High density lipoproteins (HDL) have a strong inverse correlation with atherosclerotic cardiovascular disease, and members of kindreds with high levels of HDL (a condition termed hyperalphalipoproteinemia) appear to be protected from heart disease and have longevity. A major goal of this project is to understand the molecular and metabolic bases of hyperalphalipoproteinemia. One genetic cause of high HDL levels is deficiency of the cholesterol ester transfer protein (CETP). The metabolism of apolipoproteins in two Japanese patients, one female and one male, with this condition were studied using amino acids labeled with stable isotopes. Apolipoprotein (apo) A-1, the major HDL protein, was very slowly catabolized, explaining the high plasma levels of this protein. In contrast, apoA-11, another major HDL protein, had only slightly slower catabolism than normal, explaining its relatively normal plasma levels. Hence, deficiency of CETP has a selective effect on the metabolism of apoA-l but not apoA-ll; this may be linked to the longevity seen in these kindreds. In addition, levels of low density lipoproteins (LDL) are low in these patients. This was found to be due to rapid catabolism of LDL. Therefore, CETP deficiency significantly affects the metabolism of both HDL and LDL in an apparently favorable way. This lends support to the concept that inhibition of CETP may be clinically desirable.
