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Review

11b-Hydroxysteroid dehydrogenase 1: Regeneration of activeglucocorticoids is only part of the story

Alex Odermatt *, Petra KlusonovaDivision of Molecular and Systems Toxicology, Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel, Switzerland

A R T I C L E I N F O

Article history:Received 12 July 2014Received in revised form 13 August 2014Accepted 14 August 2014Available online xxx

Keywords:11b-Hydroxysteroid dehydrogenaseMetabolismGlucocorticoidBile acidCholesterolXenobioticCarbonyl reduction

A B S T R A C T

11b-Hydroxysteroid dehydrogenase 1 (11b-HSD1) is an endoplasmic reticulum membrane enzymewith its catalytic site facing the luminal space. It functions primarily as a reductase, driven by thesupply of its cosubstrate NADPH by hexose-6-phosphate dehydrogenase (H6PDH). Extensive researchhas been performed on the role of 11b-HSD1 in the regeneration of active glucocorticoids and its role ininflammation and metabolic disease. Besides its important role in the fine-tuning of glucocorticoidaction, 11b-HSD1 is a multi-functional carbonyl reductase converting several 11- and 7-oxosterols intothe respective 7-hydroxylated forms. Moreover, 11b-HSD1 has a role in phase I biotransformationreactions and catalyzes the carbonyl reduction of several non-steroidal xenobiotics. Recentobservations from experiments using selective inhibitors and studies with transgenic mice indicateda role for 11b-HSD1 in oxysterol metabolism and in bile acid homeostasis, with evidence forglucocorticoid-independent effects on gene expression. This review focuses on the promiscuity of11b-HSD1 to accept structurally distinct substrates and discusses recent progress mainly onnon-glucocorticoid substrates.This article is part of a Special Issue entitled ‘Enzyme Promiscuity and Diversity’.

ã 2014 Elsevier Ltd. All rights reserved.

Contents

1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 002. Glucocorticoids as substrates of 11b-HSD1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 003. Other steroid substrates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 004. Role of 11b-HSD1 ?in the reduction of 7-oxolithocholic acid and impact on bile acid homeostasis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 005. A role for 11b-HSD1 ?in the metabolism of 7-oxocholesterol and association with atherosclerosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 006. Carbonyl reduction of non-steroidal compounds by 11b-HSD1 . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 007. Conclusions and outlook . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Acknowledgement . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 00

Contents lists available at ScienceDirect

Journal of Steroid Biochemistry & Molecular Biology

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1. Introduction

Glucocorticoids are essential endocrine hormones involved inthe regulation of almost all major physiological functions,including energy metabolism, cell proliferation and differentiation,reproduction, immune system, and cardiovascular and brainfunction. Upon the loss of adrenal glucocorticoid production,without hormonal substitution, the human organism survives

* Corresponding author.E-mail address: alex.odermatt@unibas.ch (A. Odermatt).

http://dx.doi.org/10.1016/j.jsbmb.2014.08.0110960-0760/ã 2014 Elsevier Ltd. All rights reserved.

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only for a couple of days, emphasizing its importance. Thus,disturbances of glucocorticoid homeostasis are linked withseveral major diseases such as osteoporosis, metabolicsyndrome, cardiovascular complications, immune and psychiatricdisorders [1,2]. The identification and characterization of theadrenal corticosteroid hormones and the discovery of theanti-inflammatory effects of the glucocorticoid cortisone inpatients with rheumatoid arthritis was later honored by the NobelPrize to Drs. Philip S. Hench, Edward C. Kendall and TadeusReichstein. This intensified the research on glucocorticoids andboosted the development of synthetic glucocorticoids; many ofthem are still widely used in therapy [2,3]. Glucocorticoids are of

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therapeutic value and they still belong to the most widelyprescribed drugs. Interestingly, cortisone and the syntheticderivative prednisone, which is widely used as co-medicationafter organ transplantation [4], both are inactive by themselvesand need to undergo metabolic activation (see Section 2).

During evolution, several mechanisms appeared that allow afine-tuned regulation of glucocorticoid signaling and downstreameffects. This includes two nuclear receptors with moderate andhigh affinity for glucocorticoids (i.e., glucocorticoid receptor (GR)and mineralocorticoid receptor (MR)) and two short-chaindehydrogenase/reductase (SDR) enzymes (i.e., 11b-hydroxysteroiddehydrogenase 1 (11b-HSD1) and 11b-HSD2) that interconvertactive (cortisol, corticosterone) and inactive glucocorticoids(cortisone, 11-dehydrocorticosterone).

