Oxidized free fatty acids (Ox-FFA) have profound effect on cells. Most of these effects are deleterious and pro-atherogenic. Surprisingly, they also have beneficial effects such as induction of catalase. These could be some of the """"""""hidden"""""""" effects of PPAR signaling as some of the PPAR ligands are known activators of catalase, a peroxisomal enzyme. On the other hand, the activation of antioxidant enzymes could also represent cellular defense to an oxidative stress. Understanding the basis of these effects would help us to determine conditions under which the anti-atherogenic effects would prevail over their pro- atherogenic effects. Ox-FFA are poorly transported into cells and poorly utilized for esterification reactions. Thus, small amounts of Ox-FFA that enter the cell might be more readily available for intracellular signaling pathways, i.e. as ligands for PPARs, or destined for degradation pathways. The overall hypothesis of the proposal is, """"""""Cells regulate the uptake and presence of Ox-FFA. The small amounts of Ox-FFA that enter the cell could act as PPAR ligands. Their degradation in peroxisomes would generate H202 thus accounting for their toxicity. The induction of antioxidant enzymes by Ox-FFA might be in response to the generation of H202 or via PPARs"""""""".
AIM 1 : To determine why the uptake of Ox-FFA is poor as compared to that of unoxidized fatty acids. We propose that the increased polarity of Ox-FFA and/or a saturable membrane protein or domain might contribute to the poor uptake of Ox-FFA. Using chemical modifications and membrane alterations, we will determine the changes in the uptake of Ox-FFA. We will also determine the intracellular fate of Ox-FFA.
AIM 2 : To determine the potential degradation of Ox-FFA in the peroxisomes generating H202. We will determine the intracellular degradation of Ox-FFA such as generation of H202 and other polar products as a measure of peroxisomal oxidation. Using acyl CoA oxidase knock out mice, we will determine whether the effects of Ox-FFA could be attributed to its ability to affect peroxisomal metabolism. We will also demonstrate whether Ox-FFA, analogous to the fibrates would induce peroxisomes in animal and cell culture models.
AIM 3 : To determine whether cellular PPAR and non-PPAR mediated cellular responses to Ox-FFA. Using biochemical and molecular approaches, we will determine and delineate PPAR dependent and independent effects of Ox-FFA.
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