The regulation of tissue-specific actions of glucocorticoids (GCs) goes far beyond the effects of the fluctuation of their circulating levels and can be controlled by local intracellular enzymes. In the past few years, evidence is being gathered not only on the relevance of such enzymes to GC physiological actions but also on their involvement in the pathophysiology of certain chronic disease states, in which circulating GC levels are not necessarily altered. These enzymes are hydroxysteroid dehydrogenases (11β-HSDs; EC 126.96.36.199), which interconvert inactive GCs and the active GCs (Gathercole & Stewart, 2010; Seckl & Walker, 2004; Stewart, 2005; Tomlinson et al., 2004).
2. Regulation of glucocorticoid synthesis by the hypothalamus-pituitary-adrenal axis
GCs are part of the hypothalamus-pituitary-adrenal (HPA) axis, a tighly controlled endocrine component with essential roles in the regulation of physiological processes, such as stress responses, energy metabolism, electrolyte levels, blood pressure, immunity, cognitive functions and cell proliferation and differentiation (Atanasov & Odermatt, 2007; Papadimitriou & Priftis, 2009). Cortisol constitutes the main active hormone of the HPA axis and is released by the adrenal gland under the control of the remaining hormones of the axis. Corticotropin-releasing hormone (CRH), produced by hypothalamic neurons, is released onto the anterior pituitary where it stimulates the synthesis and secretion of the adenocorticotropic hormone (ACTH) into the blood. This occurs in a pulsatile manner and with circadian rhythmicity, with higher levels being secreted in early morning and lowering through the afternoon and night (Gathercole & Stewart, 2010; White, 2008b). ACTH acts on the melanocortin 2 receptor (MC2R) in the adrenal cortex and has only a half-life of 10 min. There, it acutely increases cortisol and androgen production as well as the expression of the enzymes involved in their biosynthetic pathways, having a trophic effect on the adrenal cortex. Enhanced production of cortisol negatively regulates the synthesis and release of both CRH and ACTH by the hypothalamus and the pituitary, respectively, despite the ability of the hypothalamus to change the “set point” for the HPA axis to a higher level during severe or chronic stress. Regulators of the HPA axis include neurogenic and systemic stress (White, 2008b).
The zona fasciculata of the adrenal cortex is where the synthesis of most cortisol occurs. Through the stimulating action of ACTH, cholesterol esters, stored in the cytoplasm of these cells, are unsterified by cholesterol ester hydrolase and converted sequentially to pregnenolone [by cytochrome P450 (CYP) 11A1], progesterone [by 3β-hydroxysteroid dehydrogenase (3β-HSD)], 17-hydroxyprogesterone (by CYP17, 17-hydroxylase function), 11-deoxycortisol (by CYP21A2, 21-hydroxylase function) and cortisol (by CYP11B1, 11-hydroxylase function). As a minor pathway in humans, progesterone is converted to 11-deoxycorticosterone (by CYP11B2, 11-hydroxylase function) and then to corticosterone (by CYP11B2, 18-hydroxylase function). Plasma cortisol has a half-life of 70-120 min where it circulates bound to corticosteroid-binding globulin (CBG or transcortin; 90%) and to albumin (5-7%). The remaining constitutes the free, active, fraction (Tomlinson et al., 2004; White, 2008a).
Most cortisol actions take place through binding to GC receptors (GR) and mineralocorticoid receptors (MR) (Dzyakanchuk et al., 2009), nuclear receptors that are members of the steroid hormone receptor family (Gathercole & Stewart, 2010). Cortisol as well as the main GC in rodents, corticosterone, are active steroids whereas cortisone and 11-dehydrocorticosterone, the latter in rodents, are inactive steroids (Tomlinson et al., 2004). Upon GC-binding, the GR moves into the nucleus where it binds specific GC response elements (GRE) and recruits co-activators and co-repressors, which, once bound, enhance or repress gene transcription (Gathercole & Stewart, 2010). Cortisol and corticosterone are secreted in high amounts [15 mg/d (Cope & Black, 1958; Esteban et al., 1991) and 2 mg/d (Peterson & Pierce, 1960), respectively]. Cortisol concentration in the adrenal vein is about 3.7 nmol/mL whereas cortisone level is 0.13 nmol/mL, contrasting with 0.18 nmol/mL and 0.03 nmol/mL, respectively, in the vena cava (Tortorella et al., 1999). However, free cortisone concentrations are similar to those of free cortisol because of the lower binding of the former to CBG (Tomlinson et al., 2004). Cortisol is inactivated in the liver through conjugation with glucuronide and sulfate and subsequently excreted in the urine (Tomlinson et al., 2004; White, 2008b). In the liver, 5α- and 5β-reductases also inactivate cortisol and cortisone, in conjunction with 3α-HSD, to tetrahydrometabolites: 5α-tetrahydrocortisol, 5β-tetrahydrocortisol and tetrahydrocortisone (Campino et al., 2010; Russell & Wilson, 1994).
