INHIBITION OF FATTY-ACID AND CHOLESTEROL-SYNTHESIS BY STIMULATION OF AMP-ACTIVATED PROTEIN-KINASE
INHIBITION OF FATTY-ACID AND CHOLESTEROL-SYNTHESIS BY STIMULATION OF AMP-ACTIVATED PROTEIN-KINASE
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DOI：
10.1096/fasebj.9.7.7737463
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发表时间：
1995-04-01
期刊：
影响因子：
4.8
通讯作者：
VANDENBERGHE, G
中科院分区：
文献类型：
--
作者：
HENIN, N;VINCENT, MF;VANDENBERGHE, G
AMP激活的蛋白激酶是一种多底物蛋白激酶，在肝脏中，使乙酰辅酶A羧化酶（脂肪酸合成的限速酶）和3-羟基-3-甲基戊二酰辅酶A还原酶（胆固醇合成的限速酶）AICAR失活。发现5-氨基-4-咪唑甲酰胺核苷酸（5-amino 4-imidazolecarboxamide ribotide，ZMP）刺激大鼠肝AMP活化蛋白激酶高达10倍，根据以前的观察，向分离的大鼠肝细胞的悬浮液中加入50-500 μ M的AICA核苷（对应于ZMP的核苷），导致后者的毫摩尔浓度的积累。这伴随着乙酰辅酶A羧化酶和3-羟基-3-甲基戊二酰辅酶A还原酶的剂量依赖性失活。将50-500 μ M的AICA核苷加入到在各种底物（包括葡萄糖和乳酸/丙酮酸）存在下孵育的肝细胞悬浮液中，引起脂肪酸和胆固醇合成的平行抑制。对于乳酸/丙酮酸（10/1 mM），在约100 μ M时获得半数最大抑制，在500 μ M时几乎完全抑制。这些发现为同时控制甘油三酯和胆固醇合成的AMP激活的蛋白激酶的药理刺激剂打开了新的前景。
AMP-activated protein kinase is a multisubstrate protein kinase that, in liver, inactivates both acetyl-CoA carboxylase, the rate-limiting enzyme of fatty acid synthesis, and 3-hydroxy-3-methyl-glutaryl-CoA reductase, the rate-limiting enzyme of cholesterol synthesis, AICAR (5-amino 4-imidazolecarboxamide ribotide, ZMP) was found to stimulate up to 10-fold rat liver AMP-activated protein kinase, with a half-maximal effect at approximately 5 mM. In accordance with previous observations, addition to suspensions of isolated rat hepatocytes of 50-500 mu M AICAriboside, the nucleoside corresponding to ZMP, resulted in the accumulation of millimolar concentrations of the latter. This was accompanied by a dose-dependent inactivation of both acetyl-CoA carboxylase and 3-hydroxy-3-methylglutaryl-CoA reductase. Addition of 50-500 mu M AICAriboside to hepatocyte suspensions incubated in the presence of various substrates, including glucose and lactate/pyruvate, caused a parallel inhibition of both fatty acid and cholesterol synthesis, With lactate/pyruvate (10/1 mM), half-maximal inhibition was obtained at approximately 100 mu M, and near-complete inhibition at 500 mu M AICAriboside. These findings open new perspectives for the simultaneous control of triglyceride and cholesterol synthesis by pharmacological stimulators of AMP-activated protein kinase.