Farnesol is not the nonsterol regulator mediating degradation of HMG-CoA reductase in rat liver.
Farnesol is not the nonsterol regulator mediating degradation of HMG-CoA reductase in rat liver.
复制标题
金合欢醇不是介导大鼠肝脏中 HMG-CoA 还原酶降解的非甾醇调节剂。
DOI：
10.1006/abbi.1996.0180
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发表时间：
1996
影响因子：
3.9
通讯作者：
Ness,GC
中科院分区：
文献类型：
--
作者：
Keller,RK;Zhao,Z;Chambers,C;Ness,GC
最近的一份报告，其中使用培养的肿瘤细胞，确定法尼醇为3-羟基-3-甲基戊二酰辅酶A（HMG-CoA）还原酶加速降解所需的非甾醇甲羟戊酸衍生代谢物（C. C.科雷尔湖Ng和P.A. Edwards，1994，J.Biol.Chem.269，17390-17393）。我们研究了这一建议的联系，在动物中通过测量肝脏法尼醇水平和HMG-CoA还原酶降解率的条件下，以前显示改变还原酶的稳定性。在正常大鼠中，通过高压液相色谱法定量的肝脏法尼醇水平为0.10 ± 0.08 μg/g，HMG-CoA还原酶的半衰期为2.5 h。以1 g/kg体重给予甲羟戊酸内酯以提供除胆固醇外的所有非甾醇代谢物，使法尼醇水平增加6倍，而不显著影响还原酶的半衰期。用角鲨烯合成酶抑制剂萨拉戈萨酸A治疗大鼠，使肝脏法尼醇水平升高10倍，并使HMG-CoA还原酶的半衰期降低至0.25小时。然而，尽管HMG-CoA还原酶蛋白显著稳定，但喂食洛伐他汀并没有降低肝脏法尼醇水平。此外，用500 mg/kg体重的法尼醇对大鼠进行插管未能降低HMG-CoA还原酶蛋白的半衰期，改变酶活性水平，或改变免疫反应性蛋白的水平，尽管肝脏法尼醇水平增加了1000倍。这些观察结果表明，法尼醇本身不会诱导大鼠肝脏中HMG-CoA还原酶的加速降解。
A recent report, in which cultured tumor cells were used, identified farnesol as the nonsterol mevalonate-derived metabolite required for the accelerated degradation of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase (C. C. Correll, L. Ng, and P. A. Edwards, 1994,J. Biol. Chem.269, 17390–17393). We examined this proposed linkage in animals by measuring hepatic farnesol levels and rates of HMG-CoA reductase degradation under conditions previously shown to alter the stability of the reductase. In normal rats, the hepatic farnesol level, quantified by high-pressure liquid chromatography, was 0.10 ± 0.08 μg/g and the half-life of HMG-CoA reductase was 2.5 h. Administration of mevalonolactone at 1 g/kg body wt to provide all nonsterol metabolites in addition to cholesterol increased farnesol levels 6-fold without significantly affecting the half-life of the reductase. Treatment of rats with zaragozic acid A, an inhibitor of squalene synthase, raised hepatic farnesol levels 10-fold and decreased the half-life of HMG-CoA reductase to 0.25 h. However, feeding lovastatin to rats did not lower hepatic farnesol levels despite a marked stabilization of HMG-CoA reductase protein. Moreover, intubation of rats with 500 mg/kg body wt of farnesol failed to decrease the half-life of HMG-CoA reductase protein, alter the levels of enzyme activity, or change of the levels of immunoreactive protein despite an increase of 1000-fold in hepatic farnesol levels. These observations indicate that farnesol per se does not induce accelerated degradation of HMG-CoA reductase in rat liver.