Rapid hepatic metabolism of 7-ketocholesterol by 11beta-hydroxysteroid dehydrogenase type 1: species-specific differences between the rat, human, and hamster enzyme.
Rapid hepatic metabolism of 7-ketocholesterol by 11beta-hydroxysteroid dehydrogenase type 1: species-specific differences between the rat, human, and hamster enzyme.
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11β-羟基类固醇脱氢酶 1 型 7-酮胆固醇的快速肝代谢：大鼠、人类和仓鼠酶之间的物种特异性差异。
DOI：
10.1074/jbc.m313615200
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
A. Odermatt
中科院分区：
文献类型：
--
作者：
Roberto A. S. Schweizer;M. Zürcher;Z. Balázs;B. Dick;A. Odermatt
11 β-羟基类固醇脱氢酶1型（11 β-HSD 1）通过将无活性的11-酮糖皮质激素转化为活性的11 β-羟基糖皮质激素而在糖皮质激素受体的局部活化中的作用已得到充分证实。目前，11 β-HSD 1被认为是治疗肥胖和糖尿病患者的有希望的靶点。在这里，我们证明了11 β-HSD 1在7-酮胆固醇（7 KC）代谢中的作用，7-酮胆固醇是主要的膳食氧化固醇。比较重组11 β-HSD 1，瞬时表达在人胚肾293细胞，揭示了立体特异性相互转换的7 KC和7 β-羟基胆固醇的大鼠和人11 β-HSD 1，而仓鼠酶相互转换7 α-羟基胆固醇，7 β-羟基胆固醇，和7 KC。与有效催化氧化和还原的裂解物相反，完整细胞仅还原7 KC。使用大鼠和仓鼠肝匀浆、完整大鼠肝细胞和完整仓鼠肝组织切片证实了这些发现。通过甘珀酸（CBX）或2 '-羟基黄烷酮抑制11 β-HSD 1后，7 KC的减少被消除。在体内，大鼠灌胃后，7 KC迅速出现在肝脏中，并转化为7 β-羟基胆固醇。CBX显著降低7 β-羟基胆固醇与7 KC的比率，支持细胞培养实验中7 KC向7 β-羟基胆固醇的11 β-HSD 1依赖性降低的证据。CBX抑制11 β-HSD 1后，7 KC倾向于在肝脏中蓄积，血浆7 KC浓度升高。总之，我们的研究结果表明，11 β-HSD 1有效地催化了饮食7 KC快速肝脏代谢的第一步，这可以解释为什么饮食7 KC对动脉粥样硬化的发展几乎没有影响。
The role of 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) in the local activation of the glucocorticoid receptor by converting inactive 11-ketoglucocorticoids to active 11beta-hydroxyglucocorticoids is well established. Currently, 11beta-HSD1 is considered a promising target for treatment of obese and diabetic patients. Here, we demonstrate a role of 11beta-HSD1 in the metabolism of 7-ketocholesterol (7KC), the major dietary oxysterol. Comparison of recombinant 11beta-HSD1, transiently expressed in human embryonic kidney 293 cells, revealed the stereo-specific interconversion of 7KC and 7beta-hydroxycholesterol by rat and human 11beta-HSD1, whereas the hamster enzyme interconverted 7alpha-hydroxycholesterol, 7beta-hydroxycholesterol, and 7KC. In contrast to lysates, which efficiently catalyzed both oxidation and reduction, intact cells exclusively reduced 7KC. These findings were confirmed using rat and hamster liver homogenates, intact rat hepatocytes, and intact hamster liver tissue slices. Reduction of 7KC was abolished upon inhibition of 11beta-HSD1 by carbenoxolone (CBX) or 2'-hydroxyflavanone. In vivo, after gavage feeding rats, 7KC rapidly appeared in the liver and was converted to 7beta-hydroxycholesterol. CBX significantly decreased the ratio of 7beta-hydroxycholesterol to 7KC, supporting the evidence from cell culture experiments for 11beta-HSD1-dependent reduction of 7KC to 7beta-hydroxycholesterol. Upon inhibition of 11beta-HSD1 by CBX, 7KC tended to accumulate in the liver, and plasma 7KC concentration increased. Together, our results suggest that 11beta-HSD1 efficiently catalyzes the first step in the rapid hepatic metabolism of dietary 7KC, which may explain why dietary 7KC has little or no effect on the development of atherosclerosis.
大鼠肝脏中胆固醇 7 α-羟化酶被竞争性抑制剂 7-氧代胆固醇上调。
DOI：
10.1111/j.1432-1033.1993.tb18082.x
发表时间：
1993
期刊：
European journal of biochemistry
影响因子：
--
作者：
Breuer,O;Sudjana-Sugiaman,E;Eggertsen,G;Chiang,JY;Björkhem,I
通讯作者：
Björkhem,I
甾醇 27-羟化酶缺陷型小鼠中 7-酮胆固醇肝脏代谢的反常增强。
DOI：
10.1016/s1388-1981(02)00156-7
发表时间：
2002
期刊：
Biochimica et biophysica acta
影响因子：
--
作者：
Lyons,MalcolmA;Maeda,Nobuyo;Brown,AndrewJ
通讯作者：
Brown,AndrewJ
糖皮质激素抑制脱氢表雄酮 7-羟基和 7-氧代代谢物的相互转化：11β-羟基类固醇脱氢酶的作用？
影响因子：
3.9
作者：
Robinzon,Boaz;Michael,KristyK;Ripp,SharonL;Winters,StephenJ;Prough,RussellA
通讯作者：
Prough,RussellA