Molecular and Cellular Endocrinology 301 (2009) 7–19

Contents lists available at ScienceDirect

Molecular and Cellular Endocrinology

journal homepage: www.elsevier.com/locate/mce

Review Integrated view on 17beta-hydroxysteroid dehydrogenases

Gabriele Moeller a,∗, Jerzy Adamski a,b a Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics, Genome Analysis Center, Neuherberg, Germany b Lehrstuhl für Experimentelle Genetik, Technische Universität München, Freising-Weihenstephan, Germany article info abstract

Article history: 17beta-Hydroxysteroid dehydrogenases (17beta-HSDs) are important in steroid metabolism. Received 20 August 2008 Long known members of the family seemed to be well characterised concerning their role in Received in revised form 27 October 2008 the regulation of the biological potency of steroid hormones, but today more and more evidence points Accepted 27 October 2008 to pivotal contributions of these enzymes in a variety of other metabolic pathways. Therefore, studies on 17beta-HSDs develop towards metabolomic survey. Latest research results give new insights into the Keywords: complex metabolic interconnectivity of the 17beta-HSDs. In this paper metabolic activities of 17beta-HSDs Steroid metabolism will be compared, their interplay with endogenous substrates summarised, and interlacing pathways 17beta-Hydroxysteroid dehydrogenase Multifunctionality depicted. Strategies on deciphering the physiological role of 17beta-HSDs and the genetic predisposition for associated diseases will be presented. © 2008 Elsevier Ireland Ltd. All rights reserved.

Contents

1. Introduction ...... 8 2. Novel functional aspects of selected 17beta-HSDs ...... 8 2.1. Functional assignments of 17beta-HSD6 ...... 8 2.2. Regulation of 17beta-HSD7 in different species ...... 8 2.3. Where does 17beta-HSD8 belong to? ...... 8 2.4. 17beta-HSD10 in neuronal diseases ...... 8 2.5. A controversial discussion on the role of 17beta-HSD12 ...... 9 2.6. 17beta-HSD type 11 and type 13, two enzymes with fairly high similarity ...... 10 2.7. Detailed characterisation of 17beta-HSD14 ...... 11 3. Crystal structures of 17beta-HSDs ...... 11 4. Animal models for 17beta-HSDs ...... 12 5. Polymorphisms in HSD17B in connection to diseases ...... 12 5.1. HSD17B1 ...... 14 5.2. HSD17B2 ...... 14 5.3. HSD17B3 ...... 14 5.4. HSD17B4 ...... 14 5.5. AKR1C3...... 14 5.6. HSD17B6 ...... 15 5.7. HSD17B7...... 15 6. Outlook ...... 15 References ...... 15

Abbreviations: 17beta-HSD, 17beta-hydroxysteroid dehydrogenase; HSD17B, 17beta-hydroxysteroid dehydrogenase ; SDR, short chain dehydrogenase/reductase; AKR, aldoketo-reductase; PPAR, peroxisome proliferator-activated receptor; SNP, single nucleotide polymorphism. ∗ Corresponding author at: Helmholtz Zentrum München, German Research Center for Environmental Health, Institute of Experimental Genetics, Genome Analysis Center, Ingolstaedter Landstrasse 1, 85764 Neuherberg, Germany. Tel.: +49 89 3187 3230; fax: +49 89 3187 3225. E-mail address: [email protected] (G. Moeller).

0303-7207/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.mce.2008.10.040 8 G. Moeller, J. Adamski / Molecular and Cellular Endocrinology 301 (2009) 7–19