11b-HSD2 is an endoplasmic reticulum (ER) membraneprotein and acts exclusively as an oxidase on endogenousglucocorticoids, thereby playing an important role in thetissue-specific inactivation of glucocorticoids (recently reviewedin [5]). It utilizes NAD+ as a cofactor and is expressed inmineralocorticoid target tissues such as kidney, colon and sweatglands where it serves to protect the MR from excessive activationby glucocorticoids, thereby rendering access of aldosterone to thereceptor. 11b-HSD2 is also expressed in placenta to protect thefetus from high maternal glucocorticoids.

The ability of liver tissue homogenates to metabolize adrenalhormones has already been described in the 1950s [6]; however,11b-HSD1 was finally purified from rat liver microsomes and clonedmore than 30 years later [7,8]. Purified 11b-HSD1 and lysatesexpressing recombinant 11b-HSD1 exhibit both dehydrogenase andreductase activity [9]; however, in intact hepatocytes and macro-phage the enzyme functions predominantly as a reductase [10].Kinetic studies of 11b-HSD1 expressed in cultured cells usingrecombinant Vaccinia virus suggested that cofactor availabilitymight determine the reaction direction of 11b-HSD1 [9]. Thedetermination of the intracellular localization then revealed that11b-HSD1 is an integral membrane enzyme of the ER with a lumenalorientation of its active site [11–13]. The subsequent identification ofthe luminal enzyme hexose-6-phosphate dehydrogenase (H6PDH)as a supplier of NADPH [14,15] provided an explanation for thereaction direction of 11b-HSD1 in intact cells. H6PDH catalyzes thefirst two steps of the pentose phosphate pathway in the ER andrepresents a major source of intraluminal NADPH. In contrast to thecytosolic glucose-6-phosphate dehydrogenase, H6PDH has abroader substrate specifity, not discriminating between glucose-6-phosphate, galactose-6-phosphate, 2-deoxyglucose-6-phosphateand other hexose-6-derivatives [16–19]. Nevertheless, it is believedthat under physiological conditions, H6PDH utilizes glucose-6-phosphate as its main substrate [18]. The intraluminal substratesupply is maintained by a specific glucose-6-phosphate transporter[20]. The disruption of the functional cooperation between11b-HSD1 and H6PDH upon tissue homogenization or cell lysisprovides an explanation for the observed loss of 11-oxoreductaseactivity [14]. It was shown that the reductase activity of 11b-HSD1 isdependent on a high NADPH/NADP+ ratio [21]. Importantly, thedemonstration of a physical interaction between H6PDH and11b-HSD1 suggested a coupling of 11b-HSD1 activity and themetabolic state of the cell [22,23]. In most organs, 11b-HSD1 iscoexpressed with H6PDH [24]. Thus, 11b-HSD1 functions in vivopredominantly as a reductase and its activity is dependent on theavailability of hexose-6-phosphates and NADPH.

2. Glucocorticoids as substrates of 11b-HSD1

Initially,11b-HSD1 has been identified in a search for the enzymeinterconverting cortisol and cortisone [8]; hence, the first substratesidentified for this enzyme were glucocorticoids (cortisone and

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cortisol in humans, 11-dehydrocorticosterone and corticosterone inrodents). As mentioned above in most organs and cell types analyzedso far, 11b-HSD1 is coexpressed with H6PDH and it therefore has animportant role in the regeneration of active glucocorticoids and inthe prolongation of their biological half-life. The highly efficienthepatic conversion to their potent 11b-hydroxylated forms explainsthe therapeutic effect of the endogenous 11-oxoglucocorticoidcortisone and the synthetic prednisone. The tissue-specific inter-conversion of glucocorticoids by 11b-HSD1 and 11b-HSD2 allows afine-tuned regulation of the threshold concentrations of glucocorti-coids that are required to exert a biological effect in a given cell typeand tissue. Interestingly, the synthetic glucocorticoids bearing afluoride atom at position 9 of the steroid backbone like dexametha-sone,betamethasone, 9a-fluorocortisol andtriamcinoloneaswellasthe androgen fluoxymesterone are barely metabolized by 11b-HSD2in vitro and the ratio of 11b-hydroxyl to 11-oxo derivative is far onthe side of the active 11b-hydroxyl form ([25–28] and ownunpublished observations). Thus, these synthetic glucocorticoidscircumvent the tissue-specific modulation of the endogenousglucocorticoids and of synthetic non-fluorinated forms such asprednisone/prednisolone that generally have less severe adverseeffects than the fluorinated derivatives upon prolonged systemicadministration.