3. Regulation of tissue glucocorticoid availability
3.1. 11β-Hydroxysteroid dehydrogenase type 2
Cortisol is inactivated to cortisone, in humans, or corticosterone to 11-dehydrocorticosterone, in rodents, in order to avoid deleterious actions of active GCs overstimulation of the MR. This occurs because cortisol and aldosterone have the same
Congenital deficiency of 11β-HSD2 in humans (Dave-Sharma et al., 1998; Gathercole & Stewart, 2010; Stewart et al., 1996), transgenic deletion in mice (Kotelevtsev et al., 1999) or pharmacological inhibition of 11β-HSD2 results in a clinical condition termed apparent mineralocorticoid excess (AME) syndrome (Sundbom et al., 2008). Affected subjects, despite having normal circulating levels of cortisol and no disturbances of the HPA axis, present with sodium retention, hypertension and hypokalemia (Anagnostis et al., 2009; Andrews et al., 2003; Edwards et al., 1988; Gathercole & Stewart, 2010; Monder et al., 1986; Mune et al., 1995; Palermo et al., 2004; Quinkler & Stewart, 2003; Stewart et al., 1996; Walker, B. & Andrew, 2006). These alterations arise from the activity of GCs on MR-expressing cells since the lack of GC inactivation allows their mineralocorticoid action. In this sense, AME has been considered a ‘Cushing’s disease of the kidney’ (Stewart, 2005).
3.2. 11β-Hydroxysteroid dehydrogenase type 1
Opposite to 11β-HSD2, 11β-HSD1 reactivates inactive cortisone in humans (11-dehydrocorticosterone in rodents) back into cortisol (corticosterone in rodents) within cells expressing the enzyme (Anagnostis et al., 2009; Chapman et al., 2006; Espindola-Antunes & Kater, 2007; Stewart & Krozowski, 1999). This enzyme is in higher amounts in the liver, adipose tissue (AT), lung and the central nervous system. However, pancreas, kidney cortex, adrenal cortex, cardiac myocytes, bone, placenta, uterus, testis, oocytes and luteinized granulosa cells of the ovary, eye, pituitary, fibroblasts and immune, skeletal and smooth muscle cells are also sites of 11β-HSD1 expression (Anagnostis et al., 2009; Bujalska et al., 1997; Cooper & Stewart, 2009; Espindola-Antunes & Kater, 2007; Stewart & Krozowski, 1999; Tomlinson et al., 2004; Whorwood et al., 2001). In these locations, it is associated with GR rather than with MR (Walker, B. & Andrew, 2006). Acting as a reductase, it assures that GCs have access to GR since GR affinity for cortisol is relatively low, what becomes particularly relevant when cortisol levels are at their lowest due to their circadian variation (while cortisone levels remain constant) (Walker, B. & Andrew, 2006; Walker, B. et al., 1995).
Both 11β-HSD1 and 11β-HSD2 are located in the endoplasmic reticulum (ER). However, 11β-HSD1 is facing the lumen (Gathercole & Stewart, 2010; Ozols, 1995) where hexose-6-phosphate dehydrogenase (H6PDH) coexists and converts glucose-6-phosphate to 6-phosphogluconolactone in a reaction that regenerates NADPH from NADP+ (Atanasov et al., 2008; Bujalska et al., 2005; Draper et al., 2003; Dzyakanchuk et al., 2009). The resulting high concentration of NADPH provides the reducing equivalents necessary for 11β-HSD1 activity. Another advantage of this cellular location is the maintenance of important intra-chain disulfide bonds within the 11β-HSD1 protein (Ozols, 1995; Tomlinson et al., 2004). Human 11β-HSD1 has three putative glycosylation sites: asparagine-X-serine sites at positions 123–125, 162–164 and 207–209 of the protein. However, it seems that, although not required for enzyme activity (Walker, E. et al., 2001) nor correct protein folding, glycosylation of 11β-HSD1 may be necessary for preventing protein aggregation and for stabilizing its structure within the ER (Tomlinson et al., 2004).
