Cholesterol and lipoprotein metabolism in aging - Reversal of hypercholesterolemia by growth hormone treatment in old rats

Plasma cholesterol levels increase with age, as does the incidence of coron ary heart disease. The mechanisms responsible for the age-related hyperchol esterolemia are not well understood. An interesting hypothesis suggests tha t the relative deficiency in growth hormone (GH), which occurs with aging, contributes to the development of the age-related hypercholesterolemia, bec ause GH has beneficial effects on cholesterol metabolism. In the present wo rk, we tested this hypothesis by the administration of GH to normal rats of varying ages. Plasma lipids and hepatic cholesterol metabolism were charac terized in 2-, 12-, and Is-month-old male Sprague-Dawley rats. In 2-month-o ld rats, GH specifically stimulated the hepatic low density lipoprotein (LD L) receptor expression in a dose-dependent way, both at the protein level a nd at the mRNA level. Concomitantly, plasma cholesterol increased by approx imate to 30% within the large high density lipoprotein and LDL fractions. I n 12-month-old animals, cholesterol 7 alpha-hydroxylase (C7 alpha OH) activ ity was reduced, whereas hepatic LDL receptors and plasma total cholesterol were unchanged. GH treatment (1 mg kg(-1) d(-1)) normalized the activity o f C7 alpha OH and had effects on plasma cholesterol and LDL receptors simil ar to these seen In 2-month-old animals. In 18-month-old rats, plasma chole sterol was increased 2-fold, whereas hepatic LDL receptor expression and C7 alpha OH activity were similar to those of the 12-month-old animals. Infus ion of CH to 18-month-old rats had similar effects on hepatic C7 alpha OH a nd LDL receptors as seen in 12-month-old rats. However, GH treatment strong ly reduced the hypercholesterolemia in 18-month-old animals. We conclude th at the age-dependent increase of plasma cholesterol in rats can be reversed by the administration of GH, presumably through the pleiotropic effects of this hormone on Lipoprotein metabolism.