11beta-Hydroxysteroid dehydrogenase type 1 as a pharmacological target in metabolic disease

The metabolic syndrome is a collection of associated disorders, affected by lifestyle, genetic predisposition and environment, and emerges as a consequence of the Western society lifestyle. It describes a variety of cardiovascular and atherosclerotic risk factors including insulin resistance, obesity, dyslipidemia and arterial hypertension. The connection between insulin resistance and diabetes mellitus type 2 has been well established, and the major abnormalities are peripheral insulin resistance, beta-cell dysfunction and increased endogenous glucose production.

Glucocorticoids have received considerable interest among the many factors that play a role in the metabolic syndrome. Excess glucocorticoid levels cause glucose intolerance and insulin resistance, as demonstrated by the clinical picture of Cushing s syndrome, which closely resembles the metabolic syndrome. A further understanding of the disease mechanisms behind the metabolic syndrome is essential to diminish its increasing impact on health of the Western population. Novel pharmacological treatment strategies based on modulation of glucocorticoid function is a feasible approach to combat this metabolic disease.

Glucocorticoids are steroid hormones that belong to the superfamily of ligand-activated nuclear receptors. An emerging concept describes tissue-specific metabolic reactions that many hormones undergo, including steroids, resulting in a pre-receptor control mechanism. The OH/keto group on the C11-position in glucocorticoids determines if the steroid can activate its receptor or is 'inert'. The enzyme responsible for this conversion of glucocorticoids is 11beta-hydroxysteroid dehydrogenase (11beta-HSD). Two different isozymes of 11beta-HSD (11beta-HSD1 and 11beta-HSD2) are described. Their functions are to activate and inactivate glucocorticoids in a tissue-dependent manner. 11beta-HSD1 mediates activation of the glucocorticoid precursor cortisone (in humans) to the active glucocorticoid receptor ligand cortisol. It is widely expressed in central and peripheral tissues involved in glucose and carbohydrate metabolism, including liver and adipose tissue. Because of the beneficial effects of reduced tissue glucocorticoid levels in the metabolic syndrome and related disorders, 11beta-HSD1 is a pursued target of pharmacological intervention.

The aims of the study were to investigate structure-function relationships and functional effects of 11beta-HSD1. The results show that the hydrophobic enzyme 11beta-HSD1 can be expressed with high activity as a full length, membrane bound enzyme in the yeast system Pichia pastoris and can be purified as a soluble, N-terminally truncated form expressed in E.coli, by using metal-chelate chromatography. The full-length and truncated enzymes have equivalent enzymatic properties in regard to glucocorticoid metabolism. 11beta-HSD1 orthologs from human, rat, mouse and guinea pig show considerable inter-species variations as inferred by primary structure determinations and inhibitor characterization. A 11beta-HSD1 selective arylsulfonamidothiazole inhibitor class was investigated and is currently developed as a promising tool for the treatment of insulinresistance. Several derivatives were analyzed and show a high degree of species selectivity, with different inhibitor mechanisms and low nM affinities towards the human enzyme.

11beta-HSD1 mediates glucocorticoid-activation in pancreatic islets of Langerhans, and thereby regulates glucose-stimulated insulin secretion. Whereas glucocorticoids suppress insulin secretion in the insulin resistant ob/ob mouse model, they increase insulin release in lean mice. Hence it is postulated that the known beneficial effects of 11beta-HSD1-inhibition in the pharmacological treatment of diabetes mellitus can be extended to include improved insulin release in diabetic mice. Glucocorticoid-activation in lean mice may at an early phase lead to increased insulin secretion and priming of the â-cells to stress-adaptation, whereas long-term exposure leads to a decrease in insulin secretion.

A novel role of 11beta-HSD1 in 7-oxosterol metabolism was discovered and investigated using recombinant 11beta-HSD1 orthologs. The enzymatic origin of endogenous 7beta-OH-cholesterol in humans is assigned to 11beta- HSD1, possibly pointing to an involvement in atherosclerosis. Species differences in 7-oxysterol metabolism can be explained on the basis of 11beta-HSD1 specificities.

List of scientific papers

I. Hult M, Jornvall H, Oppermann UC (1998). Selective inhibition of human type 1 11beta-hydroxysteroid dehydrogenase by synthetic steroids and xenobiotics. FEBS Lett. 441(1): 25-8.
https://pubmed.ncbi.nlm.nih.gov/9877158

II. Hult M, Shafqat N, Elleby B, Mitschke D, Svensson S, Forsgren M, Barf T, Vallgarda J, Arahamsen L, Oppermann U (2004). Active site variability of type 1 11beta-hydroxysteroid dehydrogenase revealed by selective inhibitors and cross-species comparisons. [Manuscript]

III. Davani B, Khan A, Hult M, Martensson E, Okret S, Efendic S, Jornvall H, Oppermann UC (2000). Type 1 11beta -hydroxysteroid dehydrogenase mediates glucocorticoid activation and insulin release in pancreatic islets. J Biol Chem. 275(45): 34841-4.
https://pubmed.ncbi.nlm.nih.gov/10973946

IV. Hult M, Ortsater H, Schuster G, Graedler F, Ploner A, Adamski J, Jornvall H, Bergsten P, Oppermann U (2004). Glucocorticoids increase insulin secretion in lean mice through multiple pathways and mechanisms. [Manuscript]

V. Hult M, Elleby B, Shafqat N, Svensson S, Rane A, Jornvall H, Arahamsen L, Oppermann U (2004). Human and rodent type 1 11beta-hydroxysteroid dehydrogenase are 7beta-hydroxycholesterol dehydrogenases involved in oxysterol metabolism. Cell Mol Life Sci. 61: 992-9.