An established genetic cause of hyperalphalipoproteinemia is deficiency of the cholesterol ester transfer protein (CETP). Using endogenous labeling with amino acids labeled with stable isotopes, we established that the catabolic rates of HDL apolipoproteins A-I and A-II were substantially slower than in normal subjects, accounting for their higher levels. This suggests that reverse cholesterol transport may actually be delayed in CETP deficiency, and that the high levels of HDL may be protective by a different mechanism. In addition, levels of low density lipoproteins (LDL) and its associated apolipoprotein apoB, are significantly lower than normal in these patients. This was found to be due to rapid catabolism of LDL apoB compared with normal. However, LDL from a CETP deficient patient was not catabolized faster in normal subjects, suggesting that the LDL receptor is unregulated in this condition. Increased LDL receptor expression with low levels of LDL may be a second factor contribution to the possible longevity seen in this condition. The HDL particles LpA-I and LpA-I:A-II were isolated from three patients with CETP deficiency and comprehensively characterized. The particles are larger and more lipid-enriched, and contain a population of apoE-rich particles. LpA-I:A-II particles have a higher ratio of apoA-I to apoA-II. Both LpA-I and LpA-I:A-II from CETP deficient subjects have higher affinity but less binding capacity to Hep G2 cells compared with normal particles. An assay to quantitate CETP activity in the plasma has been developed. This will permit the detailed assessment of the influence of CETP activity on HDL metabolism. Ongoing studies involve further investigation into the metabolism of apolipoproteins in CETP deficiency and in other patients with hyperalphalipoproteinemia. These studies included subjects of age 19 to 67 years. 60% of the subjects were women. Four of the subjects were Asian.