1. Introduction Promoter activity through the NF-Y binding site was decreased by forskolin mimicking downstream action of LH and regulation in 17beta-hydroxysteroid dehydrogenases (17beta-HSDs) catalyse this manner of rat 17beta-HSD7 in pregnancy was postulated (Risk the interconversion between the active and inactive forms of spe- et al., 2005). For the human and murine 17beta-HSD7 promoters cific steroidal hormones on the final steps of their biosynthesis. analyses were performed by bioinformatic methods and experi- They are named according to their ability to catalyse oxidation mental approaches (Ohnesorg and Adamski, 2005, 2006; Ohnesorg or reduction of the 17-hydroxy or 17-keto functions of spe- et al., 2006). Transcription factor binding sites frequently found cific physiologically relevant steroids. This catalysis is co-factor in promoters of cholesterol metabolising enzymes like hepatocyte (NAD(P)/NAD(P)H) dependent. Up to now, 14 types of 17beta- nuclear factor (HNF4), SP1 (one in mouse, two in human), sterol reg- HSDs are reported in vertebrates of which 12 are also present in ulatory element binding protein (SREBP), and NF-Y were identified humans, while 17beta-HSD6 and 9 are only reported for rodents. in both species as well as a cAMP-response element-binding pro- With the exception of 17beta-HSD5, which is a member of the tein (CREB) and a vitamin D receptor/retinoid X receptor (VDR/RXR) aldoketo-reductase (AKR) family, all 17beta-HSDs belong to the binding site (Ohnesorg et al., 2006). Additionally, only in mouse a short chain dehydrogenase/reductase (SDR) superfamily. In ver- receptor (PR) and a steroidogenic factor 1/ recep- tebrates the enzymes show generally low tor homolog 1(SF1/LRH-1) binding site were detected indicating a (15–20%) but some elements characteristic for SDR members are probable involvement of murine 17beta-HSD7 also in sex steroid very similar, e.g. the Rossman fold involved in cofactor binding and synthesis (Ohnesorg et al., 2006). Promoter analyses in the liver several conserved motifs including the active center motif “YXXXK” cell lines HepG2 and Hepa1-6 showed changes in consequence (Oppermann et al., 2003). Despite this structural conservation, sub- of cholesterol addition or on lipid deprivation but not on estra- strate specificities among the family members are diverse and for diol administration (Ohnesorg and Adamski, 2006; Ohnesorg et al., some 17beta-HSDs substrates such as fatty acids or bile acids are 2006). Altogether, the observations suggest a predominant involve- preferred over sex steroids. ment of 17beta-HSD7 in cholesterol metabolism in both species. The relevance of 17beta-HSD7 in cholesterol synthesis over that 2. Novel functional aspects of selected 17beta-HSDs in synthesis in sex steroids like is also illustrated by the observation that knockout mice do not survive until puberty (Shehu The multifunctionality of 17beta-HSDs was already addressed et al., 2008). in an earlier review (Moeller and Adamski, 2006). This report now will focus on latest findings on 17beta-HSD function, mostly for the 2.3. Where does 17beta-HSD8 belong to? enzymes with broad substrate specificity, and will mention some aspects concerning the role of 17beta-HSDs in disease. The major role of 17beta-HSD8 in mammalian metabolism is still not clear. The was described to catalyse the oxidation 2.1. Functional assignments of 17beta-HSD6 of estradiol, and DHT (Fomitcheva et al., 1998) and to be associated with polycystic disease (Aziz et al., 1993). 17beta-HSD6 was identified in rat as 17beta- and 3alpha-HSD Sequence comparison showed homology to bacterial enzymes of and the nearest human homolog, the retinol dehydrogenase RoDH1, the fatty acid metabolism (Fomitcheva et al., 1998) and modelling showed in vitro the same activities (Biswas and Russell, 1997). experiments predicted the involvement of 17beta-HSD8 in the This human homolog was later discovered to be a 3(alpha->beta)- respective pathway (Pletnev and Duax, 2005). However, experi- hydroxysteroid epimerase (HSE) (Huang and Luu-The, 2000, 2001). mental proof for this suggested activity is still pending. Support However, human HSE is listed as HSD17B6 in databases. for a more important role in fatty acid conversion may come from the observation that 17beta-HSD8 is located in mitochon- 2.2. Regulation of 17beta-HSD7 in different species dria (Witkowski et al., in preparation), the compartment in which fatty acid breakdown takes place. Also the tissue distribution of 17beta-HSD7 was first detected as prolactin receptor-associated 17beta-HSD8 in mouse and humans points to a role not primarily protein in rat (Duan et al., 1996). The murine homolog was desribed in sex steroid metabolism. In mouse high expression was detected as 17beta-HSD due to its ability to catalyse the conversion of in kidney, liver, ovaries, testis and other tissues (Aziz et al., 1993; to estradiol. Detection of a high expression level in the ovary led to Fomitcheva et al., 1998; Pelletier et al., 2005). On mRNA level, the assumption that 17beta-HSD7 plays an important role in preg- human 17beta-HSD8 expression was found to be fairly widespread nancy (Nokelainen et al., 1998). Later, the human enzyme was found with highest levels in , placenta and kidney (Ohno et al., to be expressed also in liver and fetal brain (Krazeisen et al., 1999). 2008). Support for a role in steroid metabolism on the other hand Subsequently, bioinformatic predictions suggested a participation comes from a study in which the promoter region of human 17beta- in cholesterol synthesis (Breitling et al., 2001), which was later HSD8 and its regulation in the HepG2 liver cell line was analysed. experimentally proven (Marijanovic et al., 2003). The enzyme was The minimal promoter region harbours two CCAAT boxes that were shown to exhibit 3beta-reductase activity catalysing the reduction shown to be binding sites for C/EBPbeta, a steroid regulated tran- of zymosterone to zymosterol in the cholesterol synthesis pathway scription factor (Villar et al., 2007). and to rescue a yeast strain deficient in ERG27, the yeast homolog to 17beta-HSD7 (Marijanovic et al., 2003). Beside this, 17beta-HSD7 2.4. 17beta-HSD10 in neuronal diseases over-expression was able to revert cholesterol auxotrophy of NS0 cells (Seth et al., 2005). Among all 17beta-HSDs, 17beta-HSD10 seems to be the enzyme The final proof for the major biological function of 17beta-HSD7 with the broadest substrate specificity. At least in vitro the enzyme is still missing. In this regard, promoter analyses are expected to catalyses the conversion of a lot of substrates including straight give further insights into the enzyme’s metabolic pathway pref- and branched fatty acids, bile acids, and sex steroids (Table 1). erences. The rat 17beta-HSD7 promoter was analysed in a luteal Additionally, a protein–protein interaction with amyloid beta (A␤) cell line in dependence of luteinizing hormone (LH) and binding is described for the enzyme (Yan et al., 1997). It is therefore not sites for specificity protein 1 transcription factor (SP1) and CAAT- surprising that the enzyme is found in literature under several box transcription factor (NF-Y) were identified (Risk et al., 2005). names: endoplasmic reticulum-associated-binding protein (ERAB) G. Moeller, J. Adamski / Molecular and Cellular Endocrinology 301 (2009) 7–19 9

