Regulation of ACAT in diabetes and insuliln resistant

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Regulation of acyl-coenzyme A : cholesterol acyltransferase (ACAT) under various pathological conditions was examined. Mouse macrophage-derived J774 cells are converted to foam cell with acetylated LDL by accumulating cholesterol esters. Addition of glibenclamide, a drug for controlling hyperglycemia in diabetic patients, significantly inhibited cholesterol ester accumulation. ACAT assay in vitro using the extracts of J774 cells demonstrated that glibenclamide acts as an inhibitor for ACAT. Expression of ACAT-1, a major ACAT isozyme in monocyte-macrophages, was induced by 1,25-dihydroxyvitamin D3 or 9-cis-retinoic acid in human monocytic THP-1 cells. ACAT- 1 increases during spontaneous differentiation of human monocyte-macrophages. When human monocyte-macrophages were incubated with an HMG-CoA reductase inhibitor, cerivastatin, ACAT- 1 induction was significantly suppressed. Addition of mevalonate or geranylgeranylpyrophosphate reversed the effect of cerinvastatin, indicating that geranylgeranylation of an unknown protein is involved in ACAT- 1 induction during human monocyte-macrophage differentiation. We finally examined the effects of various cytokmes on ACAT- 1 expression in human monoyte-macrophages during differentiation. Transforming growth factor P further accelerated ACAT 1 induction during monocyte-macrophage differentiation at the mRNA levels.