11β-Hydroxysteroid dehydrogenase 1: Regeneration of active glucocorticoids is only part of the story

11β-Hydroxysteroid dehydrogenase 1 (11β-HSD1) is an endoplasmic reticulum membrane enzyme with its catalytic site facing the luminal space. It functions primarily as a reductase, driven by the supply of its cosubstrate NADPH by hexose-6-phosphate dehydrogenase (H6PDH). Extensive research has been performed on the role of 11β-HSD1 in the regeneration of active glucocorticoids and its role in inflammation and metabolic disease. Besides its important role in the fine-tuning of glucocorticoid action, 11β-HSD1 is a multi-functional carbonyl reductase converting several 11- and 7-oxosterols into the respective 7-hydroxylated forms. Moreover, 11β-HSD1 has a role in phase I biotransformation reactions and catalyzes the carbonyl reduction of several non-steroidal xenobiotics. Recent observations from experiments using selective inhibitors and studies with transgenic mice indicated a role for 11β-HSD1 in oxysterol metabolism and in bile acid homeostasis, with evidence for glucocorticoid-independent effects on gene expression. This review focuses on the promiscuity of 11β-HSD1 to accept structurally distinct substrates and discusses recent progress mainly on non-glucocorticoid substrates. This article is part of a Special Issue entitled 'Enzyme Promiscuity and Diversity'.