Table 1 Substrate specificity of human 17beta-hydroxysteroid dehydrogenases.

17beta-HSD type Cofactor preference Substrate specificities References

1 NADP/NADPH , Puranen et al. (1997); Dumont et al. (1992) 2 NAD/NADH Estrogens, androgens, progestins Suzuki et al. (2000), Wu et al. (1993) 3 NADP/NADPH Androgens, estrogens Geissler et al. (1994) 4a NAD/NADH Very long chain fatty acids, branched fatty acids, bile Adamski et al. (1992), Dieuaide-Noubhani et al. (1997), acids, estrogensb, androgensb Dieuaide-Noubhani et al. (1996), Suzuki et al. (1997), van Grunsven et al. (1999, 1998), Van Veldhoven et al. (1996) 5 NAD(P)/NAD(P)H Androgens, progestins, estrogens, prostaglandin Matsuura et al. (1998), Penning et al. (2000), Steckelbroeck et al. (2004) 6 NAD(P)/NAD(P)H Androgens, estrogensc Belyaeva et al. (2007), Biswas and Russell (1997), Huang and Luu-The (2000, 2001) 7d NADP/NADPH Sterols, estrogens, androgens, progestins Marijanovic et al. (2003), Torn et al. (2003) 8 NAD/NADH Estrogens, androgens Ohno et al. (2008) 10 NAD/NADH Short chain fatty acids, branched fatty acids, bile acids, He et al. (1999, 1998, 2005, 2003), Ofman et al. (2003), Shafqat et al. estrogens, androgens, progestins, corticosteroids (2003) 11 NAD/NADH Estrogens, androgens Brereton et al. (2001), Li et al. (1998) 12 NADP/NADPH Branched and long chain fatty acids, estrogens, Blanchard and Luu-The (2007), Entchev et al. (2008) 2806, Luu-The et al. androgensc (2006), Moon and Horton (2003) 13 Not known Not known 14 NAD/NADH Estrogens, androgens Lukacik et al. (2007)

a For SDR domain. b Shown in pig. c Shown in rodents. d For product of the HSD17B7 gene on 1q23.3 (for different HSD17B7 genes, see Moeller and Adamski, 2006).

