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  • Introduction Glucocorticoids are released in

    2022-08-12

    Introduction Glucocorticoids are released in response to stress and play an important role in inflammation, cellular growth, development, body fluid homeostasis, carbohydrate, lipid, and protein metabolism. However, circulating glucocorticoid excess has been associated with a classical phenotype of adverse metabolic features including central obesity, insulin resistance, type 2 diabetes and hepatic triacylglycerol (TAG) accumulation. These effects are exemplified in patients with Cushing’s disease, which is characterised by increased glucocorticoid secretion due to pituitary adenoma autonomously secreting ACTH [1]. The majority of glucocorticoid actions are mediated through a classical steroid hormone pathway whereby upon glucocorticoid binding in the cytosol to its cognate glucocorticoid receptor (GR), there is dissociation from the associated heat shock protein complex and subsequent translocation to the nucleus where the glucocorticoid-GR complex binds to glucocorticoid response elements to alter gene transcription. Importantly, and independent of circulating levels, glucocorticoid action is also regulated at a pre-receptor level within key target tissues, including the liver, by a series of enzymes that can either enhance their clearance or augment their action. In this regard, the 11β-HSD isozymes and the 5α-reductases (5αR) have been extensively described. 11β-HSD1 catalyses the conversion of inactive cortisone to active 17 aag and global deletion of 11β-HSD1 has been associated with increased insulin sensitivity, protection from hepatic steatosis, reduced expression of lipolytic enzymes in adipose tissue and a beneficial metabolic phenotype in mice [[2], [3], [4], [5]]. Furthermore, hepatic over-expression of 11β-HSD1 has been linked to increased hepatic TAG content in mice [6]. In humans, there is evidence of decreased hepatic 11β-HSD1 activity in obese patients [7,8]. Similarly, deletion of 5αR type 1 has been associated with increased hepatic lipid accumulation in mice [9,10], whilst, in urinary steroid profiles from obese patients, 5αR activity increases with indices of insulin resistance [11,12]. 5β-reductase (AKR1D1) is a member of the aldo-keto-reductase (AKR) superfamily 1 of enzymes and is the first member of the 1D subfamily (AKR1D1), along with the rat (AKR1D2) and the rabbit (AKR1D3) 5β-reductase isoforms [13,14]. The role of AKR1D1 to regulate glucocorticoid (and other steroid hormone) action has not been examined in detail and there are currently no published data that have tried to assess its importance in regulating glucocorticoid action using appropriate in vitro cell systems. The enzyme encoded by this gene has a molecular weight of 37 kDa. It utilizes NADPH as an electron donor and catalyses a stereospecific irreversible double bond reduction between the 4th and the 5th carbon of the A-ring of steroids. It is highly expressed in the liver where it uses the C19-C27 steroids (including cortisol, cortisone, testosterone and androstenedione) as substrates to generate all 5β-reduced dihydrosteroid metabolites [15,16]. Both cortisol and cortisone are metabolized to 5β-dihydrocortisol and 5β-dihydrocortisone respectively by AKR1D1, and are then subsequently converted, in a non-rate limiting step, to their tetrahydro-metabolites (tetrahydrocortisol, 5β-THF and tetrahydrocortisone, 5β-THE) by 3α-hydroxysteroid dehydrogenases, AKR1C1, AKR1C2, AKR1C3, AKR1C4, which are all expressed in human liver [17]. Thus, enzymes from the same gene family work sequentially to produce tetrahydro-steroids. The demonstration that AKR1D1 can alter glucocorticoid availability to impact upon cellular function is currently lacking, although several studies have characterised the ability of AKR1D1 to metabolize steroid hormones and bile acid (BA) intermediates [15,18,19] using purified recombinant protein. However, little is known about the ability of this enzyme to regulate steroid hormone availability using intact cellular systems. The aim of our study was therefore to demonstrate that in appropriate human cell models (notably liver derived cell lines where AKR1D1 is highly expressed), AKR1D1 is able to metabolize glucocorticoids and regulate GR activation and down-stream gene transcription.