Effect of Probucol in Lecithin-Cholesterol Acyltransferase–Deficient Mice

Abstract

Abstract-Cellular cholesterol release takes place by at least 2 distinct mechanisms: the lecithin-cholesterol acyltransferase (LCAT)-driven net efflux by cholesterol diffusion and the generation of high density lipoprotein (HDL) with cellular cholesterol and phospholipid on the cell-apolipoprotein interaction. Therefore, LCAT deficiency impairs the former pathway, and the latter can be inhibited by probucol, which interferes with the apolipoprotein-cell interaction. Hence, probucol was given to the LCAT-deficient mice in the attempt to suppress both of these pathways. The mice were fed low (0.2%) and high (1.2%) cholesterol diets containing 0.5% probucol for 2 weeks. LCAT deficiency and probucol markedly decreased plasma HDL, and the effects were synergistic. Tissue cholesterol content was lower in the adrenal glands and ovaries in the LCAT-deficient mice and in the probucol-treated mice, suggesting that HDL is a main cholesterol provider for these organs. It was also moderately decreased in the spleen of the low cholesterol-fed female mice and in the thyroid gland of the low cholesterol-fed male mice. On the other hand, the esterified cholesterol content in the liver was substantially increased by the probucol treatment with a high cholesterol diet in the LCAT-deficient mice but not in the wild-type mice. Among the groups, there was no significant difference in the tissue cholesterol levels in other organs, such as the liver, spleen, thymus, brain, erythrocytes, thyroid gland, testis, and aorta, resulting from either LCAT deficiency or probucol. Thus, the apolipoprotein-mediated mechanism plays a significant role in the export of cellular cholesterol in the liver, indicating that the liver is a major site of the HDL assembly. Otherwise, tissue cholesterol homeostasis can largely be maintained in mice even when the assembly of new HDL is inhibited by probucol in the absence of LCAT. Nonspecific diffusion of cholesterol perhaps adequately maintains the homeostasis in the experimental condition. Key Words: high density lipoproteins Ⅲ lecithin-cholesterol acyltransferase Ⅲ cholesterol efflux Ⅲ cholesterol homeostasis Ⅲ probucol H igh density lipoprotein (HDL) is given a key role in the hypothesis of a cholesterol transport pathway from the peripheral tissues to the liver. The physiological importance of this transport system lies in the fact that cholesterol is not catabolized in the peripheral tissues and must be transported to its catabolic sites, mainly, the liver (for its conversion to bile acids) and, to a much lesser extent, the steroidogenic cells. The hypothesis is extended to the "antiatherogenic" function of this transport pathway, which is based on experimental data indicating that HDL removes the accumulated cholesterol from the cells in vitro 1 and epidemiological evidence indicating that the plasma HDL level is negatively correlated with the risk of coronary heart disease. 2 The most critical biological step of this pathway is the release of cholesterol from the cells. At least 2 distinct mechanisms a...

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