11?-Hydroxysteroid dehydrogenase (HSD-11? or 11?-HSD) enzymes catalyze the conversion of inert 11 keto-products (cortisone) to active cortisol, or vice versa, thus regulating the access of glucocorticoids to the steroid receptors.
The human genome encodes two distinct HSD-11? isozymes (HSD-11? Type 1 and HSD-11? Type 2) on distinct genes. The dehydrogenase activity of a HSD-11? converts a 11beta-hydroxysteroid to the corresponding 11-oxosteroid by reducing NADP+ or NAD+. HSD-11?s are part of the larger class of oxidoreductases and HSD-11? Type 1 has oxidoreductase activity (the reverse of dehydrogenase activity). HSD-11?s participate in c21-steroid hormone metabolism and androgen and estrogen metabolism.
Several structures for HSD-11? Type 1 have been solved to date with various mutations and inhibitors. There are no known structures for HSD-11? Type 2.
Cortisol, a glucocorticoid, binds the glucocorticoid receptor. However, because of its molecular similarity to aldosterone it also binds the mineralcorticoid receptor at higher concentrations. Both aldosterone and cortisol have a similar affinity for the mineralocorticoid receptor; however, there is vastly more cortisol in circulation than aldosterone. To prevent over-stimulation of the mineralocorticoid receptor by cortisol, HSD-11?s convert the biologically active cortisol to the inactive cortisone, which can no longer bind the mineralocorticoid receptor. HSD-11?s co-localizes with intracellular adrenal steroid receptors. Licorice, which contains glycyrrhizinic acid and enoxolone, can inhibit HSD-11? and lead to a mineralocorticoid excess syndrome. Cortisol levels consequently rise, and cortisol binding to the mineralocorticoid receptor produces clinical signs and symptoms of hypokalemia, alkalosis and hypertension (i.e. mineralocorticoid excess).
|Enzyme||Gene||Cofactor Dependence||Expression||Reactions catalyzed|
|HSD-11? Type 1||HSD11B1||NADPH-dependent||Highly expressed in key metabolic tissues including liver, adipose tissue, and the central nervous system.||Reduces cortisone and oxidizes cortisol to cortisone.|
|HSD-11? Type 2||HSD11B2||NAD+-dependent||Expressed in aldosterone-selective tissues, including kidneys, liver, lungs, colon, salivary glands, HSD2 neurons and placenta.||Oxidizes cortisol to cortisone.|
HSD-11?s are enzymes involved in steroid hormone physiology. HSD-11? Type 1 is found in metabolic tissues targeted by glucocorticoids and converts cortisone to active cortisol. HSD-11? Type 1 acts as a reductase producing active cortisol and the amplification of glucocorticoids. This enzyme is most abundant in the liver but can be found in most tissues in the body. HSD11B- Type 1 amplifies glucocorticoid concentrations in the liver and adipose tissue, glucocorticoid excess induces obesity with other features such as hypertension and diabetes mellitus.
HSD-11? Type 2 is expressed by aldosterone-selective tissues and protects the mineralocorticoid receptor from the activation by cortisol by converting it to cortisone using the enzyme 11-Oxoreductase. HSD-11? Type 2 protects tissues from continuous activation by decreasing local cortisol levels and preventing 11-Oxoreductase from activating. In tissues that do not express the mineralocorticoid receptor, such as the placenta and testis, it protects cells from the growth-inhibiting and/or pro-apoptotic effects of cortisol, particularly during embryonic development. Mutations in this gene cause the syndrome of apparent mineralocorticoid excess and hypertension.
The since the main functions of this HSD-11?s are for the regulation of glucocorticoids, the two isozymes are linked to various overstimulation or depletion of glucocorticosteroids that result in chemical imbalances in the human body. The effects of the enzyme as it relates to specific body functions and its associated disorders are listed below.
