Role of apoA-II in lipid metabolism and atherosclerosis: advances in the study of an enigmatic protein

Our understanding of apolipoprotein A-II (apoA-II) physiology is much more limited than that of apoA-I. However, important and rather surprising advan ces have been produced, mainly through analysis of genetically modified mic e. These results reveal a positive association of apoA-II with FFA and VLDL triglyceride plasma concentrations; however, whether this is due to increa sed V-LDL synthesis or to decreased VLDL catabolism remains a matter of con troversy. As apoA-II-deficient mice present a phenotype of insulin hypersen sitivity, a function of apoA-II in regulating FFA metabolism seems likely. Studies of human beings have shown the apoA-II locus to be a determinant of FFA plasma levels, and several genome-wide searches of different populatio ns with type 2 diabetes have found linkage to an apoA-II intragenic marker, making apoA-II an attractive candidate gene for this disease. The increase d concentration of apoB-containing lipoproteins present in apoA-II transgen ic mice explains, in part, why these animals present increased atherosclero sis susceptibility. In addition, apoA-II transgenic mice also present impai rment of two major HDL antiatherogenic functions: reverse cholesterol trans port and protection of LDL oxidative modification. The apoA-II locus has al so been suggested as an important genetic determinant of HDL cholesterol co ncentration, even though there is a major species-specific difference betwe en the effects of mouse and human apoA-II. As antagonizing apoA-I antiather ogenic actions can hardly be considered die apoA-II function in HDL, this r emains a topic for future investigations. We suggest that the existence of apoA-II or apoA-I in HDL could be an important signal for specific interact ion with HDL receptors such as cubilin or heat shock protein 60.