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.

在各种病理条件下检查了酰基辅酶A：胆固醇酰基转移酶（ACAT）的调节。小鼠巨噬细胞衍生的J774细胞通过积累胆固醇酯通过乙酰化LDL转化为泡沫细胞。添加Glibenclamide是一种用于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细胞提取物在体外测定ACAT分析表明，Glibenclamide是ACAT的抑制剂。 1,25-二羟基维生素D3或9- cis-近访酸在人类单核细胞THP-1细胞中诱导ACAT-1，单核细胞巨噬细胞中主要的ACAT同工酶的表达。 ACAT-1在人类单核细胞巨噬细胞的自发分化过程中增加。当人类单核细胞巨噬细胞与HMG-COA还原酶抑制剂（cerivastatin）孵育时，ACAT-1诱导被显着抑制。甲基甲酸盐或黄烷基呼吸磷酸盐的添加逆转了Cerinvastatin的作用，表明未知蛋白的黄烷基凝聚酰化参与了人类单核细胞巨噬细胞分化过程中ACAT-1诱导。最终，我们研究了各种细胞因素对分化过程中人类巨噬细胞中ACAT-1表达的影响。转化生长因子P进一步加速了在mRNA水平的单核细胞巨噬细胞分化过程中的ACAT 1诱导。