The production of the active endogenous 11b-hydroxygluco-corticoids is tightly controlled by the hypothalamus–pituitary–adrenal axis. In humans, over 95% of circulating cortisol is bound tocortisol-binding globulin; thus, only a small fraction is unboundand physiologically available. The inactive form cortisone isapproximately 50% protein-bound and a higher fraction is availableto peripheral target cells expressing 11b-HSD1. The activeglucocorticoids generated by 11b-HSD1 then enhance the localGR-dependent effects on gene expression. Understanding therelative contribution of the fraction of the active glucocorticoidsformed by 11b-HSD1 compared with that released from theadrenals clearly needs further research.

An over production of glucocorticoids due to adrenal tumors oradministration of high doses of glucocorticoids for a prolongedperiod of time during therapy can cause Cushing’s disease, withmetabolic disturbances resembling those observed in patientswith metabolic syndrome [29]. Since circulating glucocorticoidlevels are not elevated in patients with metabolic syndrome, it waspostulated that an elevated local regeneration of active glucocorti-coids by 11b-HSD1 may be an important factor in the developmentof complications associated with the metabolic syndrome [30,31].Therefore, a number of transgenic mouse models with alteredexpression of 11b-HSD1 have been developed and were investi-gated for changes in metabolic functions [32,33].

Early studies on global 11b-HSD1 knock-out mice were verypromising, with data showing an improved insulin sensitivity andplasma lipid profile [34]. The 11b-HSD1-null mice, developed onan obesity-resistant MF1 background, displayed reduced activa-tion of the major gluconeogenic enzymes glucose-6-phosphataseand phosphoenolpyruvate carboxykinase upon fasting, possiblydue to decreased intrahepatic corticosterone levels, and theyresisted hyperglycemia upon high-fat diet. The same mice werereported to have increased insulin sensitivity, lower circulatingtriglycerides, possibly due to increased fat catabolism, andincreased plasma levels of anti-atherogenic HDL cholesterol[35]. To further establish the role of 11b-HSD1 in obesity-relatedcomplications, MF1-based HSD11B1�/� mice were backcrossed toan obesity prone C57BL/6J background. Similarly, these miceexhibited an improved glucose tolerance and insulin sensitivity aswell as a favorable lipid profile on a high-fat and high-cholesteroldiet [36]. These observations were contrasted by a recent study byHarno et al. who constructed a global HSD11B1 knock-out mousestrain on a C57BL/6J background [37]. Surprisingly, these mice did

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not show an improved metabolic phenotype, they were notresistant to the adverse effects caused by a high-fat diet. Thereasons for the discrepancy between these studies using differentHSD11B1-deficient mice could be due to differences in thebackground of the strain, different age of the animals used anddifferent composition of their diet. Nevertheless, based on thesestudies, one could conclude that the global absence of11b-HSD1 has only moderate effects on metabolic functions.

Nevertheless, thestudybyMasuzaki etal. ontransgenicmiceoverexpressing 11b-HSD1 under the control of the AP2-promoter in theadipose tissue supported an important role for 11b-HSD1 in thecontrol of metabolic functions and boosted research on this target[38,39]. The most prominent effect of adipose 11b-HSD1 overexpression was a pronounced visceral obesity, most likely caused byincreased adipocyte size, accompanied by insulin and leptinresistance, elevated levels of circulating non-esterified fatty acidsand triglycerides aswellas increasedbloodpressure. However, so far,it is still not fully clear whether these effects were indeed caused byenhanced adipose levels of glucocorticoids or whether a dysregu-lation of other substrates/products may be involved. Also, due to theimportance of these observations, the impact of elevated adipose11b-HSD1 expression should be confirmed independently by otherinvestigators. In contrast to the adipose over expression, and ratherunexpectedly, an elevated expression of 11b-HSD1 specifically in theliver did not cause obesity and led to rather moderate metabolicdisturbances including hepatic lipid synthesis due to an enhancedexpression of fatty acid synthase and LXRa accompanied withhepatic steatosis, elevated plasma non-esterified fatty acids andinsulin [40]. These mice developed modest insulin resistance andhypertension. Again, it is not fully clear whether the observed effectswere fully glucocorticoid-dependent or whether other mediatorsmight also be involved.

