Decreased Hepatic Uptake and Processing of High Density Lipoprotein Unesterified Cholesterol and Cholesteryl Ester with Age in the Rat

Abstract

As part of a study of the effects of aging on lipoprotein metabolism, the uptake and processing in vivo of cholesterol from high density lipoprotein (HDL) was compared in young (3 months of age) and mature (10-12 months of age) rats by studying the fate of HDL [³H] unesterified cholesterol or [^3H] cholesteryl ester after intravenous administration. Radioactivity from [³H] unesterified cholesterol was cleared from the blood more slowly in older rats, and this difference was accounted for by decreased uptake by the liver. Uptake by other tissues was unaffected. In addition, a shift in the distribution of radioactivity across the plasma lipoprotein density range from the d=1.125-1.250g/ml (HDL₃) to the d=1.050-1.085g/ml (HDL₁) fraction was observed in the mature as compared to the young rat group. The secretion of radioactivity from [³H] unesterified cholesterol into bile was also decreased in the older animals, particularly in the first hour after injection of the label. In the case of HDL labeled with [³H] cholesteryl ester, clearance from the blood was similar in both age groups in the first 30min after injection, but was significantly lower in older rats at later time points. After 180min, less radioactivity was found in the VLDL density fraction in mature as compared to young rats, suggesting that hepatic secretion of VLDL cholesterol originating from HDL cholesteryl ester is less efficient in the older animals. The amount of radioactivity from HDL [³H] cholesteryl ester secreted in bile was less in the mature rat group at all time points measured. In addition, labeled bile acid from both HDL unesterified and esterified cholesterol accumulated in the liver to a greater extent in older as compared to younger animals. These results demonstrate that the efficiency of reverse cholesterol transport associated with HDL decreases with age in the rat, and that both slower biliary excretion and slower hepatic metabolism of HDL unesterified cholesterol and cholesteryl ester contribute to this process. It is likely that this effect is associated with the increase in plasma cholesterol levels which occurs with age. Caution is necessary when applying these results to species having the cholesteryl ester transfer protein.