The enzyme lecithin:cholesterol acyl transferase (LCAT) has long been associated with HDL metabolism. Using transgenic New Zealand White rabbits (NZW-LCAT), we have demonstrated that overexpression of LCAT not only raises HDL, it also lowers the concentration of LDL and prevents diet-induced atherosclerosis. We have generated LDL-receptor deficient (WHHL) rabbits overexpressing human LCAT to test the hypothesis that LCAT overexpression mediates it's effects through the LDL receptors. Male WHHL rabbits were identified as either homozygous (-/-) or heterozygous (+/-). Animals were maintained on a regular chow diet for 12-16 months. Aortae were harvested under general anesthesia and analyzed by quantitative planimetry as well as by determination of the aortic free cholesterol (chol)and esterified cholesterol (CE) content. In the presence of one functional LDL receptor allele, there was normalization of both the apolipoprotein B and apolipoprotein A-I in LCAT WHHL +/- kinetics. However, in the WHHL -/-, the kinetics of these lipoproteins were unaffected by LCAT overexpression, and atherogenesis was unaffected. Thus, overexpression of LCAT in rabbits modulates both HDL and LDL metabolism via the LDL receptor. A single functional allele protects heterozygous LDL receptor deficient rabbits from atherosclerosis. LCAT's antiatherogenic effect requires functional LDL receptors.