(Yan et al., 1997), short chain L-3-hydroxyacyl-CoA dehydroge- near to normal (Lenski et al., 2007). Beside single base exchanges nase (SCHAD), 3-hydroxyacyl-CoA dehydrogenase type II (HADH2) in HSD17B10 also gene duplications in the region of the HSD17B10 (He et al., 1998), 17beta-HSD10 (He et al., 1999), 2-methyl-3- and HUWE1 (E3 ubiquitin ligase) genes on the X-chromosome were hydroxybutyryl-CoA dehydrogenase (MHBD) (Ofman et al., 2003), detected and seem to be associated with mild or moderate men- and amyloid binding alcohol dehydrogenase (ABAD) (Du Yan et al., tal retardation in six different XLMR-families (Froyen et al., 2008). 2000). The length of the duplicated fragments differed from 0.4 to 0.8 The most striking observation regarding this enzyme is its megabases. In all cases no disease-causing in HSD17B10 involvement in neuronal diseases like Alzheimer’s disease (AD) could be observed but increased 17beta-HSD10 transcript levels and X-linked mental retardation (XLMR). Already in 1997 bind- were measured. Expression of some enzymes of the 17beta-HSD10 ing of the enzyme to amyloid beta (A␤) was observed (Yan et metabolic pathway was differentially regulated as well (Froyen et al., 1997). Expression of 17beta-HSD10 is enhanced in the brains al., 2008). of Alzheimer patients (Yang et al., 2007) and to study associated effects, a mouse model was established over-expressing human 2.5. A controversial discussion on the role of 17beta-HSD12 A␤ and human 17beta-HSD10 in the brain (Lustbader et al., 2004). The transgenic mice show that the binding of A␤ to 17beta-HSD10 Similar to 17beta-HSD8, the major biological role of 17beta- leads to mitochondrial dysfunction resulting in neuronal stress HSD12 in either sex steroid or lipid metabolism is not yet clear, and impairment of learning and memory. A␤-binding to 17beta- as there are arguments for both assumptions. The human enzyme HSD10 was found to compromise 17beta-HSD10 functions since it shares a fairly high sequence homology of 36% with human 17beta- interferes with cofactor binding. A first effort for therapeutic inter- HSD3 (compared to 15–20% to other 17beta-HSD family members vention in this AD model was made. A 17beta-HSD10 peptide could (Mindnich et al., 2004)) an enzyme that is exclusively involved in be designed specifically inhibiting 17beta-HSD10-A␤ interaction sex steroid metabolism (see Table 1). This may hint to a function and suppressing A␤-induced apoptosis and free-radical genera- of 17beta-HSD12 in steroidogenesis. Indeed, recombinant 17beta- tion in neurons (Lustbader et al., 2004). Several other studies were HSD12 expressed in HEK293 cells has been shown to catalyse performed concerning the consequences of this protein–protein the reduction of estrone to estradiol (Luu-The et al., 2006) and interaction (Ren et al., 2008; Yan and Stern, 2005; Yao et al., 2007). 17beta-HSD12 was suggested to be the predominant source of The 17beta-HSD10-A␤ interactions were also verified and closer estrogens in women before menopause due to the high expres- characterised in vitro by surface plasmon resonance experiments sion and activity in placenta and ovary (Luu-The et al., 2006)– (Yan et al., 2007). by the way, a hypothesis that is biased since the authors tested Genetic alterations of HSD17B10 can lead to X-linked mental only steroidogenic tissues for enzyme expression. Another study retardations (XLMR). Two amino acid mutations, R130C and L122V, would support as well an estrogenic role of 17beta-HSD12. By with loss of MHBD-function cause a severe form of XLMR (Ofman immunohistochemistry, 17beta-HSD12 was found to be signifi- et al., 2003). Lately, also an exonic silent c.574C/A (R192R) cantly increased in cancer tissue and it was suggested that in exon 5 of 17beta-HSD10 was detected when a family suffer- this enzyme would influence development (Song et ing from X-linked mental retardation MRXS10 with symptoms of al., 2006). mild mental retardation, choreoathetosis, and abnormal behaviour On the other hand, a major role for 17beta-HSD12 in fatty acid was investigated (Lenski et al., 2007). Although no amino acid metabolism seems also probable, since human 17beta-HSD12 was exchange occurs, the mutation seems to have a strong influence initially characterised as ketoacylreductase (KAR) due to its homol- on splicing. Only 30–40% of full-length protein could be detected ogy to the yeast enzyme YBR159w, which is active in fatty acid in lymphoblastoidic cell lines of patients and transcripts with loss elongation (Moon and Horton, 2003). Another homolog of 17beta- of exon 5 leading to premature stop in exon 6 were found beside HSD12, the LET-767 of C. elegans, is required for the synthesis of another deletion product. The MHBD activity in patient cells was monomethyl branched and long chain fatty acids as shown in a 10 G. Moeller, J. Adamski / Molecular and Cellular Endocrinology 301 (2009) 7–19

Table 2 Tissue distribution of human 17beta-hydroxysteroid dehydrogenases.

17beta-HSD type Synonymes Tissue distribution (by Northern, RT-PCR or Reference for experimental data Gene name Expression profile NCBI immunological methods) Unigenea (EST counts)

1 Placenta, ovary, , breast Ghersevich et al. (1994), Luu-The et HSD17B1 Strongly restricted al. (1990), Maentausta et al. (1991), Poutanen et al. (1992) 2 Liver, intestine, endometrium, placenta, Casey et al. (1994), Miettinen et al. HSD17B2 Selectively distributed pancreas, prostate, colon (1996), Wu et al. (1993) 3 Testis (brain, blood, skin, adipose tissue) Corbould et al. (2002), Geissler et al. HSD17B3 Strongly restricted (1994), Gnatenko et al. (2005), Hoppe et al. (2006), Steckelbroeck et al. (1999) 4 MFP-2 Liver, heart, prostate, testis, lung, skeletal Adamski et al. (1995) HSD17B4 Ubiquitous muscle, kidney, pancreas, thymus, ovary, intestine, placenta, brain, spleen, colon, lymphocytes 5 AKR1C3 Prostate, mammary gland, liver, kidney lung, Lin et al. (1997), Penning et al. AKR1C3 Nearly ubiquitous heart small intestine, colon, uterus, testis, (2000), Quinkler et al. (2004) brain, skeletal muscle adipose tissue 6 HSE Liver, testis, lung, spleen, brain, ovary, kidney, Belyaeva et al. (2007), Huang and HSD17B6 Selectively distributed adrenal, prostate Luu-The (2000) 7 Ovary, uterus, placenta, liver, breast, testis, Krazeisen et al. (1999), Mackenzie et HSD17B7 Widely distributed neuronal tissue, adrenal gland, small intestine, al. (2008), Torn et al. (2003) lung, thymus, prostate, adipose tissue, and others 8 Ke6 Prostate, placenta, kidney, brain, cerebellum, Ohno et al. (2008) HSD17B8 Widely distributed heart, lung, small intestine, ovary, testis, adrenal, stomach 10 HADH2, SCHAD, ABAD, Liver, small intestine, colon, kidney, heart, He et al. (2001, 2000) HSD17B10 Nearly ubiquitous ERAB, MHBD brain, placenta, lung, ovary, testis, spleen, thymus, prostate, peripheral blood leukocyte 11 DHRS8, retSDR2 Liver, pancreas, intestine, kidney, adrenal Chai et al. (2003), Li et al. (1998) HSD17B11 Nearly ubiquitous gland, heart, lung testis ovary, placenta, sebaceous gland 12 KAR heart, skeletal muscle, liver, kidney, adrenal Luu-The et al. (2006), Moon and HSD17B12 Ubiquitous gland, testis, placenta, cerebrum, pancreas, Horton (2003), Sakurai et al. (2006) stomach, small intestine, large intestine, trachea, lung and thyroid, esophagus, prostate, aorta, urinary bladder, spleen, skin, brain, ovary, breast uterus, vagina 13 SCDR9 Liver ( marrow, lung, ovary, testis, kidney, Liu et al. (2007) HSD17B13 Strongly restricted skeletal muscle brain, bladder) 14 DHRS10, retSDR3 Brain, liver, placenta, breast Jansson et al. (2006), Lukacik et al. HSD17B14 Widely distributed (2007)

