IN-VIVO CHOLESTEROL KINETICS IN APOLIPOPROTEIN E-DEFICIENT AND CONTROL MICE

The in vivo total body cholesterol transport of homozygous apoE-defici ent (-/-) and control (+/+) mice was evaluated by compartmental analys is of plasma cholesterol decay. Body cholesterol fractional catabolic rates of chow fed mutants were less (-/-, 0.17 +/- 0.02; +/+, 0.51 +/- 0.06 day(-1)) and body cholesterol contents greater (-/-, 68 +/- 5; /+, 48 +/- 5 mu mol) than controls. The body cholesterol expansion of the chow-fed mutant was extracellular with at least half in plasma. Ch olesterol transport, i.e., the mass entering, moving through, and exit ing the body each day, was similar (-/-, 6.9 +/- 0.7; +/+, 8.5 +/- 0.9 mu mol/day) for homozygotes and controls on chow, and both tripled wi th cholesterol feeding. Differing from controls, however, mutants had considerable expansions of plasma and body cholesterol (-/-, 166 +/- 2 1; +/+, 59 +/- 11 mu mol) with increments in peripheral tissue cholest erol contents. Cholesterol feeding increased control hepatic cholester ol without a change in plasma, whereas mutants had large increments in plasma cholesterol with no change in liver. Consistent with impaired hepatic uptake of cholesterol, mutants had much slower plasma clearanc e of lipoprotein cholesterol, as well as slower transfer to catabolic pools than normals. Treatment of homozygotes with lovastatin doubled b oth plasma cholesterol concentration and body cholesterol transport in dicating the importance of apoE-dependent cell cholesterol transfer in synthetic down-regulation with this agent. These data indicate that m ice lacking apoE have lower affinity hepatic uptake of plasma remnant cholesterol. This is an important factor in producing a lower total bo dy cholesterol fractional catabolic rate which results in a considerab le increase in body cholesterol mass to achieve transport capacities e quivalent to mice with apoE.