The promising results reported by the initial studies of transgeneknockout and adipose over expression of 11b-HSD1 stimulated thedevelopment of pharmaceutical inhibitors, and several preclinicalstudies showed improved metabolic functions [33]. However,subsequent clinical trials with selected compounds showed onlyvery moderate effects and at high drug dose [41,42].

Importantly, a recent study comparing treatments with twodistinct 11b-HSD1 inhibitors found a reduction of body weight inboth control and 11b-HSD1 knockout mice, although only at highdosage, suggesting that at least part of the beneficial effects areoff-target [37]. Additionally, Lavery et al. recently reported thatthe specific deletion of 11b-HSD1 in the liver caused only verymodest metabolic effects, either on low- or high-fat diet [43].They did not observe a dramatic derangement of the expression ofglucocorticoid-dependent genes. Their study emphasized theimportance of extra hepatic tissues in the metabolic effectsobserved in global 11b-HSD1-deficient mice. Interestingly, theintra-hepatic concentrations of corticosterone were found to benormal in liver-specific 11b-HSD1-deficient mice and 11-dehydrocorticosterone was even moderately decreased [43,44].Thus, the statement made in many research papers that 11b-HSD1 is responsible for the intra-tissue concentrations of activeglucocorticoids has to be revisited. The impact of 11b-HSD1 onglucocorticoid action seems to be largely restricted to specific celltypes within a given organ. A role of 11b-HSD1 in the fine-tuningof glucocorticoid effects is in line with the rather moderate effectsof pharmacological inhibition.

Thus, despite the extensive research on this enzyme, there arestill several open questions regarding its high expression in theliver but rather minor contribution to the regulation of glucocorti-coid-dependent effects, the overall contribution to glucocorticoidhomeostasis, the role in the modulation of corticosteroid effects inthe tissues such as adipose, adrenals and immune cells, and therole in the metabolism of other substrates. The reason why

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11b-HSD1 is facing the ER lumen still remains unclear, despite itsinteraction with H6PDH [45]. If the main function of 11b-HSD1 isto provide active glucocorticoids to the GR, one would expect acytoplasmic orientation of the enzyme. Thus, uncovering thereason for the specific compartmentalization of the enzyme shouldprovide further insight into its physiological roles.

3. Other steroid substrates

Besides glucocorticoids, other 11-oxygenated steroids such as11-oxyprogesterones, 11-oxypregnenolones and 11-oxyandrogenshave been identified as substrates as well as inhibitors of11b-HSD1 that thus might modulate the interconversion ofglucocorticoids in certain situations (Fig. 1) (reviewed in [46]).The physiological role of these metabolites remains largelyunknown. It has been shown that 11-oxyprogesterones besidesactivating progesterone receptors (PR) can activate MR and GR,suggesting interactions between progestin- and corticosteroid-mediated regulation of gene expression, which could be relevantduring pregnancy where the concentration of progesterone and itsmetabolites increases dramatically and in situations of stress andinflammation [47,48].

Several 11-oxyandrogens that are produced in the adrenalsupon hydroxylation by CYP11B1 and further metabolized inperipheral tissues have been identified. It was reported that11b-hydroxyandrostenedione is the second most abundantC19 steroid present in the adrenal vein of women before andafter ACTH stimulation [49,50]. It was shown that 11b-HSD1and 11b-HSD2 both can convert 11b-hydroxyandrostenedione and11b-hydroxytestosterone to the respective 11-oxoandrogens11-oxoandrostenedione and 11-oxotestosterone [51]. A subsequentstudy showed that these steroids can be further metabolized by5a-reductase to 11-oxy-5a-androstanedione and 11-oxydihydro-testosterone, whereby the latter showed comparable activity toactivate the androgen receptor (AR) than testosterone and11-dihydrotestosterone, thus, representing potential promotersof AR-dependent prostate cancer cell proliferation [52]. Interest-ingly, 11b-HSD1 is not able to reduce the 5a-reduced androgens11-oxo-5a-androstanedione and 11-oxodihydrotestosterone intothe respective hydroxylated forms, despite coexpression withH6PDH. The role of 11b-HSD1 in the adrenals as well as in theprostate and the consequences of altered expression, for example,in the presence of inflammatory cytokines, on the production of11-oxoandrogens deserves some further attention.