a http://www.ncbi.nlm.nih.gov/sites/entrez?db=unigene&cmd=search&term=. recent study (Entchev et al., 2008). The expression pattern of human 2.6. 17beta-HSD type 11 and type 13, two enzymes with fairly 17beta-HSD12 – the enzyme was found in heart, skeletal muscle, high similarity liver, kidney, adrenal gland, testis and placenta (Sakurai et al., 2006) – and additional database information (Table 2) seem to be more Only lately the cloning of the human short chain dehydroge- in concordance with an involvement of the enzyme in a metabolic nase/reductase SCDR9 was reported (Liu et al., 2007). The sequence pathway common to a broad range of tissues as it is the case for information was deposited as entry AY268355 in the NCBI database the lipid metabolism. The broadly distributed expression of the and is identical to entry NM 178135 that has been reserved for a enzyme in mouse promotes the latter hypothesis (Blanchard and dehydrogenase named 17beta-HSD13. An alignment of the amino Luu-The, 2007). Further support for the role in fatty acid comes acid sequence of the human SCDR9 reveals 78% similarity (65% from a recent study, in which 17beta-HSD12 was analysed on identity) to 17beta-HSD11 also known as Pan1b and retinal short- transcriptional and activity level in cell lines. Over-expression or chain dehydrogenase/reductase (DHRS8). Both genes are located on knockdown of 17beta-HSD12 did not influence the estradiol pro- chromosomal position 4q22.1, a region known to harbour a clus- duction (Day et al., 2008) making the role of 17beta-HSD12 in sex ter of retSDRs, which implies a participation in retinol metabolism. steroid metabolism less probable. In another recent study, Nagasaki However, 17beta-HSD11has the ability to catalyse the conversion of et al. addressed this issue in a different way (Nagasaki et al., in 17beta-hydroxysteroids such as 5alpha-androstane-3beta, 17beta- press). The siRNA mediated knockdown of HSD17B12 in the breast diol and estradiol but retinoids are not substrates for the enzyme carcinoma cell line SK-BR-3 resulted in a significant growth inhibi- (Brereton et al., 2001; Li et al., 1998). For 17beta-HSD13 enzymatic tion, which was recovered by the addition of fatty acids (arachidonic activity with retinol and steroid substrates has not yet been tested. acid). Unfortunately, the ability of recombinant 17beta-HSD12 to On the other hand, tissue distribution and subcellular localisa- catalyse reactions of fatty acid metabolism was never tested by any tion (Tables 2 and 3) give strong indication that the major roles of of the authors. both enzymes may not be related to sex steroid metabolism. Human However, on overall, a long line of evidence points to a primary 17beta-HSD 11 is not only found in steroidogenic tissues but has a involvement of 17beta-HSD12 in fatty acid metabolism in different broader tissue distribution as it is detected also in the pancreas, kid- species. ney, liver, lung and heart (Chai et al., 2003). The enzyme was isolated G. Moeller, J. Adamski / Molecular and Cellular Endocrinology 301 (2009) 7–19 11

