The cholesterol ester transfer protein (CETP) transfers lipids such as cholesterol and triglycerides among apoB-containing lipoproteins (VLDL, LDL) and apoA-I-containing lipoproteins (HDL). Genetic deficiency of CETP causes low levels of apoB and LDL and high levels of apoA-I and HDL, and has been proposed to be a protective condition against the development of coronary heart disease. We intensively investigated the lipoprotein metabolism in two unrelated patients with CETP deficiency using both endogenous labeling with stable isotopes and exogenously labeled radiotracers. We established that the catabolic rates of both apoA-I and HDL-cholesterol ester were substantially slower than in normal subjects, accounting for their higher plasma 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. We also determined that the rate of conversion of VLDL to LDL is significantly delayed in CETP deficiency, resulting in markedly increased catabolism of VLDL before its conversion to LDL. This accounts for the low plasma levels of apoB and LDL cholesterol in these subjects. These combined results suggest that pharmacologic inhibition of CETP would be likely to delay catabolism of HDL and to cause metabolic channelling of VLDL to a degradation pathway rather than to LDL formation. 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. 56% of the subjects were women. Six of the subjects were Asian.
