Inhibition of hydroxymethylglutaryl coenzyme A reductase activity does not affect the secretion rate of apolipoproteins B and AI by CaCo-2 cells.
It is believed that the major mechanisms by which hydroxymethylglutaryl coenzyme A reductase inhibitors lower plasma cholesterol levels are by inducing hepatic low-density lipoprotein (LDL) receptor activity and by decreasing apolipoprotein B (apoB) secretion by the liver. However, the intestine is also an important cholesterogenic organ and the possibility that this class of drugs may alter lipoprotein secretion by the intestine has not been fully studied. The purpose of the present study was to examine the possible role of cholesterol in regulating apoB secretion by the intestine by testing if the suppression of cholesterol synthesis by the reductase inhibitor lovastatin affected the secretion of apoB by CaCo-2 human intestinal cells. Differentiated post-confluent CaCo-2 cells were incubated for 24-72 h in serum-free medium in the presence or absence of 5 microM lovastatin, and the secretion rate of lipids, as well as apoB and apolipoprotein AI (apoAI) into the medium, was measured. Lovastatin markedly inhibited the incorporation of [1-14C]acetate into cholesterol for at least 48 h, lowered the content of esterified cholesterol in cells, and reduced their rate of cholesterol secretion. However, under basal conditions lovastatin had no effect 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 alter 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 explained by an increase in the rate of LDL degradation. Furthermore, supplementation with mevalonic acid only reversed about one-half of the effect of lovastatin, suggesting that this effect was at least parly nonspecific or unrelated to inhibition of cholesterol biosynthesis. There was also no specific effect of lovastatin on apoAI secretion. When cells were cultured with [1-14C]acetate for 24 or 72 h, the specific activity of cholesterol in medium at the end of the incubation was the same as in cells, suggesting that cholesterol used for lipoprotein secretion was in equilibrium with bulk cellular cholesterol and was not from a segregated compartment derived from newly synthesized cholesterol. This may explain why apoB secretion by CaCo-2 cells was unaffected by inhibition of cholesterol synthesis with lovastatin.
Pau
E
E
Department of Medicine, University of British Columbia, Vancouver, Canada.
He
Y
Y
Lougheed
M
M
Steinbrecher
U P
UP
D000085:Acetates / Q000378:metabolism; D000230:Adenocarcinoma / Q000378:metabolism; D016632:Apolipoprotein A-I / Q000378:metabolism*; D001055:Apolipoproteins B / Q000378:metabolism*; D002784:Cholesterol / Q000096:biosynthesis* / Q000378:metabolism; D002788:Cholesterol Esters / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007413:Intestinal Mucosa / Q000187:drug effects / Q000378:metabolism*; D008077:Lipoproteins, LDL / Q000378:metabolism; D008148:Lovastatin / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D019301:Oleic Acid; D009829:Oleic Acids / Q000494:pharmacology; D014280:Triglycerides / Q000378:metabolism; D014407:Tumor Cells, Cultured
D000085:Acetates; D016632:Apolipoprotein A-I; D001055:Apolipoproteins B; D002788:Cholesterol Esters; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D008077:Lipoproteins, LDL; D009829:Oleic Acids; D014280:Triglycerides; D019301:Oleic Acid; D002784:Cholesterol; D008148:Lovastatin; D008798:Mevalonic Acid