Interestingly, due to rotational symmetry of steroid molecules,11b-HSD1 can in addition to position 11 act on position 7 of thesteroid backbone [53–58]. In vitro studies using liver homogenatesand recombinant enzymes demonstrated the interconversion of7-oxodehydroepiandrosterone and 7a- and 7b-hydroxydehydroe-piandrosterone by 11b-HSD1 [57,58]. As with glucocorticoids, thereaction direction was strongly dependent on the NADPH supplyby coexpression with H6PDH [58]. Significant species-specificdifferences were observed, with the human enzyme almostexclusively forming 7b-hydroxydehydroepiandrosterone and themouse and rat enzymes preferentially forming 7a-hydroxydehy-droepiandrosterone (own unpublished results). Other steroidsserving as 11b-HSD1 substrates include 7-oxygenated metabolitesof epiandrosterone, pregnenolone and 5a-androstane-3b-ol-17-one [57,58]. Furthermore, Hu et al. provided evidence for a role of11b-HSD1 in the interconversion of 7-oxygenated testosterone[59]. Whether these 7-oxygenated steroid metabolites are justdegradation products to be conjugated and excreted or whetherthey have physiological roles remains largely unknown.

Based on in vitro data, Muller et al. hypothesized thatdehydroepiandrosterone might exert anti-glucocorticoid effectsvia cholesterol 7a-hydroxylase (CYP7B1)-mediated generation of

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Fig. 1. Scheme of 11b-HSD1 substrates. G6P, glucose-6-phosphate; 6PG, 6-phosphogluconate.

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7a-hydroxydehydroepiandrosterone and subsequent inhibition of11b-HSD1-dependent generation of active glucocorticoids [60].However, this hypothesis was not supported by experiments usingthe EtC cerebellar granule cell line [61]. Additionally, it was shownthat 11b-HSD1 functions as a oxoreductase in cells coexpressingH6PDH and that the 7-hydroxylated steroids preferentiallyinhibit the oxidation reaction of the enzyme [62]. An alternativeexplanation for the beneficial effects of dehydroepiandrosteronesupplementation observed in patients with arthritis, Alzheimer’sdisease and in patients with complications related to aging [60]might be the modulation of the expression levels of 11b-HSD1 and11b-HSD2 [63–65]. Treatment with DHEA, in vitro and in vivo, ledto altered expression of C/EBP transcription factors and to areduced expression of 11b-HSD1 and an enhanced expression of11b-HSD2. It is not clear, however, whether these effects werecaused by DHEA or its metabolites.

4. Role of 11b-HSD1 in the reduction of 7-oxolithocholic acidand impact on bile acid homeostasis

One of the most recently identified substrates of 11b-HSD1 is7-oxolithocholic acid (7-oxoLCA) (Fig. 1) [66], a secondary bile acidformed from chenodeoxycholic acid (CDCA) and ursodeoxycholicacid (UDCA) by microorganisms in the intestinal tract [67]. Thecirculating concentrations of 7-oxoLCA are very low in humans;however, in some species such as guinea pigs, 7-oxoLCA is a majorbile acid. The first reports on the existence of 7-oxo bile acidreductase activity in human liver date back to the early 80s[68–70]. These observations were corroborated by in vitro studiesusing different subcellular fractions of human and rat livers [71,72].These experiments suggested that the enzyme responsible for

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7-oxoLCA reduction was located in the microsomal membrane andpreferentially used NADPH. The enzyme catalyzing the reductionof 7-oxoLCA, 11b-HSD1, was identified almost 30 years later [66].It was shown that human liver microsomes reduce 7-oxoLCAmainly to CDCA and to a lower extent to UDCA. The reactioncould be completely abolished by structurally distinct selective11b-HSD1 inhibitors, and the fact that 7-oxoLCA reductionwas dependent on cofactor NADPH and was stimulated byglucose-6-phosphate suggested the involvement of H6PDH.Interestingly, 11b-HSD1 not only reduced free 7-oxoLCA but alsoits taurine- and glycine-conjugated forms, suggesting that theD-ring substituents play a minor role for substrate specificity.

A comparison of recombinant 11b-HSD1 from different speciesrevealed significant differences. While human 11b-HSD1 preferen-tially formed CDCA from 7-oxoLCA, the rat and mouse enzymesproduced comparable amounts of CDCA and UDCA. Importantly,guinea pig 11b-HSD1 showed background activity toward 7-oxoLCAand its conjugated forms, providing an explanation for theaccumulation of this secondary bile acid in this species. Theassumption that 7-oxoLCA does not bind to the guinea pig enzymewas further supported by the observation that 7-oxoLCA did notaffect 11b-HSD1-dependent cortisone reduction.

