SELECTIVE UPTAKE OF HDL CHOLESTERYL ESTERS IS ACTIVE IN TRANSGENIC MICE EXPRESSING HUMAN APOLIPOPROTEIN-A-I

The direct non-endocytotic uptake of cholesteryl esters (CE) from high density lipoprotein (HDL) plays a major role in I-IDL CE metabolism i n rats and rabbits. In vitro evidence indicates it may also play such a role in humans. However, a study in mice (tracing the CE and apoA-I moieties of HDL) concluded that, while selective uptake played a role in normal animals, it did not in transgenic mice which express predomi nantly human apoA-I (Chajek-Shaul et al., 1991. Proc. Natl. Acad. Sci. USA, 88: 6731-6735); thus human apoA-I was apparently unable to suppo rt selective uptake. These conclusions rested on plasma decay data tha t represent a composite of all tissue and which may obscure tissue-spe cific factors. Thus we reexamined the matter by measuring the rates of uptake of HDL components by individual tissues using intracellularly trapped tracers. Plasma decay data were much as reported in the refere nced study Nonetheless the fractional rate of uptake of HDL CE was gre ater than that of apoA-I in adrenal gland and liver, indicating select ive uptake. Kidney took up apoA-I tracer at a greater fractional rate than CE tracer, apparently by filtration and reabsorption of free apoA -I, and this uptake was at a greater fractional rate in the transgenic mice than in normal mice. Thus, the lack of evidence for selective up take in the plasma decay data of the transgenic mice was explained by a higher rate of renal uptake of apoA-I and not by a diminished rate o f selective uptake in other tissues. This result was the same whether examined using tracers incorporated into normal or transgenic mouse HD L. The result was also confirmed using synthetic HDL that carried [C-1 4]sucrose octaoleate as an independent marker of HDL particle uptake. Thus, human apoA-I supports selective uptake with no substantial evide nce that it is less efficacious than mouse apoA-I.