11β-HSD1 in intact cells such as hepatocytes (Jamieson et al., 1995) and adipocytes (Bujalska et al., 2002a; Bujalska et al., 2002b) [as well as in myocytes (Whorwood et al., 2001)] works mainly as a reductase, which is revealed by the higher affinity of the enzyme derived from these locations for cortisone than for cortisol (Stewart et al., 1994). However, i
As with 11β-HSD2, congenital deficiency of 11β-HSD1 has been described in humans and gives rise to the apparent cortisone reductase deficiency syndrome (Phillipov et al., 1996). In this case, the lack of regeneration of cortisol in peripheral tissues results in the compensatory activation of the HPA axis translation into increased secretion of androgens by the adrenals, which, in affected females, originates hirsutism and oligomenorrhea. 11β-HSD1 congenital deficiency does not appear to protect against obesity. Curiously, the co-inheritance of inactivating mutations in both
3.3. Glucocorticoid deficiency
GC deficiency, seen in Addison’s disease or ACTH deficiency, presents with weight loss and hypoglycemia as clinical features, that seem opposite to those of Cushing’s syndrome (Walker, B., 2007). Some of these features of GC deficiency may be recapitulated in animals with type 2 diabetes mellitus (T2DM) and obesity after treatment with the GR antagonist RU38486 (mifepristone), which present with normalized blood glucose and ameliorated insulin resistance (IR) (Bitar, 2001; Gettys et al., 1997; Havel et al., 1996; Jacobson et al., 2005; Kusunoki et al., 1995; Walker, B., 2007; Watts et al., 2005). However, RU38486 may induce compensation from the HPA axis since it blocks GR involved in the HPA axis negative feedback control. Furthermore, progesterone receptor actions of the drug may also influence energy homeostasis (Picard et al., 2002). These effects of GC deficiency are in favor of the usefulness of strategies of reducing GCs action in the management of blood glucose levels and insulin sensitivity and, possibly, body weight.
3.4. Glucocorticoid excess
Although the elevation of GC levels in situations of stress is essential for survival, their chronic augmentation is associated with deleterious health outcomes. Opposite to their deficit, chronically elevated GC levels cause obesity, T2DM, heart disease, mood disorders and memory impairments (Wamil & Seckl, 2007). Elevated GC levels occur in Cushing’s syndrome due to increased pathological secretion from the adrenal cortex (endogenous) or from prolonged anti-inflammatory GC treatment (iatrogenic) (Newell-Price et al., 2006). Cushing´s disease, a specific type of ACTH-dependent Cushing’s syndrome, is characterized by increased ACTH secretion from a pituitary adenoma that in turn results in higher cortisol secretion from the adrenals (Cushing, 1932). Cushing’s syndrome features include hypertension, rapidly accumulating visceral AT, IR (50% develop T2DM or impaired glucose tolerance) and hepatic steatosis (Stewart, 2005); muscle weakness, dyslipidemia, mood disturbances and infertility (Carroll & Findling, 2010; Newell-Price et al., 2006) are also frequently found. Although many of the clinical components (central weight gain, glucose intolerance and hypertension) are seen in other common conditions, identifying features unusual for the patient´s age (e.g. early onset osteoporosis or hypertension), features more specific to Cushing's syndrome (e.g. easy bruising, facial plethora and violaceous striae) and patients with incidental adrenal mass or polycystic ovary syndrome should be helpful for the diagnosis (Carroll & Findling, 2010).
In effect, Cushing’s syndrome represents a secondary cause of metabolic syndrome (MetSyn) (Stewart, 2005). Circulating cortisol concentrations are higher in patients with the MetSyn, hypertension or impaired glucose tolerance compared with healthy subjects, both in basal conditions and during dynamic stimulation (Anagnostis et al., 2009; Duclos et al., 2005; Misra et al., 2008; Phillips et al., 1998; Sen et al., 2008; Weigensberg et al., 2008), despite being within the normal range (Sen et al., 2008; Walker, B., 2006). This suggests increased activity of cortisol in the periphery and dysregulation of the HPA axis (Sen et al., 2008; Walker, B., 2006). However, it has also been proposed that variations in tissue cortisol concentrations could occur without any changes in plasma cortisol levels, provided that the latter are maintained by normal feedback regulation of the HPA axis (Walker, B. & Andrew, 2006). In regard to the visceral AT, this effect has been termed ‘Cushing’s disease of the omentum’ (Bujalska et al., 1997; Stewart, 2005). Increased 11β-HSD1 activity in visceral AT may generate increased cortisol levels within both the AT and the liver and, thereby promotes features of the MetSyn (Walker, B. & Andrew, 2006). The rate of regeneration of cortisol in the visceral AT has been estimated to be sufficient to increase the concentration of cortisol in the portal vein (from about 120 nmol/L in the systemic circulation to about 155 nmol/L in the portal vein) and this has been confirmed in mice overexpressing 11β-HSD1 in the AT (Masuzaki et al., 2001; Walker, B. & Andrew, 2006).
