Regulation of ACAT in diabetes and insuliln resistant

ACAT 在糖尿病和胰岛素抵抗中的调节

基本信息

批准号：
12671118
负责人：
MIYAZAKI Akira
金额：
$ 2.18万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-12671118/
关键词：
ACAT macrophage atherosclerosis foam cells cholesterol ester differentiation

项目摘要

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.

检查了各种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。添加格列本脲（一种控制糖尿病患者高血糖的药物）可显着抑制胆固醇酯的积累。使用 J774 细胞提取物进行的体外 ACAT 测定表明，格列本脲可作为 ACAT 的抑制剂。 ACAT-1（单核巨噬细胞中的主要 ACAT 同工酶）的表达由 1,25-二羟基维生素 D3 或 9-顺式视黄酸在人单核 THP-1 细胞中诱导。 ACAT-1 在人类单核巨噬细胞自发分化过程中增加。当人单核细胞-巨噬细胞与 HMG-CoA 还原酶抑制剂西立伐他汀一起孵育时，ACAT-1 诱导被显着抑制。添加甲羟戊酸或香叶基香叶基焦磷酸可逆转西林伐他汀的作用，表明未知蛋白的香叶基香叶基化参与人单核细胞-巨噬细胞分化过程中的ACAT-1诱导。最后，我们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。转化生长因子 P 在单核细胞-巨噬细胞分化过程中在 mRNA 水平上进一步加速了 ACAT 1 的诱导。