Recent experiments then showed that liver homogenates andmicrosomes of 11b-HSD1-deficient mice were unable to reduce7-oxoLCA and an accumulation of this bile acid was observed bothin plasma and liver tissue samples of these transgenic mice [73].Since 11b-HSD1 seems to be the only enzyme metabolizing7-oxoLCA, an accumulation of this bile acid may serve as abiomarker for 11b-HSD1 deficiency; however, whether itrepresents a useful marker for pharmaceutical inhibition of theenzyme remains to be evaluated.

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11b-HSD1 disruption seems to affect not only circulating andhepatic 7-oxoLCA content but it appears to affect bile acidhomeostasis more generally [44]. Both global and liver-specificknock-out mice displayed elevated circulating unconjugated bileacids, whereby the effect was more pronounced upon systemicdisruption of 11b-HSD1. Also, the intrahepatic content ofunconjugated bile acids was increased in liver-specificknockout mice. These changes in bile acid concentrations wereaccompanied by altered expression of hepatic genes involved inbile acid homeostasis such as a decrease in CYP7A1 mRNAexpression, the rate-limiting enzyme in bile acid synthesis, and anincrease in SHP mRNA expression, a coregulator of FXR-mediatedsignaling. These changes likely occurred as an adaptation toincreased bile acids that were shown to regulate de novobiosynthesis via FXR/SHP-mediated suppression of CYP7A1.Besides facilitation of lipid absorbtion and maintenance ofcholesterol homeostasis, the role of bile acids as signalingmolecules has been recently established [74]. Bile acids modulateseveral signaling pathways included in the regulation of de novolipogenesis, lipoprotein metabolism and transport, gluconeogene-sis and insulin sensitivity. As a possible explanation for theincrease in unconjugated bile acids, a decreased expression ofFATB5, an enzyme catalyzing an intermediate step in bile acidconjugation, was shown in 11b-HSD1-deficient mice [44].Importantly, no changes in FATB5 expression were found inliver-specific GR knockdown mice. These observations suggest thatsome of the metabolic effects of 11b-HSD1 modulation areindependent of its role in glucocorticoid metabolism. The alteredbile acid concentrations may further contribute to the metaboliceffects following 11b-HSD1 inhibition.

5. A role for 11b-HSD1 in the metabolism of 7-oxocholesteroland association with atherosclerosis

An early study by Song et al. characterized a purified hamster7a-hydroxysteroid dehydrogenase enzyme, which had an almostidentical N-terminal amino acid sequence than human 11b-HSD1[75]. The cloning of hamster 11b-HSD1 then revealed the identityof the enzyme purified previously by Song et al. [76]. It was foundthat hamster 11b-HSD1, in line with observations on glucocorti-coid metabolism, predominantly functioned as a reductase inintact cells and the formation of 7a-hydroxycholesterol wasslightly preferred over 7b-hydroxycholesterol when 7-oxocholes-terol was supplied as substrate. The ability of human, rat andmouse 11b-HSD1 to metabolize 7-oxocholesterol was demon-strated by two independent studies using recombinant enzymes,cell lysates and liver homogenates [76,77]. Interestingly, whilepurified enzymes and preparations of lysed cells and tissuehomogenates were able to oxidize 7b-hydroxycholesterol (but not7a-hydroxycholesterol), the dehydrogenase activity could not bedetected in intact cells and exclusive reduction of 7-oxocholesterolwas observed [76]. A species comparison further revealed very low7-oxoreductase activity for canine 11b-HSD1 and only backgroundactivity for the guinea pig enzyme [78]. Furthermore, the role of11b-HSD1 in the metabolism of dietary 7-oxocholesterol wasstudied in vivo in Sprague Dawley rats [76]. Upon oral administra-tion of 7-oxocholesterol and the 11b-HSD1 inhibitor carbenox-olone, an accumulation of 7-oxocholesterol was observed inplasma and liver tissue samples. A role for 11b-HSD1 in themetabolism of 7-oxocholesterol was further supported by a recentstudies of Mitic et al. using transgenic mice [79,80]. An increasedratio of 7-oxocholesterol to 7-hydroxycholesterol was found inliver tissues of 11b-HSD1-deficient mice, H6PDH-deficient miceand 11b-HSD1/H6PDH double knockout mice. Interestingly, thetotal hepatic levels of these oxysterols were significantly decreasedin these transgenic mice, suggesting compensatory effects.

