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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.

调节酰基辅酶A：胆固醇酰基转移酶（ACAT）在各种病理条件下进行了检查。小鼠巨噬细胞来源的J774细胞通过积累胆固醇酯而被乙酰化LDL转化为泡沫细胞。添加格列本脲（一种用于控制糖尿病患者高血糖的药物）可显著抑制胆固醇酯蓄积。使用J774细胞提取物进行的体外ACAT试验表明，格列本脲可作为ACAT的抑制剂。在人单核细胞THP-1细胞中，1，25-二羟维生素D3或9-顺式维甲酸诱导单核-巨噬细胞中主要ACAT同工酶ACAT-1的表达。ACAT- 1在人单核细胞-巨噬细胞的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孵育时，ACAT- 1诱导被显著抑制。添加甲羟戊酸或香叶基香叶基焦磷酸逆转了cerinvastatin的作用，表明在人单核细胞-巨噬细胞分化过程中，未知蛋白的香叶基香叶基化参与ACAT- 1诱导。最后，我们研究了不同浓度对人单核细胞-巨噬细胞分化过程中ACAT- 1表达的影响。转化生长因子P在mRNA水平上进一步加速单核细胞-巨噬细胞分化过程中ACAT 1的诱导。