Our understanding of
apolipoprotein A-II (
apoA-II) physiology is much more limited than that of
apoA-I. However, important and rather surprising advances have been produced, mainly through analysis of genetically modified mice. These results reveal a positive association of
apoA-II with FFA and
VLDL triglyceride plasma concentrations; however, whether this is due to increased VLDL synthesis or to decreased VLDL catabolism remains a matter of controversy. As
apoA-II-deficient mice present a phenotype of
insulin hypersensitivity, 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 populations with
type 2 diabetes have found linkage to an
apoA-II intragenic marker, making
apoA-II an attractive candidate gene for this disease. The increased concentration of
apoB-containing
lipoproteins present in
apoA-II transgenic mice explains, in part, why these animals present increased
atherosclerosis susceptibility. In addition,
apoA-II transgenic mice also present impairment of two major HDL antiatherogenic functions: reverse
cholesterol transport and protection of
LDL oxidative modification. The
apoA-II locus has also been suggested as an important genetic determinant of
HDL cholesterol concentration, even though there is a major species-specific difference between the effects of mouse and human
apoA-II. As antagonizing
apoA-I antiatherogenic actions can hardly be considered the
apoA-II function in HDL, this remains 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 interaction with HDL receptors such as
cubilin or
heat shock protein 60.