Age-related decreases in tissue sterol acquisition are mediated by changes in cholesterol synthesis and not low density lipoprotein uptake in the rat

The present investigation compared plasma cholesterol levels and lipoprotein profiles, and absolute rates of sterol synthesis and low density lipoprotein (LDL) uptake in various organs of immature (4 weeks old) and mature (15 weeks) rats. The plasma cholesterol level and its distribution among the major lipoprotein density fractions were similar in both groups. Using [³H]water as a substrate for measuring sterol synthesis in vivo, the content of newly synthesized cholesterol (³H-labeled digitonin-precipitable sterols; [³H]DPS) was several fold higher in all tissues of the young, compared to the old, rats when normalized per g of tissue. In contrast, whole-body [³H]DPS content was identical at 29.5 and 29.3 μmol/hr in young and old rats, respectively, despite a 4.4-fold difference in body weight (102 vs. 453 g). The importance of different organs to total-body sterol synthesis remained similar with increasing age although the skin (11 vs. 24% of total) rather than the small bowel (15 vs. 8%) became the second most important organ after the liver (49 vs. 45%) in the older animals. When LDL uptake was determined in these same organs, using a constant infusion technique, the rates of clearance were higher only in the adrenal glands, adipose tissue, and skin of the young animals; whereas these rates were essentially the same in the liver and gastrointestinal tract, the two organs that are quantitatively most important for LDL catabolism. Even when these clearance rates were normalized to the whole organ or to 100 g of body weight, the differences in LDL uptake in the two age groups were minor compared to the major decrease in rates of cholesterol synthesis that were observed with aging. Finally, calculation of absolute rates of tissue cholesterol acquisition from both sources indicated that, in most organs, the majority of tissue cholesterol was derived from local synthesis rather than from LDL uptake in both age groups and that, with increasing age, total cholesterol acquisition decreased several-fold primarily as a consequence of the diminished rate of sterol synthesis. These studies demonstrate that the growth and ageing in the rat there is a dramatic decrease in the rate of tissue cholesterol synthesis while the uptake of LDL-cholesterol remains essentially unchanged.