins in regulating hepatic UCP-2. The peroxisome proliferator-activated rece ptor-alpha (PPAR alpha) agonist Wy-14643 stimulated UCP-2 mRNA levels as ef fectively as EPA. These data indicate that UCP-2 is upregulated by polyunsa turated fatty acids, potentially through a prostaglandin/PPAR alpha -mediat ed pathway.