Gemfibrozil lowers plasma lipids and increases polyunsaturated fatty acid content and oxidative susceptibility of lipoproteins in hypertriglyceridemia

Abstract

Background: Gemfibrozil is an effective drug in the treatment of hypertriglyceridemia and its effects on morbidity and mortality seem out of proportion to its lipid lowering actions. There is considerable interest in its potential effects on lipoprotein fatty acid composition and consequent effect on oxidative susceptibility. Experimental results are not conclusive regarding whether gemfibrozil alters lipid composition or oxidative susceptibility of lipoproteins in humans. Here we investigate this question using different methodology than employed in previous investigations. Methods: Eleven hypertriglyceridemic individuals completed a 12-week course of gemfibrozil therapy (600 mg twice daily) intended to primarily evaluate a new way of assessing lipoprotein susceptibility to oxidation in relation to changes in the fatty acid profile. We measured susceptibility of lipoproteins in the plasma macromolecule fraction to copper-mediated oxidation. In addition, plasma lipids were separated into phospholipid (PL), cholesterol ester (CE) and triglyceride (TG) fractions and the fatty acid composition of these classes determined by gas–liquid chromatography. The relation between changes in lipid concentration, fatty acid composition and oxidative parameters (principally lag time) was examined by correlational analysis. Results: Triglyceride concentrations and total cholesterol concentrations responded appropriately to gemfibrozil (lowered by 55% and 15%, respectively). Polyunsaturated fatty acid (PUFA) proportion increased significantly in cholesterol ester and phospholipid fractions of plasma lipids at the expense of saturated fatty acids (SFA) and monounsaturated fatty acids (MUFA). Oxidative parameters also changed significantly. Lag time (LT) and maximal extent of oxidation showed the most significant changes. Lag time, the principle measure of lipoprotein susceptibility to oxidation, was decreased by gemfibrozil. The increase in polyunsaturated fatty acid content in phospholipid and cholesterol ester significantly correlated with decreased lag time. Conclusion: These data support the notion that gemfibrozil increases the proportion of polyunsaturated fatty acids in plasma lipids and that this increase is associated with an increase in lipoprotein oxidative susceptibility as measured by lag time in hypertriglyceridemia.