Digoxin and ouabain increase the synthesis of cholesterol in human liver cells
Digoxin and ouabain increase the synthesis of cholesterol in human liver cells
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DOI：
10.1007/s00018-009-9018-5
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发表时间：
2009-05-01
影响因子：
8
通讯作者：
Riganti, C.
中科院分区：
文献类型：
--
作者：
Campia, I.;Gazzano, E.;Riganti, C.
地高辛和哇巴因是抑制Na+/K+-ATP酶的类固醇药物，广泛用于治疗心脏病。它们还可能具有其他作用，例如对类固醇激素的代谢的影响，尽管到目前为止还没有证据表明这些心脏活性糖苷对胆固醇合成的影响。在这里，我们报道地高辛和哇巴因增加了人肝 HepG2 细胞中胆固醇的合成，增强了 3-羟基-3-甲基戊二酰辅酶 A 还原酶 (HMGCR)（胆固醇合成的限速酶）的活性和表达。这种效应是通过甾醇调节元件结合蛋白-2 (SREBP-2) 与 HMGCR 启动子的结合介导的，并且在 SREBP-2 沉默或胆固醇含量增加的细胞中消失。地高辛和哇巴因与胆固醇竞争与 SREBP 裂解激活蛋白的结合，是人肝细胞中胆固醇合成的关键调节剂。
Digoxin and ouabain are steroid drugs that inhibit the Na+/K+-ATPase, and are widely used in the treatment of heart diseases. They may also have additional effects, such as on metabolism of steroid hormones, although until now no evidence has been provided about the effects of these cardioactive glycosides on the synthesis of cholesterol. Here we report that digoxin and ouabain increased the synthesis of cholesterol in human liver HepG2 cells, enhancing the activity and the expression of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), the rate-limiting enzyme of the cholesterol synthesis. This effect was mediated by the binding of the sterol regulatory element binding protein-2 (SREBP-2) to the HMGCR promoter, and was lost in cells silenced for SREBP-2 or loaded with increasing amounts of cholesterol. Digoxin and ouabain competed with cholesterol for binding to the SREBP-cleavage-activating protein, and are critical regulators of cholesterol synthesis in human liver cells.