Regulation of ACAT in diabetes and insuliln resistant

观察不同病理条件下酰基辅酶A：胆固醇酰基转移酶（ACAT）的调节。小鼠巨噬细胞来源的J774细胞通过积累胆固醇酯转化为具有乙酰化LDL的泡沫细胞。加入格列本脲，一种控制糖尿病患者高血糖的药物，可以显著抑制胆固醇酯的积累。体外ACAT实验表明，格列本脲对J774细胞提取物有抑制作用。1,25-二羟基维生素D3或9-顺式维甲酸诱导单核巨噬细胞中主要的ACAT同工酶ACAT-1的表达。ACAT- 1在人单核巨噬细胞自发分化过程中升高。当人单核巨噬细胞与HMG-CoA还原酶抑制剂cerivastatin孵育时，ACAT- 1的诱导被显著抑制。添加甲羟戊酸盐或香叶基焦磷酸可逆转cerinvastatin的作用，表明在人单核巨噬细胞分化过程中，一种未知蛋白的香叶基酰化参与了ACAT- 1的诱导。我们最后研究了不同细胞因子对人单核巨噬细胞分化过程中ACAT- 1表达的影响。在单核-巨噬细胞分化过程中，转化生长因子P在mRNA水平上进一步加速ACAT 1的诱导。

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.