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  • In C BL mice activation of

    2019-07-24

    In C57BL/6 mice, activation of FXR by the agonist GW4064 increased SR-BI mRNA and protein expression and increased fasting plasma corticosterone levels after overnight fasting [37]. As described before, the receptor SR-BI regulates transport of cholesteryl esters from HDL and LDL [38] into the adrenals [37]. No effect on plasma ACTH levels, adrenal weight, or adrenal expression of steroidogenic genes was seen, however [37]. Furthermore, FXR is also known to regulate HSD3B2 expression in human adrenocortical cells [39], which is important for conversion of pregnenolone to progesterone. This regulation does not exist in mice. Transfection of H295R adrenocortical cells with FXR expression vector increased FXR expression levels and treatment with chenodeoxycholic acid (CDCA) caused a 25-fold increase in the mRNA for organic solute transporter alpha (OSTα), a known FXR target gene, and HSD3B2 mRNA levels [39]. OSTα/OSTß – most likely a facilitative transporter, which can export or import dependent on concentration gradients – is not only expressed on the basolateral membrane of enterocytes, where it plays a critical role in the intestinal (-)-Bicuculline methiodide of bile acids and the enterohepatic circulation, but also in many other tissues including the adrenal glands [40,41]. The function of this heteromeric transporter is presumably to facilitate the uptake of conjugated bile acids into the adrenals and to export conjugated steroid intermediates from the adrenal into circulation [42] (Fig. 1). Bile acids are not only able to interfere with steroidogenesis but also with glucocorticoid catabolism in liver and kidney affecting various enzymatic steps (Fig. 2). Bile acids abrogate 11β-HSD2 activity, important for cortisol breakdown, in vitro in HEK-293 cells [43] and bile duct-ligated rats display reduced 11β-HSD2 mRNA levels in the kidney [44]. Another molecular link between bile acid and steroid metabolism is the cytochrome P450 enzyme CYP3A4 (Fig. 2), responsible for hydroxylation and elimination of bile acids [45], as shown both in vitro as well as in vivo studies [46]. The expression of Cyp3A4 – or Cyp3a11 in rodents – in the liver is induced by elevated concentrations of secondary bile acids via the pregnane X receptor (PXR) and by the primary bile acid CDCA via FXR [46]. CYP3A4, however, is not only crucial for catabolism of bile acids when in excess, but also plays a role in catabolism of cortisol [47]. Cortisol as well as cortisone are broken down into tetrahydrometabolites by 5α-reductase and 5β-reductase as well as 3α-hydroxsteroid dehydrogenase (3α-HSD) in the liver [14]. Both 5β-reductase and 3α-HSD are involved in bile acid synthesis [48] and 5β-reductase activity is inhibited by various bile acids in vitro [2]. Obstructive cholestasis in rats also reduces transcript abundance of 5β-reductase and 3α-HSD [2]. Dietary CDCA reduced urinary excretion of 3α,5β-tetrahydrocorticosterone in rats – a finding that was mirrored by diminished urinary excretion of 3α,5β-tetrahydrocortisol in eight women with obstructive jaundice [2]. An additional parallel between bile acid and steroid synthesis is the regulation of the hepatic and adrenal cholesterol homeostasis. The liver X receptors (LXRα and LXRß) are nuclear hormone receptors activated by oxysterols, endogenous metabolites of cholesterol [49]. LXRs form heterodimers with retinoid X receptors (RXRs) to regulate transcription [50] of ATP-binding cassette (ABC) transporters (ABCA1, ABCG1 and ABCG5/ABCG8), sterol regulatory element-binding protein 1c (SREBP-1c) [[51], [52], [53], [54]], apolipoprotein E (apoE) [55] and cholesterol 7alpha-hydroxlase (CYP7A1) [56,57], which is the rate-limiting step in the catabolism of hepatic cholesterol to bile acids. The adrenal gland also expresses high quantities of LXRβ and LXRα, the latter modulating the transcription of important genes involved in three major pathways of adrenal cholesterol utilization [58]: 1) cholesterol efflux (ABCA1, ABCG1), 2) storage (apoE, SREBP-1c), 3) conversion to steroid hormones (StAR). LXRα thus functions as a safety mechanism preventing overaccumulation of free cholesterol, as an increase in intracellular free cholesterol activates LXRα and causes an upregulation of apoE, SREBP-1c, ABCA1 as well as StAR and steroidogenic enzymes [58].