ACAT (acyl-coenzyme A: cholesterol acyltransferase) と泡沫細胞コレステロール引き抜きの制御機構

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  • Activation of acyl-coenzyme A: cholesterol acyltransferase by acetylated low dnsity lipoprotein in rat peritoneal macrophages

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Acyl-coenzyme A: cholesterol acyltransferase (ACAT), an integral membrane protein located in the endoplasmic reticulum, catalyzes the intracellular formation of cholesteryl esters (CE) from cholesterol and long-chain fatty acyl-coenzyme A. Pathologically, this enzyme is expected to play an important role in foam cell formation in atherosclerotic lesions. Cytoplasmic CE accumulated in foam cells undergo a continual shuttle between hydrolysis to free cholesterol by neutral cholesteryl ester hydrase and re-esterification to CE by ACAT. This CE turnover is known as CE cycle. Since the turnover rate of CE cycle serves as a regulatory step of high density lipoprotein (HDL)-induced cholesterol efflux from cells, the molecular mechanism for the regulation of ACAT activityis to be elucidated.<br>To clarify the ACAT regulatory mechanism during foam cell formation, we first cloned rat ACAT cDNA and examined effects of acetylated low density lipoprotein (acetyl-LDL) on ACAT in rat peritoneal macrophages. Rat ACAT cDNA consisted of an open reading frame of 1, 635 bp with its deduced protein sequence of 545 amino acids. When resident peritoneal macrophages were incubated with 50μg/ml of acetyl-LDL for 16 hours (CE accumulation at this stage was 35nmol/mg cell protein), the ACAT activity of these cell homogenate was increased 7-fold when determined by the reconstituted assay using cholesterol/phosphatidylcholine liposomes. The ACAT protein of these cell homogenates determined by Western blot with an anti-ACAT antibody (DM10) was also increased 4-fold above control. However, a corresponding increase in their mRNA level determined by Northern blot using rat ACAT cDNA (300-1, 300 of its open reading frame) as a probe was relatively low (1-2-folds). These results suggest that ACAT activation by acetyl-LDL occurs not only at a transcriptional level but also at a posttranscriptional level.

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