Lavery Gareth G, Walker Elizabeth A, Draper Nicole, Jeyasuria Pancharatnam, Marcos Josep, Shackleton Cedric H L, Parker Keith L, White Perrin C, Stewart Paul M
Department of Internal Medicine and Pediatrics, University of Texas Southwestern Medical Center, Dallas, Texas 75390, USA.
J Biol Chem. 2006 Mar 10;281(10):6546-51. doi: 10.1074/jbc.M512635200. Epub 2005 Dec 15.
The local generation of active glucocorticoid by NADPH-dependent, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) oxoreductase activity, has emerged as an important factor in regulating hepatic glucose output and visceral adiposity. We have proposed that this NADPH is generated within the endoplasmic reticulum by the enzyme hexose-6-phosphate dehydrogenase. To address this hypothesis, we generated mice with a targeted inactivation of the H6PD gene. These mice were unable to convert 11-dehydrocorticosterone (11-DHC) to corticosterone but demonstrated increased corticosterone to 11-DHC conversion consistent with lack of 11beta-HSD1 oxoreductase and a concomitant increase in dehydrogenase activity. This increased corticosterone clearance in the knock-out mice resulted in a reduction in circulating corticosterone levels. Our studies define the critical requirement of hexose-6-phosphate dehydrogenase for 11beta-HSD1 oxoreductase activity and add a new dimension to the investigation of 11beta-HSD1 as a therapeutic target in patients with the metabolic syndrome.
通过依赖烟酰胺腺嘌呤二核苷酸磷酸（NADPH）的11β-羟基类固醇脱氢酶1型（11β-HSD1）氧化还原酶活性在局部生成活性糖皮质激素，已成为调节肝脏葡萄糖输出和内脏脂肪的一个重要因素。我们提出，这种NADPH是由己糖-6-磷酸脱氢酶在内质网内生成的。为验证这一假说，我们构建了H6PD基因靶向失活的小鼠。这些小鼠无法将11-脱氢皮质酮（11-DHC）转化为皮质酮，但皮质酮向11-DHC的转化增加，这与缺乏11β-HSD1氧化还原酶以及脱氢酶活性的相应增加一致。基因敲除小鼠中皮质酮清除增加导致循环皮质酮水平降低。我们的研究确定了己糖-6-磷酸脱氢酶对11β-HSD1氧化还原酶活性的关键需求，并为将11β-HSD1作为代谢综合征患者治疗靶点的研究增添了新内容。
