11β-Hydroxysteroid dehydrogenase type 1

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) is an enzyme that plays a crucial role in the human body's hormone regulation, particularly in the conversion of cortisone to its active form, cortisol. This enzyme is part of the 11β-Hydroxysteroid dehydrogenase family, which includes another isoform known as 11β-Hydroxysteroid dehydrogenase type 2 (11β-HSD2). 11β-HSD1 is predominantly found in liver and adipose tissue, where it acts primarily as a reductase, converting cortisone to cortisol, the active glucocorticoid.

Function

The main function of 11β-HSD1 is to regulate the local effects of glucocorticoids within cells by modulating the conversion of inactive cortisone to active cortisol. This process is essential for the proper functioning of glucocorticoid-responsive tissues, including the liver, adipose tissue, and central nervous system. By controlling the local concentration of cortisol, 11β-HSD1 plays a significant role in the metabolic syndrome, obesity, diabetes mellitus type 2, and Cushing's syndrome.

Structure

11β-HSD1 is encoded by the HSD11B1 gene located on chromosome 1. The enzyme is a member of the short-chain dehydrogenase/reductase (SDR) family and possesses a typical NADP(H) binding domain. Its structure allows for the specific recognition and conversion of cortisone to cortisol, a reaction that is reversible but primarily operates in the direction of cortisol production in vivo.

Pathophysiology

Alterations in 11β-HSD1 activity have been implicated in several metabolic disorders. Overexpression of 11β-HSD1 in adipose tissue has been linked to the development of obesity and insulin resistance, as increased levels of cortisol within fat cells promote lipid accumulation and impair glucose uptake. Conversely, reduced 11β-HSD1 activity in the liver may contribute to impaired glucose tolerance and hyperglycemia by decreasing the hepatic sensitivity to insulin.

Clinical Significance

Given its role in metabolic regulation, 11β-HSD1 is a target for therapeutic intervention in conditions such as type 2 diabetes and obesity. Inhibitors of 11β-HSD1 have been explored as potential treatments to reduce the adverse effects of excessive glucocorticoid activity in these disorders. Additionally, understanding the enzyme's function and regulation could lead to new insights into the pathogenesis of metabolic syndrome and related conditions.

Research Directions

Current research on 11β-HSD1 is focused on elucidating its precise mechanisms of action and regulation, as well as its interactions with other metabolic pathways. Studies are also underway to develop specific inhibitors or modulators of 11β-HSD1 activity that could be used in the treatment of metabolic diseases.