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    • Rare mutations can impair the molecular function of GR

    2022-06-14

    Rare mutations can impair the molecular function of GR and alter tissue sensitivity to GCs in humans, resulting in primary generalized GC resistance (PGGR) and hypersensitivity (PGGH) [14]. Familial and sporadic PGGR, or Chrousos Syndrome, is characterized by general and partial insensitivity of tissues to GC and compensatory hyperactivation of the HPA axis. PGGH represents the opposite, with GC hypersensitivity and consequent hypoactivation of the HPA axis. As the cost of whole-genome sequencing declines, it is becoming feasible to examine the relationship between mutations and polymorphisms in the GR gene and the considerable variation between patients in their response to GC treatment.
    GR Ligands Are Commonly Prescribed Drugs GCs and their synthetic analogs are among the most widely prescribed drugs in the world. Their anti-inflammatory and immunosuppressive properties are important for the treatment of rheumatoid arthritis, cerebral edema, asthma, and other allergic reactions, and the prevention of organ transplant rejection and graft-versus-host disease 15, 16. GCs are more potent than are nonsteroidal anti-inflammatory drugs (NSAIDS, e.g., aspirin), yet up to one-third of patients with severe ghrelin receptor antagonist may be unresponsive to them [17]. GC resistance is likely a result of complex interactions between an individual’s genetic make-up and the environment. In addition, GCs cause undesirable metabolic effects that can prematurely end treatment. Features of metabolic syndrome, including obesity, dyslipidemia, insulin resistance, and type 2 diabetes mellitus, are prevalent, as well as osteoporosis and muscle atrophy [4]. Metabolic dysfunction arising from the chronic use of GC medication, termed ‘Cushing’s syndrome’, is related to Cushing’s disease, but more common in western societies that frequently prescribe GC drugs. Although many of the problems stemming from chronic GC excess can be explained by the acute effects of GC that induce insulin resistance, raise plasma glucose, and increase protein catabolism, the underlying molecular mechanism(s) explaining how prolonged activation of GR causes weight gain is poorly understood. Indeed, GCs acutely induce lipolysis in human adipose tissue [13] and, consistent with their catabolic effects, cause rats to lose weight over time 18, 19. A possible explanation for this paradox may involve depot-specific responses to excess GC that simultaneously trigger the breakdown and growth of limb and abdominal adipose tissue, respectively [13]. GCs facilitate adipocyte differentiation 20, 21, although whether this contributes to the obesity of Cushing’s syndrome is unknown. While more work is needed to resolve the paradox, it serves as a reminder of the limitations of rodent models to provide insight into human physiology.
    Tissue-Specific Function for GR Intense effort has been dedicated to understanding how ubiquitously expressed GR elicits complex tissue-specific effects by controlling distinct gene programs in different cell types. Not surprisingly, mechanisms involving both GC availability and GR function provide answers. Cell type-specific GC availability is modulated by a pair of hydroxysteroid 11-beta dehydrogenase (HSD11B) enzymes that control intracellular cortisol and/or cortisone levels. HSD11B1 converts the inert GC cortisone to cortisol, while HSD11B2 catalyzes the reverse reaction. Through distinct tissue-specific expression profiles, they amplify or mute responses to the circulating cortisol level set by the HPA axis [22]. HSD11B2 is found in kidney, lung, colon, salivary glands, and HSD2 neurons, all of which are responsive to aldosterone, an activating ligand for the mineralocorticoid nuclear receptor (MR). Given that cortisol also activates MR, HSD11B2 prevents its illicit activation by decreasing intracellular cortisol concentrations. HSD11B1 is expressed in key metabolic tissues, such as adipose, to amplify GC signaling. For example, HSD11B1 overexpression in mouse brown adipose tissue (BAT) decreases BAT thermogenic activity, while pharmacological HSD11B1 inhibition or knockdown enhances its function [23], consistent with corticosterone inhibition of BAT in rodents [24], and demonstrating that local GC levels matter. Of note, local levels of GCs may also be affected by extra-adrenal GC synthesis. For example, local GC production by the intestinal epithelium may regulate intestinal immune responses [25].