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Despite these findings the physiological relevance of the11b-HSD1-mediated metabolism of 7-oxygenated cholesterol stillremains unclear.

One of the possible roles of 11b-HSD1 that has been addressedwas the control of the amounts of 7-oxocholesterol and7-hydroxycholesterol in the arterial wall and its contribution toatherosclerotic plaque development [80]. The formation ofatherosclerotic plaques is associated with an accumulation ofapoB-lipoproteins underneath the endothelial cell layer of bloodvessels and the subsequent production of chemoattractants suchas monocyte chemoattractant protein 1 (MCP1) that triggersmonocyte infiltration and inflammation. An imbalance betweencholesterol influx, esterification and efflux leads to the accumu-lation of lipid particles, containing a high content of cholesteroland its oxidized metabolites, inside the cytoplasm of macro-phages that are then called foam cells [81]. 7-oxocholesterol,which is toxic for cells, is a major constituent of these lipiddroplets; therefore, its metabolism by 11b-HSD1 that is highlyexpressed in macrophages [82] may be critical during plaqueprogression. 7-oxocholesterol has been shown to inhibit choles-terol efflux and ultimately induce ER-stress and apoptosis in foamcells. The expected result of an inhibition of 11b-HSD1 would bean accelerated atherosclerotic plaque progression due to a higher7-oxocholesterol content and an altered inflammatory responsedue to the decreased regeneration of active glucocorticoids. It istherefore rather surprising that 7-oxocholesterol did notaccumulate in blood vessel wall cells upon disruption of 11b-HSD1 and that inhibition of 11b-HSD1 even resulted in adecreased aortic cholesterol accumulation in atheroscleroticApoE�/� mice [80]. The 11b-HSD1 inhibition in ApoE �/� micewas accompanied with decreased systemic levels of cholesteroland triglycerides that could contribute to the overall effects;however, the authors also showed lower levels of MCP1 upon11b-HSD1 inhibition, suggesting that at least part of the observedprotective effects were caused locally in arterial walls [83].Recently, this assumption was supported by Luo et al. whoapplied an 11b-HSD1 inhibitor treatment regimen that improvedatherosclerosis but did not affect the systemic lipid profile inApoE �/�mice [84]. They performed gene expression profiling andfound that the major changes included a decrease in proin-flammatory signaling pathways and chemokines in foam cells andvascular smooth muscle cells. Moreover, bone marrow trans-plantation experiments, where the bone marrow was transferredfrom 11b-HSD1-deficient mice on a ApoE�/� background intoApoE�/� mice with destroyed bone marrow, resulted in adecreased atherosclerosis progression, suggesting that macro-phage 11b-HSD1 indeed plays an important role in plaqueformation [85]. It is unclear at present whether these effects areglucocorticoid-dependent or whether there is a role for other11b-HSD1 substrates such as 7-oxygenated sterols, whichwarrants further research.

6. Carbonyl reduction of non-steroidal compounds by 11b-HSD1

The promiscuity of 11b-HSD1 function is further highlighted byits role as a microsomal carbonyl reductase involved in phase Ibiotransformation reactions (reviewed in [46,86,87]). Most carbonylreductases are members of the familyof aldo-keto reductases (AKRs)and short-chain dehydrogenases/reductases (SDRs); however,11b-HSD1 and the less well characterized multi-functional enzymeDHRS7 (SDR34C1, also known as retSDR4) [88], so far represent theonly NADPH-dependent enzymes known to face the ER lumen. Thereason for their luminal orientation is still not fully understood, but itmay allow protecting the cytoplasm from potentially reactiveintermediate metabolites. A close proximity of 11b-HSD1 and

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DHRS7 in the ER with enzymes such as UDP-glucuronosyltransfer-ases may allow efficient conjugation of the generated hydroxylatedproducts; however, this has not yet been demonstrated.

The ability of 11b-HSD1 to function as a carbonyl reductase onnon-steroidal xenobiotics has been suggested in early studies byMaser and Netter who used mouse liver microsomes to provideevidence that 11b-HSD1 catalyzes the reduction of metyrapone[89]. This reaction was dependent on NADPH and inhibited bydihydrotestosterone. Later, the enzyme involved was confirmed tobe 11b-HSD1 and other substrates such as p-nitroacetophenoneand p-nitrobenzaldehyde were described [90,91]. Further studiesidentified additional non-steroidal compounds as substrates of11b-HSD1, namely ketoprofen, DFU-lactol, the anti-cancer drugcandidate oracin, the tobacco constituent nicotine-derived nitro-samineketone (NNK) and the fungicide triadimefon ([92–98], for amore comprehensive review see also [46]). For the latter, livermicrosomes from 11b-HSD1-deficient mice and distinct selectiveinhibitors were used to provide evidence that 11b-HSD1 is themajor microsomal enzyme catalyzing the carbonyl reduction [98].

