Methionine-induced hyperhomocysteinemia impairs the antioxidant ability of high-density lipoproteins without reducing in vivo macrophage-specific reverse cholesterol transport

Abstract

Scope: High plasma homocysteine concentrations have been associated with increased risk of cardiovascular disease both in humans and experimental animal models, whereas plasma HDL-cholesterol concentration is inversely correlated with such disorders. This work aimed to study the impact of methionine-induced hyperhomocysteinemia (HHcy) on two major antiatherogenic functions of HDL, namely their capacity to prevent LDL oxidation and induce in vivo macrophage-specific reverse cholesterol transport.

Methods and results: Methionine-induced HHcy in mice resulted in an approximately 20% decreased concentration of HDL-cholesterol and HDL main protein component, apolipoprotein A-I. The HDL potential to resist oxidation as well as to prevent LDL oxidative modification was impaired in hyperhomocysteinemic mice. Activities of paraoxonase-1 and platelet activation factor acetylhydrolase, two of the main HDL-associated enzymes with antioxidant activity, were reduced. The ability of HDL to efflux cholesterol from macrophages was decreased in hyperhomocysteinemic mice; however, the in vivo macrophage-specific reverse cholesterol transport measured as the output of labeled cholesterol into feces did not significantly differ between groups.

Conclusion: Our data indicate that the HDL from methionine-induced hyperhomocysteinemic mice was more prone to oxidation and displayed lower capacity to protect LDL against oxidative modification than that of control mice, highlighting a mechanism by which a diet-induced HHcy may facilitate progression of atherosclerosis.

Keywords: HDL; Homocysteine; Hyperhomocysteinemia; Methionine; Oxidation; Reverse cholesterol transport.