HDL levels are not always predictive of risk of premature CHD. HDL is highly heterogeneous and certain subfractions of HDL may be more specific markers of CHD risk. ApoA-I and apoA-II are the two major apolipoproteins associated with HDL; the catabolism of apoA-II is slower than that of apoA-I in normal subjects. The two major classes of HDL particles include LpA-I and LpA-I:A-II. LpA-I, but not LpA-I,A-II, has been found to be specifically associated with risk of premature CHD. We have established that the catabolism of apoA-I on LpA-I is significantly faster than that of apoA-I on LpA-I:A-II, indicating that the metabolic regulation of these two HDL particles is fundamentally divergent. The most important metabolic determinant of plasma LpA-I levels is the rate of apoA-I catabolism. The major three subpopulations of LpA-I have been preparatively isolated based on their size and characterized. These three subpopulations have different lipid and apolipoprotein composition and different levels of CETP and LCAT activity, indicative of different metabolic roles. Ongoing studies are investigating the catabolism of these subpopulations, in an effort to better understand how size and lipid composition may affect LpA-I catabolism. Lecithin:cholesterol acyltransferase (LCAT) is a plasma enzyme which catalyzes the formation of HDL cholesteryl ester in plasma. We have investigated the metabolism of HDL apolipoproteins and particles in patients with classic (complete) LCAT deficiency and with a partial LCAT deficiency termed fish-eye disease (FED); these disorders are associated with very low levels of HDL but not with increased risk of premature CHD. In both types of LCAT deficiency, apoA-I and especially apoA-II were catabolized substantially faster than in controls. Furthermore, LpA-I:A-II was catabolized faster than LpA-I, resulting in a selective decrease in levels of LpA-I:A-II. This may explain why these patients are not at increased risk for premature CHD despite their low levels of HDL. Ongoing studies are focused on the investigation of HDL metabolism in other patients with low HDL and correlation of the catabolic rates of LpA-I and LpA-I:A-II with risk of premature CHD. These studies included subjects of age 19 to 53 years. 45% of the study subjects were women. The studies included two Asian and one East Indian subject.
