Evidence that the 11 β-hydroxysteroid dehydrogenase (11 β-HSD1) is regulated by pentose pathway flux -: Studies in rat adipocytes and microsomes
Evidence that the 11 β-hydroxysteroid dehydrogenase (11 β-HSD1) is regulated by pentose pathway flux -: Studies in rat adipocytes and microsomes
复制标题
DOI：
10.1074/jbc.m506026200
复制
发表时间：
2006-01-06
影响因子：
4.8
通讯作者：
Mick, GJ
中科院分区：
文献类型：
--
作者：
McCormick, KL;Wang, XD;Mick, GJ
11 β -羟基类固醇脱氢酶1型（11 β - hsd1）在脂肪、肝脏和其他组织中催化无生物活性的11酮衍生物（可的松、11-脱氢皮质酮）向活性糖皮质激素（皮质醇、皮质酮）的相互转化。它位于内质网的腔室内。由于氧还原酶需要NADPH，我们推断11 β - hsd1可能与胞质戊糖途径在代谢上相互关联，因为该途径是细胞吡啶核苷酸还原的主要生产者。为了验证这一理论，我们在分离的完整的啮齿动物脂肪细胞中同时测量了11 β - hsd1的活性和戊糖途径。已建立的通过戊糖途径（脱氢雄烯二酮或去甲肾上腺素）产生NAPDH的抑制剂抑制11 β - hsd1氧还原酶，同时降低细胞NADPH含量。相反，这些化合物略微增强了11 β - hsd1的逆反应或脱氢酶反应。重要的是，使用分离的完整微粒体，抑制剂不会直接改变串联微粒体11 β - hsd1和己糖-6-磷酸脱氢酶单元。11 β - hsd1的代谢物（皮质酮或11-脱氢皮质酮）分别抑制或增加戊糖通量，表明代谢相互联系。使用分离的完整肝脏或脂肪微粒体，葡萄糖-6-磷酸刺激11 β - hsd1氧还原酶，这种作用被葡萄糖-6-磷酸运输的选择性抑制剂阻断。总之，我们已经证明戊糖途径和11 β - hsd1氧还原酶活性之间的代谢联系依赖于细胞质内NADPH的产生。这些观察结果将胞质碳水化合物通量与旁分泌糖皮质激素的形成联系起来。这些发现的临床相关性可能与营养失调状态（如肥胖）下旁分泌糖皮质激素形成的调节密切相关。
11 beta-hydroxysteroid dehydrogenase type 1 (11 beta-HSD1) catalyzes the interconversion of biologically inactive 11 keto derivatives (cortisone, 11-dehydrocorticosterone) to active glucocorticoids (cortisol, corticosterone) in fat, liver, and other tissues. It is located in the intraluminal compartment of the endoplasmic reticulum. Inasmuch as an oxo-reductase requires NADPH, we reasoned that 11 beta-HSD1 would be metabolically interconnected with the cytosolic pentose pathway because this pathway is the primary producer of reduced cellular pyridine nucleotides. To test this theory, 11 beta-HSD1 activity and pentose pathway were simultaneously measured in isolated intact rodent adipocytes. Established inhibitors of NAPDH production via the pentose pathway (dehydroandrostenedione or norepinephrine) inhibited 11 beta-HSD1 oxo-reductase while decreasing cellular NADPH content. Conversely these compounds slightly augmented the reverse, or dehydrogenase, reaction of 11 beta-HSD1. Importantly, using isolated intact microsomes, the inhibitors did not directly alter the tandem microsomal 11 beta-HSD1 and hexose-6-phosphate dehydrogenase enzyme unit. Metabolites of 11 beta-HSD1 (corticosterone or 11-dehydrocorticosterone) inhibited or increased pentose flux, respectively, demonstrating metabolic interconnectivity. Using isolated intact liver or fat microsomes, glucose-6 phosphate stimulated 11 beta-HSD1 oxo-reductase, and this effect was blocked by selective inhibitors of glucose-6-phosphate transport. In summary, we have demonstrated a metabolic interconnection between pentose pathway and 11 beta-HSD1 oxo-reductase activities that is dependent on cytosolic NADPH production. These observations link cytosolic carbohydrate flux with paracrine glucocorticoid formation. The clinical relevance of these findings may be germane to the regulation of paracrine glucocorticoid formation in disturbed nutritional states such as obesity.