Overexpression of human lecithin:cholesterol acyltransferase in cholesterol-fed rabbits: LDL metabolism and HDL metabolism are affected in a gene dose-dependent manner.

Lecithin:cholesterol acyltransferase (LCAT) is an enzyme well known for its involvement in the intravascular metabolism of high density lipoproteins; however, its role in the regulation of apolipoprotein (apo) Bcontaining lipopro- teins remains elusive. The present study was designed to in- vestigate the metabolic mechanisms responsible for the differ- ential lipoprotein response observed between cholesterol-fed hLCAT transgenic and control rabbits. '"I-labeled HDL apoA-I and L'51-labeled LDL kinetics were assessed in age- and sex-matched groups of rabbits with high (HE), low (LE), or no hLCAT expression after 6 weeks on a 0.3% cholesterol diet. In HE, the mean total cholesterol concentration on this diet, mg/dl (230 i- 50), was not significantly different from that of either LE (313 ? 46) or controls (332 ? 52) due to the elevated level of HDL-C observed in HE (127 ? 19), as compared with both LE (100 ? 33) and controls (31 ? 4). In contrast, the mean nonHDL-C concentration for HE (103 It 33) was much lower than that for either LE (213 ? 39) or controls (301 ? 55). FPLC analysis of plasma confirmed that HDL was the predominant lipoprotein class in HE on the che lesterol diet, whereas cholesteryl ester-rich, apokontaining lipoproteins characterized the plasma of LE and, most nota- bly, of controls. In vivo kinetic experiments demonstrated that the differences in HDL levels noted between the three groups were attributable to distinctive rates of apoA-I catabo- lism, with the mean fractional catabolic rate (FCR, d-') of apoA-I slowest in HE (0.282 ? 0.03), followed by LE (0.340 It 0.01) and controls (0.496 ? 0.04). A similar, but opposite, pattern was observed for nonHDL-C levels and LDL metab- olism (h-'), such that HE had the lowest nonHDL-C levels with the fastest rate of clearance (0.131 5 0.027), followed by LE (0.057 ? 0.009) and controls (0.031 ? 0.001). Strong correlations were noted between LCAT activity and both apoA-I (r = -0.868, P < 0.01) and LDL (r = 0.670, P = 0.06) FCR, indicating that LCAT activity played a major role in the mediation of lipoprotein metabo1ism.l In summary, these data are the first to show that LCAT overexpression can regulate both LDL and HDL metabolism in cholesterol-fed rabbits and provide a potential explanation for the preven- tion of diet-induced atherosclerosis observed in our previous