Table 3 to the cytosol and in the presence of NAD+ it catalyses the oxi- Subcellular localisation of 17beta-hydroxysteroid dehydrogenases. dation of estradiol to estrone, 5-androstene-3beta, 17beta-diol 17beta-HSD Localisation Reference to dehydroepiandrosterone and to a much lesser extent testos- type terone to (Lukacik et al., 2007). This implies a 1 Cytosol Maentausta et al. (1991) biological function of 17beta-HSD14 in sex steroid inactivation, 2 Endoplasmic reticulum Wu et al. (1993) although catalytic activity with estradiol is rather low. Support- 3 Endoplasmic reticulum Mindnich et al. (2005) ing evidence for a role of the enzyme in sex steroid conversion 4 Peroxisomes Markus et al. (1995) comes from the expression pattern. High expression was detected 5 Cytosol Fung et al. (2006), Pelletier et al. (2001) in brain, liver, and placenta (Lukacik et al., 2007), tissues known 6 Microsomal Huang and Luu-The (2001) to participate in local steroid metabolism (see Table 2). The lipid 7 Endoplasmic reticulum Marijanovic et al. (2003) hydroxybutyryl-CoA was no substrate for the enzyme (Lukacik 8 Mitochondria Witkowski et al. (in preparation) et al., 2007). Docking experiments on the crystal structure with 10 Mitochondria He et al. (1999) 11 Endoplasmic reticulum, Fujimoto et al. (2004), Yokoietal. estradiol were performed and due to a broad and open active site lipid droplets (2007) cleft – different from 17beta-HSD1 – this substrate molecule sits 12 Endoplasmic reticulum Moon and Horton (2003) rather loosely within the cleft. This might also explain the low 13 Endoplasmic reticulum, Horiguchi et al. (2008) kcat values measured with this substrate (Lukacik et al., 2007). lipid droplets A steroidogenic function for 17beta-HSD14 is supported by the 14 Cytosol Lukacik et al. (2007) observation that high expression of the enzyme is associated with better survival prognosis for breast cancer patients (Jansson et al., in association with lipid droplets from the human hepatocyte cell 2006). line HuH7 (Fujimoto et al., 2004). The mouse enzyme was shown to be a major PPARalpha-regulated gene in intestine (Motojima, 2004) and to localize to endoplasmic reticulum (ER) under normal con- 3. Crystal structures of 17beta-HSDs ditions while associating with lipid droplets when induced (Yokoi et al., 2007). Expression of 17beta-HSD13 is seen also in various The first report about a 17beta-HSD crystal structure was given tissues but highest in liver (Liu et al., 2007). The enzyme is found in 1993. Zhu and co-workers presented the crystal structure of + to be ER and lipid droplet associated but in difference to 17beta- human 17beta-HSD1 in complex with the cofactor NADP (Zhu HSD11 not up-regulated by the PPARalpha pathway (Horiguchi et et al., 1993). The refined structure of the enzyme was after- al., 2008). A comparison of NCBI Unigene expression profiles of the wards published in 1995 (Ghosh et al., 1995). Since then 14 more two enzymes (Table 2) points to different tasks of the enzymes 17beta-HSD1 structures were submitted to the in metabolism. Thus, a remarkable high sequence similarity does (PDB), some in complex with cofactor, some with substrate or not necessarily mean the same characteristics and function for the inhibitor and some in combination with substrate/inhibitor and enzymes. cofactor. Apart from 17beta-HSD1, the crystal structures of six more human 17beta-HSDs are now available. The three-domain 2.7. Detailed characterisation of 17beta-HSD14 enzyme 17beta-HSD4 could not be crystallised as whole protein yet. Anyhow, the structures of the single domains are published. 17beta-HSD14, also known as retSDR3/DHRS10 (Lukacik et al., Table 4 summarises the PDB entries of the human 17beta-HSD 2006), is now characterised in more detail. The enzyme localises structures.

Table 4 Crystal structures of human 17beta-hydroxysteroid dehydrogenases.

17betaHSD type pdb Complex Reference

1 1BHS Ghosh et al. (1995) 1 1FDS + estradiol Breton et al. (1996) 1 1FDT + estradiol + NADP+ Breton et al. (1996) 1 1EQU + equilin + NADP+ Sawicki et al. (1999) 1 1FDV Mutant H221L + NAD+ Mazza et al. (1998) 1 1FDU Mutant H221L + estradiol + NAD+ Mazza et al. (1998) 1 1FDW Mutant H221Q + estradiol Mazza et al. (1998) 1 1A27 C-terminal deleted + estradiol + NADP+ Mazza et al. (1998) 1 1DHT + DHT Han et al. (2000) 1 3DHE + DHEA Han et al. (2000) 1 1I5R + inhibitor EM1745 Qiu et al. (2002) 1 1JTV + testosterone Gangloff et al. (2003) 1 1QYV + NADP+ Shi and Lin (2004) 1 1QYW + andostanedione + NADP+ Shi and Lin (2004) 1 1QYX + androstenedione + NADP+ Shi and Lin (2004) 4 1ZBQ SDR-domain PDB-submission by Lukacik et al. in 2005 4 1S9C Hydratase domain Koski et al. (2005) 4 1IKT SCP-2 like domain + Triton X-100 Haapalainen et al. (2001) 5 1XF0 + androstenedione + NADP+ Qiu et al. (2004) 5 1ZQ5 + EM1404 PDB-submission by Qiu et al. in 2005 5 2FGB + PEG + NADP+ PDB-submission by Qiu et al. in 2005 8 2PD6 PDB-submission by Turnbull et al. in 2007 10 2O23 + NADP+ PDB-submission by Kavanagh et al. in 2006 10 1U7T + inhibitor + NAD+ Kissinger et al. (2004) 10 1SO8 + amyloid beta Lustbader et al. (2004) 11 1YB1 PDB-submission by Lukacik et al. in 2004 14 1YDE Lukacik et al. (2007) 12 G. Moeller, J. Adamski / Molecular and Cellular Endocrinology 301 (2009) 7–19