Effect of Hyperlipidemia on 11?-hydroxysteroid-dehydrogenase
Hyperlipidemia has a great effect on 11?-hydroxysteroid-dehydrogenase. Glucocorticoid is dependent on Glucocorticoid plasma concentration, cellular glucocorticoid receptor expression and the pre-receptor hormone metabolism that is catalyzed by 11?-HSD. There are two types of 11?-Hydroxysteroid dehydrogenases that control cortisol concentration: HSD-11? Type 1 and HSD-11? Type 2. HSD-11? Type 1 is responsible for converting cortisone to cortisol by acting as an oxo-reductase because it is NADP(H) dependent, while HSD-11? Type 2 inactivates cortisol to cortisone via NAD. 10-d hyperlipidemia increases the HSD-11? Type 1 expression in visceral and subcutaneous adipose tissues. Hyperlipidemia decreases HSD-11? Type 2 expression in the liver and adipose tissue. Hyperlipidemia has a great influence on HSD-11? Type 1 and HSD-11? Type 2. This demonstrates that there is likely a relationship between hyperlipidemia and cortisol metabolism. Cushing's Disease, synonymous with hypercortisolism, involves overwhelming the cortisol-neutralizing ability of 11?-HSD2 with high concentrations of cortisol. This allows cortisol to outcompete aldosterone and bind to mineralocorticoid receptors, resulting in the activation of several pathways that increase blood pressure.
HSD-11?s are active in organs and in the adrenal gland. The two isoenzymes take on various duties. During an active state, HSD-11? promotes the increase in glucocorticoids in the hepatocytes and also enhances gluconeogenesis. The type 2 isozyme converts active glucocorticoid hormones to inactive metabolites in target tissues such as kidney, salivary glands, intestines, etc. The activation of the two isozymes of HSD-11? in the kidneys and liver triggers the extra-adrenal formation in alloxan diabetes, which affiliates with the reduction in the synthesis of glucocorticoid hormones in the adrenal glands. The extra-adrenal formation leads to the increased local formation of corticosterone in the liver and has a high activity of reactions with gluconeogenesis. These gluconeogenesis reactions add to the continued metabolic disorders similar to that of diabetes. Thus HSD-11? Type 1 can serve as a potential treatment agents for diabetes, obesity, and metabolic syndrome due to increasing local corticosterone.
HSD-11?s are expressed in the central nervous system of aged individuals. It is essential in Hypothalamo-Pituitary-Adrenal Axis function. HSD-11?s also partakes involvement in the decline of conscious intellectual activity due to aging. The enzyme also contributes to central effects are also during the development stages. For instance, the HSD-11?s Type 2shows frequently in fetal tissues such as a newborn's brain and placenta. If there is an absence or decline in HSD-11?s Type 2 in the fetus tissues, there are negative developmental consequences such as anxiety.
HSD-11?s are partly responsible for intracellular metabolism that determine the operation of glucocorticoids within cells. Glucocorticoids impact the brain development and ultimately the function of the central nervous system. So much so, that if there is a surplus or scant amounts of it, the consequences are deformities throughout one's entire life. HSD-11? Type 1 is responsible for activating glucocorticoids while HSD-11? Type 2 is responsible for deactivating them. The consequences for HSD-11? Type 1 activating glucocorticoids is that there is a decline in cognition especially as one ages. Contrarily, the effects of HSD-11? Type 2 occur during development. Some consequences of a high expression HSD-11? Type 2 are anxiety and cardiometabolic disorders, both of which are part of the early age glucocorticoid programming.
Infants born underweight are susceptible to having metabolic disease throughout their lives. The presence of glucocorticoids has contributed to the relatively low infant birth weight. A decrease in HSD-11? Type 2 in the placenta can lead to infant restriction in growth, specifically during the first 12 months of an infant's life. The reason for this is because the HSD-11? Type 2 is meant to be expressed in high quantities in the placenta, This is so because the enzymes secure the fetus from exposure to increased levels of glucocorticoids, which are linked to underweight newborns.