Centre for Endocrinology, Diabetes and Metabolism, School of Clinical and Experimental Medicine, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Mol Cell Endocrinol. 2011 Apr 10;336(1-2):213-8. doi: 10.1016/j.mce.2010.12.004. Epub 2010 Dec 10.
Hexose-6-phosphate dehydrogenase (H6PDH) has emerged as an important factor in setting the redox status of the endoplasmic reticulum (ER) lumen. An important role of H6PDH is to generate a high NADPH/NADP(+) ratio which permits 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) to act as an oxo-reductase, catalyzing the activation of glucocorticoids (GCs). In H6PDH knockout mice 11β-HSD1 assumes dehydrogenase activity and inactivates GCs, rendering the target cell relatively GC insensitive. Consequently, H6PDHKO mice have a phenotype consistent with defects in the permissive and adaptive actions of GCs upon physiology. H6PDHKO mice have also offered an insight into muscle physiology as they also present with a severe vacuolating myopathy, abnormalities of glucose homeostasis and activation of the unfolded protein response due to ER stress, and a number of mechanisms driving this phenotype are thought to be involved. This article will review what we understand of the redox control of GC hormone metabolism regulated by H6PDH, and how H6PDHKO mice have allowed an in-depth understanding of its potentially novel, GC-independent roles in muscle physiology.
己糖-6-磷酸脱氢酶（H6PDH）已成为内质网（ER）腔还原状态的重要因素。H6PDH 的一个重要作用是产生高 NADPH/NADP(+) 比值，使 11β-羟甾类脱氢酶 1（11β-HSD1）能够作为氧化还原酶，催化糖皮质激素（GCs）的激活。在 H6PDH 敲除小鼠中，11β-HSD1 假定具有脱氢酶活性并使 GCs 失活，使靶细胞对 GCs 的敏感性相对降低。因此，H6PDHKO 小鼠的表型与 GCs 对生理学的许可和适应性作用的缺陷一致。H6PDHKO 小鼠还为肌肉生理学提供了一个深入的了解，因为它们还表现出严重的空泡性肌病、葡萄糖稳态异常以及由于内质网应激导致未折叠蛋白反应的激活，并且许多驱动这种表型的机制被认为与之相关。本文将综述我们对 H6PDH 调节的 GC 激素代谢的氧化还原控制的理解，以及 H6PDHKO 小鼠如何使我们深入了解其在肌肉生理学中潜在的新型、非 GC 依赖性作用。