Table 5 fatty acids is observed. Female mice can reproduce but with Mouse models for 17beta-hydroxysteroid dehydrogenases. reduced fertility while male are infertile due to defective sper- Enzyme Reference matogenesis (Baes et al., 2000). Excessive accumulation of fatty

Transgenic acids in Sertoli cells is the most probable reason for the degen- Human 17beta-HSD1 TG mouse Ubiquitous expression Saloniemi et al. eration of the testis and total loss of spermatogenesis at the age of (2007) 4 month (Huyghe et al., 2006b). With time, the MFP-2 knockout Human 17beta-HSD2 TG mouse Ubiquitous expression Zhongyi et al. animals develop motor deficits as well. While lesions of peripheral (2007) nerves or muscles are not observed and also no demyelination or Human 17beta-HSD10 TG mouse In neuronal tissue of Du Yan et al. (2000) CNS severe changes in Purkinje cells of the cerebellum, the knockout Knock out mice exhibited severe astrogliosis and microgliosis in the central 17beta-HSD2 KO mouse Complete Rantakari et al. nervous system predominantly within the grey matter of the brain (2008) and the spinal cord (Huyghe et al., 2006c). A comprehensive review 17beta-HSD4 KO mouse Complete Baes et al. (2000) 17beta-HSD7 KO mouse Complete Shehu et al. (2008) summarises the findings for the knockout mouse, and describes the MFP-2 enzyme and the associated disease D-bifunctional protein deficiency caused by loss of MFP-2 function in humans (Huyghe et al., 2006a). 4. Animal models for 17beta-HSDs A knockout mouse for 17beta-HSD7 just recently was published. While heterozygeous mice are viable, the complete knockout is The first mouse models for 17beta-HSDs were published in 2000, embryonal lethal. Embryos are resorbed between E10.5–11.5 of namely a knockout for 17beta-HSD4 (Baes et al., 2000) and a trans- development due to severe brain malformations and heart failure. genic mouse over-expressing human 17beta-HSD10 (Du Yan et al., The phenotype fits to a role of 17beta-HSD7 essential in cholesterol 2000). Since then, two more transgenic mice for human 17beta- synthesis (Shehu et al., 2008). HSD type 1 and 2 (Saloniemi et al., 2007; Zhongyi et al., 2007) were A transgenic mouse was produced for over-expression of human generated as well as two knockout mice for 17beta-HSD2 (Rantakari 17beta-HSD10 in neuronal tissue of the central nervous system et al., 2008) and 17beta-HSD7 (Shehu et al., 2008). An overview can (under the control of the PDGF B-chain promoter) showing an be found in Table 5. increase of 17beta-HSD10 protein in cerebral cortex, hippocam- The phenotype of transgenic mice over-expressing human pus and cerebellum. This higher 17beta-HSD10 expression seems 17beta-HSD1 (Saloniemi et al., 2007) is surprising. A predominantly to protect from cerebral infarction and ischemia (Du Yan et androgenic phenotype is observed although human 17beta-HSD1 al., 2000). The over-expression was also protective in neuronal is known to only barely convert androstenedione to testosterone stress induced by the neurotoxin MPTP and the authors stated in vitro (Puranen et al., 1997). While males are nearly normal and that the transgenic mouse could serve as model for Parkinson’s fertile increased testosterone concentration are found in females. disease (Tieu et al., 2004). Using this mouse model, a trans- Female mice show phenotypical changes in sexual characteristics genic mouse over-expressing 17beta-HSD10 beside amyloid beta and develop ovarian benign serous cystadenomas by time. The phe- (A␤) was established as a model for Alzheimer’s disease (AD) notype can be rescued with anti-estrogens or transplantation of (Lustbader et al., 2004). A more detailed description of research wild type ovaries. The authors suggest this transgenic mouse as on the latter mouse model is given in the chapter on 17beta- model for the development of 17beta-HSD1-inhibitors as drugs HSD10. against related dysfunctions in females (Saloniemi et al., 2007). The lately created 17beta-HSD2 model mice gave as well surpris- 5. Polymorphisms in HSD17B genes in connection to ing results. The observations point to the fact that 17beta-HSD2 is diseases not only involved in sex steroid metabolism. In transgenic mice, over-expression of human 17beta-HSD2 leads to growth retarda- The physiological significance of steroid hormones in diseases tion, delayed eye opening, and disrupted spermatogenesis (Zhongyi like for example cancer or is well known (Kitawaki et et al., 2007). The excess of the enzyme causes a decreased bone al., 2002; Sasano et al., 2008). Therefore, in the last years, more and formation rate at pre-pubertal age associated with lower serum more efforts were made to predict susceptibility to diseases on the IGF-I, osteocalcin and testosterone (Shen et al., 2008). The pheno- basis of gene variations in HSD17B genes. Up to now, we are aware