More recently, Meyer et al. demonstrated the 11b-HSD1-dependent formation of threohydrobupropion from bupropion, adopamine and norepinephrine reuptake inhibitor widely used fortreatment of depression and to support smoking cessation [99].Significant species-specific differences were observed in experi-ments using human, rat and mouse liver microsomes as well asrecombinant enzymes transiently expressed in HEK-293 cells.The human enzyme was clearly more active than the rat enzyme,followed by the mouse enzyme. 11b-HSD1 was found to be strictlystereoselective as no erythrohydrobupropion formation wasdetected. Measurements with liver microsomes from11b-HSD1 knockout mice showed that threohydrobupropionformation was absent while erythrohydrobupropion formationwas unaffected. A recent study by Skarydova et al. comparedvarious AKRs and SDRs and supported a major role for 11b-HSD1 inthe carbonyl reduction of bupropion to threohydrobupropion and,furthermore, indicated that AKR1C1 is responsible for erythrohy-drobupropion formation [100]. Additionally, Meyer et al. suggestedthat the simultaneous treatment with glucocorticoids andbupropion may lead to undesirable drug–drug interactions [99].In addition to the synthetic cathinone bupropion, there are a largenumber of substituted cathinones that are new popular drugs ofabuse [101]; however, nothing is known on the enzymes involvedin the carbonyl reduction of such compounds and on the effects ofthe reduced metabolites. Due to the similarity of these compoundswith bupropion [101], the substituted cathinones representpotential substrates of 11b-HSD1.

The relevance of species differences was further emphasized bya recent study on the metabolism of TAK-802, a novel drugcandidate for voiding dysfunction [102]. While human11b-HSD1 efficiently reduced TAK-802, resulting in approximatelyfive-fold higher circulating concentrations of the metabolitecompared with the parental compound, the rat enzyme showedvery low activity toward TAK-802 and only low levels of thereduced metabolite were found in plasma samples. Theseobservations further emphasize the promiscuity of 11b-HSD1 toaccept various structurally distinct substrates as well as therelevance of considering species differences.

7. Conclusions and outlook

11b-HSD1 is a multi-functional enzyme accepting besidesglucocorticoids a variety of 11- and 7-oxosterols as well asstructurally distinct non-steroidal compounds. 11b-HSD1 receivedconsiderable attention because of the association of elevatedglucocorticoids and metabolic disease and due to the interest ofthe pharmaceutical industry aiming to develop therapies to combat

Please cite this article in press as: A. Odermatt, P. Klusonova, 11b-Hydroxonly part of the story, J. Steroid Biochem. Mol. Biol. (2014), http://dx.do

diabetes and metabolic syndrome. However, none of the pharma-ceutical inhibitors entered phase III clinical trials and the clinicaleffects observed were weak to moderate. Nevertheless, therapeuticinhibition of 11b-HSD1 may also be a promising option for thetreatment of other diseases, including atherosclerosis, osteoporosis,cognitive decline, and wound healing and skin aging. In mostpreclinical and clinical studies reported in the literature it is assumedthat the observed effects of 11b-HSD1 inhibition are dependent on adecrease of active glucocorticoids; however, contribution of otherproducts of this enzyme cannot be excluded. 11b-HSD1 may exertdistinct essential roles in different tissues, depending on itscoexpression with H6PDH and possibly other interacting partnersas well as on the availability of its ligands. Further research is neededto understand the role of 11b-HSD1 in the metabolism of7-oxocholesterol, in modulating bile acid homeostasis and tounravel the physiological relevance and possible contribution ofnon-glucocorticoid functions of 11b-HSD1 to disease.

Acknowledgement

This work was supported by the Swiss National ScienceFoundation (31003A_140961). AO has a Chair for Molecular andSystems Toxicology by the Novartis Research Foundation.

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ysteroid dehydrogenase 1: Regeneration of active glucocorticoids isi.org/10.1016/j.jsbmb.2014.08.011