In agreement, transgenic mice overexpressing 11β-HSD1 selectively in the AT or in the liver faithfully recapitulate MetSyn features and
4. Epigenetics and 11β-hydroxysteroid dehydrogenase type 2
4.1. Epigenetic regulation of gene expression
Epigenetics is not a new area of investigation, as it was first described in the early 1940s (Jablonka & Lamb, 2002), but it is a hot topic of research today, since it became evident that genetic information alone is not sufficient to understand phenotypic manifestations. The way that the DNA code is translated into function depends not only on its sequence but also on the interaction with environmental factors (Ammerpoht & Siebert, 2011; Martin-Subero, 2011).
The word “epigenetic” was first described by Conrad Waddington, in 1942, as “the branch of biology which studies the causal interactions between genes and their products, which bring the phenotype into being” (Jablonka & Lamb, 2002; Waddington, 1942). Epigenetics may be seen as the link between genotype and phenotype, a phenomenon that changes the final outcome of a locus or chromosome without changing the underlying DNA sequence. In other words, epigenetics studies any potentially stable and, ideally, heritable change in gene expression or cellular phenotype that occurs without changes in Watson-Crick base-pairing of DNA (Goldberg et al., 2007; Jablonka & Lamb, 2002). By controlling gene activity and, therefore, the availability of the final gene product in the cell, epigenetic alterations can have similar effects as classical genetic mutations (Ammerpoht & Siebert, 2011).
Today’s epigenetic research is converging in the study of covalent and noncovalent modifications of DNA and histone proteins and the mechanisms by which such modifications influence overall chromatin structure. DNA methylation is perhaps the best characterized chemical modification of chromatin. In mammals, nearly all DNA methylation occurs on cytosine residues of guanidine/cytosine (CpG) dinucleotides. In genome, there are some regions especially rich in CpG in what is called CpG islands, and DNA methylation of these islands correlates with transcriptional repression. DNA methylation plays a role in many cellular processes including X chromosome inactivation in female mammals and mammalian imprinting, which can be both stably maintained (Alikhani-Koopaei et al., 2004; Drake et al., 2012; Goldberg et al., 2007).
Covalent histone modification is another epigenetic mechanism as it changes chromatin conformation, probably because charge-altering modifications, such as acetylation and phosphorylation, which can directly alter the physical properties of the chromatin fiber, lead to changes in higher-order structures. Noncovalent mechanisms such as chromatin remodeling and the incorporation of specialized histone variants provide the cell with additional tools for introducing variation into the chromatin template. Collectively, covalent modifications, nucleosome remodeling and histone variants can work together and introduce meaningful variation into the chromatin fiber. Their collective contribution to epigenetics is being explored (Drake et al., 2012; Goldberg et al., 2007).
4.2. Epigenetic mechanisms of 11β-hydroxysteroid dehydrogenase type 2 regulation
At the present moment, to our knowledge, there is no published research on epigenetic regulation of 11β-HSD1. Nevertheless, besides mutations and environmental factors (like corticosterone hormones, growth factors, shear stress, inflammatory cytokines and hypoxia) (Atanasov et al., 2003; Baserga et al., 2010; Hardy & Yang, 2002) also epigenetic phenomena can regulate 11β-HSD2 abundance and activity (please see below for references).
Additionally, these inhibitors increase mRNA abundance in various tissues (liver, kidney and lung) and decrease the urinary GC metabolite ratios [corticosterone (THB and 5α-THB)]/[11-dehydrocorticosterone (THA)] in Wistar rats, indicating higher 11β-HSD2 activity (Alikhani-Koopaei et al., 2004).
