| The American Heart Association's 2001 heart and stroke statistical update states that Coronary Heart Disease (CHD) is the single largest killer of American males and females. Both oxidation dependent (lipoprotein oxidation) and oxidation independent (hypercholesterolemia) mechanisms have been implicated in atherosclerosis, the process that leads to CHD. The present research examines mechanisms by which the primary oxidation products of linoleic acid (a dietary fatty acid) promote the risk of atherosclerosis.; Recent studies in our laboratory showed that cultured smooth muscle cells take up oxidized fatty acids very poorly. Since intestinal cells are morphologically quite distinct, we studied the uptake and subsequent metabolism of oxidized linoleic acid (ox-18:2) by Caco-2 cells and rat everted intestinal sacs. We demonstrate that ox-18:2 is transported into Caco-2 cells and is esterified into triglycerides and phospholipids. Finally, we also provide evidence that the presence of ox-18:2 does not lead to oxidative stress (production of hydrogen peroxide) within these cells. We conclude that if oxidized fatty acids are absorbed and esterified into complex lipids then they might be secreted into lipoproteins and could increase their oxidative potential.; Working with oxidized linoleic acid, we noticed a similarity in its physical properties to that of bile acids. We propose that oxidized fatty acids may mimic bile acids and form mixed micelles with cholesterol much more efficiently, as compared to unoxidized fatty acids, there by increasing the absorption of luminal cholesterol. In an in vitro assay, at concentrations of 1, 5, and 10 mM, ox-18:2 increased the micellarization of cholesterol in a dose dependent manner compared to 10 mM unoxidized linoleic acid. The uptake of cholesterol solubilized in the presence of ox-18:2, by Caco-2 cells and everted rat intestinal sacs was greater as compared cholesterol solubilized in the presence of unoxidized-18:2. In addition, when LDL r −/− mice were fed a high fat diet along with ox-18:2 their plasma cholesterol levels were greater than animals fed the high fat diet alone. From these results, we suggest that oxidized fatty acids, by enhancing the solubilization of luminal cholesterol, increase the uptake of cholesterol which might lead to hypercholesterolemia and atherosclerosis. |
