Increased Low-Density Lipoprotein Oxidation and Impaired High-Density Lipoprotein Antioxidant Defense Are Associated With Increased Macrophage Homing and Atherosclerosis in Dyslipidemic Obese Mice

Abstract

Background— Obesity-associated dyslipidemia in humans is associated with increased low-density lipoprotein (LDL) oxidation. Mice with combined leptin and LDL receptor deficiency are obese and show severe dyslipidemia and insulin resistance. We investigated the association between oxidation of apolipoprotein B–containing lipoproteins, high-density lipoprotein (HDL) antioxidant defense, and atherosclerosis in these mice. Methods and Results— LDL receptor knockout (LDLR ^−/− ), leptin-deficient (ob/ob), double-mutant (LDLR ^−/− ;ob/ob), and C57BL6 mice were fed standard chow. Double-mutant mice had higher levels of non-HDL ( P P P P −/− mice ( P P P P P P Conclusions— Dyslipidemia and insulin resistance in obese LDL receptor–deficient mice are associated with increased oxidative stress and impaired HDL-associated antioxidant defense, evidenced by decreased paraoxonase and LCAT activity. Transient LCAT overexpression was associated with a reduction of oxidative stress and atherosclerosis.