A decrease in 11β-HSD2 activity, by decreasing renal GC deactivation, is associated with hypertension (Baserga et al., 2010; Pereira et al., 2011; 2012). In order to explore the possible relevance of
So, from animal and human studies it can be hypothesized that changes in the
4.3. Intrauterine growth restriction and glucocorticoid prenatal overexposure
versusepigenetic regulation of 11β-hydroxysteroid dehydrogenase type 2
The adverse effects of GC exposure in the prenatal period are related to changes in the expression of the GR and in the intracellular availability and level of GCs, which are modulated by 11β-HSDs as described above. 11β-HSD2, due to its localization to the syncytiotrophoblast layer of the placenta (the site of maternal-fetal exchange), constitutes a functional barrier restricting the free transfer of cortisol (in humans) or corticosterone (in rodents) between the maternal and fetal compartments, by converting maternal active metabolites to the corresponding inactive forms (cortisone and 11-dehydrocorticosterone in humans and rodents, respectively). Thus, the placental 11β-HSD2 protects the fetus from exposure to high levels of maternal GCs, its enzymatic activity being positively correlated with birth weight (in humans and rats) (Albiston et al., 1994; Baserga et al., 2007; Baserga et al., 2010; Benediktsson et al., 1993; Harris & Seckl, 2011; Kajantie et al., 2003; Krozowski et al., 1995; Lesage et al., 2001; Murphy et al., 2002; Pepe et al., 1999; Ronco et al., 2010; Stewart et al., 1995; Wyrwoll et al., 2012).
In line with the above described information, in a well-characterized animal model of intrauterine growth restriction (IUGR) and adult onset hypertension [after bilateral uterine artery ligation, preformed on day 19 of gestation in Sprague-Dawley rats, uteroplacental insufficiency (UPI) occurs], Baserga
Very recently, Wyrwoll
Both syncytialization and Dex stimulate leptin secretion from both the apical and basal surfaces of human choriocarcinoma BeWo cells. Additionally, transport of exogenous leptin is also evident in both the apical to basal and reverse direction, suggesting maternal-fetal exchange of leptin across the human placenta (Wyrwoll et al., 2005). It is recognized that leptin, besides being a proinflammatory cytokine and a regulator of appetite, body fat and bone metabolism, lung development and function, immune and thyroid functions, stress response, metabolic activity by peripheral tissues and energy balance, is also important for the establishment of pregnancy (D'Ippolito et al., 2012; Denver et al., 2011; Malik et al., 2001; Mantzoros et al., 2011; Wyrwoll et al., 2005), being positively associated with fetal (Tsai et al., 2004; Vatten et al., 2002; Wyrwoll et al., 2005) and placental (Jakimiuk et al., 2003; Wyrwoll et al., 2005) growths.
5. Interplay between glucocorticoid availability, diet and fetal programming
Both fetal GC exposure and maternal nutrition contribute to fetal programming. Maternal undernutrition increases cortisol and corticosterone plasma levels (in humans or rats, respectively) in both mothers and growth-retarded fetuses (Lesage et al., 2001).
Accordingly, in pregnant Wistar rats a magnesium-deficient diet (0.003% magnesium
Recent studies have identified programming effects of leptin that influence postnatal phenotype (Granado et al., 2012). Wyrwoll
6. Environmental pollutants
versusepigenetic regulation of 11β-hydroxysteroid dehydrogenase type 2
Cadmium (Cd2+) has been classified as a human carcinogen and has been identified as a new class of endocrine disruptor (Byrne et al., 2009; Henson & Chedrese, 2004; Ronco et al., 2010; Waisberg et al., 2003; Yang et al., 2006). Neonates delivered from mothers who smoked during pregnancy have reduced birth weight, compared to those neonates from non-smoking mothers, what is correlated to placental Cd2+ concentration (Ronco et al., 2005; Ronco et al., 2010). Placentas of mothers delivering low birth weight newborns show significantly higher Cd2+ concentrations than placentas associated to normal birth weight neonates, what suggests that placental accumulation of heavy metals is related to altered fetal growth mechanisms (Llanos & Ronco, 2009; Ronco et al., 2010). Epigenetic alterations mediate some toxic effects of environmental chemicals like Cd2+ (Baccarelli & Bollati, 2009; Ronco et al., 2010), with paradoxical effects on DNA methylation during Cd2+-induced cellular transformation (Ronco et al., 2010; Takiguchi et al., 2003).
Using primary cultured human trophoblast cells as a model system Yang
The present review highlights the importance of 11β-HSDs for the modulation of tissue CG availability. As depicted above, defects on expression and/or activity of these enzymes can affect physiology and result in clinical conditions related with impaired metabolic or blood pressure control. In this regard, knowing that these enzymes can be differentially modulated within different tissues and that nutritional cues or environmental factors, like pollutants, can modify their activity opens avenues for possible interventions at the level of treatment or prevention of conditions related with dysregulated tissue GC levels.
Furthermore, the contribution of epigenetics to the demonstration that tissue GC levels or their actions can be modified through interference with the expression of
This work has been supported by FCT (Fundação para a Ciência e Tecnologia, PEst-OE/SAU/UI0038/2011) through the
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