INHIBITION OF HYDROXYMETHYLGLUTARYL COENZYME-A REDUCTASE-ACTIVITY DOES NOT AFFECT THE SECRETION RATE OF APOLIPOPROTEIN-B AND APOLIPOPROTEIN-AL BY CACO-2 CELLS

It is believed that the major mechanisms by which hydroxymethylglutary l coenzyme A reductase inhibitors lower plasma cholesterol levels are by inducing hepatic low-density lipoprotein (LDL) receptor activity an d by decreasing apolipoprotein B (apoB) secretion by the liver. Howeve r, the intestine is also an important cholesterogenic organ and the po ssibility that this class of drugs may alter lipoprotein secretion by the intestine has not been fully studied. The purpose of the present s tudy was to examine the possible role of cholesterol in regulating apo B secretion by the intestine by testing if the suppression of choleste rol synthesis by the reductase inhibitor lovastatin affected the secre tion of apoB by CaCo-2 human intestinal cells. Differentiated post-con fluent CaCo-2 cells were incubated for 24-72 h in serum-free medium in the presence or absence of 5 mu M lovastatin, and the secretion rate of lipids, as well as apoB and apolipoprotein Al (ape Al) into the med ium, was measured. Lovastatin markedly inhibited the incorporation of [1-C-14]acetate into cholesterol for at least 48 h, lowered the conten t of esterified cholesterol in cells, and reduced their rate of choles terol secretion. However, under basal conditions lovastatin had no eff ect on the secretion rate of apoB. After stimulation of apoB secretion by addition of 0.8 mM oleic acid to the medium, lovastatin did not al ter apoB secretion in the first 2 days of incubation, but reduced the content of apoB in media from the 3rd day by 30%. This could not be ex plained by an increase in the rate of LDL degradation. Furthermore, su pplementation with mevalonic acid only reversed about one-half of the effect of lovastatin, suggesting that this effect was at least partly nonspecific or unrelated to inhibition of cholesterol biosynthesis. Th ere was also no specific effect of lovastatin on apoAI secretion. When cells were cultured with [1-C-14]acetate for 24 or 72 h, the specific activity of cholesterol in medium at the end of the incubation was th e same as in cells, suggesting that cholesterol used for lipoprotein s ecretion was in equilibrium with bulk cellular cholesterol and was not from a segregated compartment derived from newly synthesized choleste rol. This may explain why apoB secretion by CaCo-2 cells was unaffecte d by inhibition of cholesterol synthesis with lovastatin.