Effect of probucol in lecithin-cholesterol acyltransferase-deficient mice - Inhibition of 2 independent cellular cholesterol-releasing pathways in vivo

Citation
S. Tomimoto et al., Effect of probucol in lecithin-cholesterol acyltransferase-deficient mice - Inhibition of 2 independent cellular cholesterol-releasing pathways in vivo, ART THROM V, 21(3), 2001, pp. 394-400
Citations number
33
Language
INGLESE
art.tipo
Article
Categorie Soggetti
Cardiovascular & Hematology Research
Journal title
ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY
ISSN journal
1079-5642 → ACNP
Volume
21
Issue
3
Year of publication
2001
Pages
394 - 400
Database
ISI
SICI code
1079-5642(200103)21:3<394:EOPILA>2.0.ZU;2-H
Abstract
Cellular cholesterol release takes place by at least 2 distinct mechanisms: the lecithin-cholesterol acyltransferase (LCAT)-driven net efflux by chole sterol diffusion and the generation of high density lipoprotein (HDL) with cellular cholesterol and phospholipid on the cell-apolipoprotein interactio n. Therefore, LCAT deficiency impairs the former pathway, and the latter ca n be inhibited by probucol, which interferes with the apolipoprotein-cell i nteraction. Hence, probucol was given to the LCAT-deficient mice in the att empt to suppress both of these pathways. The mice were fed low (0.2%) and h igh (1.2%) cholesterol diets containing 0.5% probucol for 2 weeks. LCAT def iciency and probucol markedly decreased plasma HDL, and the effects were sy nergistic. Tissue cholesterol content was lower in the adrenal glands and o varies in the LCAT-deficient mice and in the probucol-treated mice, suggest ing that HDL is a main cholesterol provider for these organs. It was also m oderately decreased in the spleen of the low cholesterol-fed female mice an d in the thyroid gland of the low cholesterol-fed male mice. On the other h and, the esterified cholesterol content in the liver was substantially incr eased by the probucol treatment with a high cholesterol diet in the LCAT-de ficient mice hut not in the wild-type mice. Among the groups, there was no significant difference in the tissue cholesterol levels in other organs, su ch as the liver, spleen, thymus, brain, erythrocytes, thyroid gland, testis , and aorta, resulting from either LCAT deficiency or probucol. Thus, the a polipoprotein-mediated mechanism plays a significant role in the export of cellular cholesterol in the liver, indicating that the liver is a major sit e of the HDL assembly. Otherwise, tissue cholesterol homeostasis can largel y be maintained in mice even when the assembly of new HDL is inhibited by p robucol in the absence of LCAT. Nonspecific diffusion of cholesterol perhap s adequately maintains the homeostasis in the experimental condition.