type seems not to be due to a reduced or androgen action of at least 35 studies dealing with the analysis of HSD17B poly- but instead to an impairment of retinoic acid signalling, since the morphisms in connection with cancer, polycystic ovary syndrome testis phenotype could be rescued by retinoic acid receptor ago- (PCOS), endometriosis as well as others diseases or phenotypes nist supply (Zhongyi et al., 2007). The complete knockout of the (Table 6). enzyme (Rantakari et al., 2008) points into the same direction. The setups between the studies vary strongly. Some of the stud- The destruction of the enzyme function leads to 70% embry- ies are cohort, others case–control studies. Sample size ranges from onic lethality and a strongly reduced lifetime. Placental size is very small (around 50) to large numbers (nearly 17,000) and par- reduced and the placental structure is abnormal. Beside that, hydro- ticipants ethnics ranges from single ethnic to multiethnic. Single cephalus is found regularly accompanied with changes in brain nucleotide polymorphism (SNP) numbers inside the studies range organisation and frequently unilateral degeneration of a kidney from 1 up to 28 SNPs per gene of interest and some studies eval- is observed while the other kidney usually is filled with fluid. uate the single SNPs, others combine SNPs for haplotype analyses. The phenotype cannot be rescued by anti-estrogens or proges- Some studies consider as well the influence of SNPs of several genes. terone. It is therefore not surprising that the outcomes of the association The knockout mouse for 17beta-HSD4 (multifunctional protein studies presented here do not allow for conclusive statements as 2 (MFP-2)) is a model for the D-bifunctional protein deficiency, a also stated in (Chu et al., 2008). Especially, most of the studies do human disease with early lethality. Homozygous knockout mice not have sufficient sample sizes to obtain the statistical power to survive but show growth retardation and death before 6 months of detect an association of disease with low or moderate penetrance age. An accumulation of very long chain fatty acids and branched variants. G. Moeller, J. Adamski / Molecular and Cellular Endocrinology 301 (2009) 7–19 13 Suzuki et al. (2005) Suzuki et al. (2005) Jones et al. (2006) , , Cunningham et al. (2007) Lan et al. (2004) Bonner et al. (2005) Figueroa et al. (2008) Qin et al. (2006) Goodarzi et al. (2008) Petry et al. (2007) Jakobsson et al. (2007) Liu et al. (2008) , van , b Suzuki et al. (1997) Grunsven et al. (1999) Paton and Pollard (2000) Moghrabi et al. (1998) Margiotti et al. (2002) , Plourde et , Zhang et al. (2003) Cunningham et al. (2007) Jansson et al. (2007) al. (2008a) , a Feigelson , Dai et al. , Travis et al. a , Kristensen et al. Cunningham et , , Hefler et al. , Setiawan et al. (2004) Plourde et al. (2008b) , , a Beesley et al. (2007)Tsuchiya et al. (2005) Sowers et al. (2006) Sowers et al. (2006) Crandall et al. (2006) Haiman et al. (2002) Dunning et al. (2004) (2004) Suzuki et al. (2005) Beesley et al. (2007) al. (2007) Lo et al. (2006) Kravitz et al. (2006a) Kravitz et al. (2006b) Mannermaa et al. (1994) (2001) et al. (2001, 2006) Wu et al. (2003) (2004) Setiawan et al. (2004) (2007) Hefler et al. (2004) Huber et al. (2005) Kraft et al. (2005) Association with other phenotypes. Some associations not finally proven. a b Lung cancer Ovarian aging Age at natural menopause Vasomotor (VMS) Mammographic density Precocious pubarche Ovarian cancer Bladder cancer PCOS Endometriosis Blood steroids Estramustine-phosphate side effects D-bifunctional protein deficiency Depression Cognitive function Diabetes Table 6 Studies on associations of polymorphisms in 17beta-hydroxysteroid dehydrogenases with diseases. IndicationBreast cancer HSD17B1 HSD17B2 HSD17B3 HSD17B4Leukaemia ACR1C3Studies with observed associations are marked bold. HSD17B6 HSD17B7 HSD17B8 Endometrial cancer Fibroadenoma Colon cancer 14 G. Moeller, J. Adamski / Molecular and Cellular Endocrinology 301 (2009) 7–19

5.1. HSD17B1 5.2. HSD17B2

Most of the studies on 17beta-HSD genes were performed Polymorphisms in HSD17B2 were so far only analysed in con- for HSD17B1 (24 studies) and therein the non-synonymous SNP nection to breast or prostate cancer in different populations. rs605059 (A/G: Ser312Gly) was analysed most frequently (17 Associations could not be found in any of the four studies times). HSD17B1 polymorphisms were investigated for 16 differ- (Cunningham et al., 2007; Jansson et al., 2007; Plourde et al., 2008a; ent indications (Table 6) and among those most deal with breast Zhang et al., 2003). cancer (8 studies), a disease in which 17beta-HSD1 plays an impor- tant role (Sasano et al., 2008; Subramanian et al., 2008; Suzuki et 5.3. HSD17B3 al., 2007). In only three of eight studies on breast cancer some direct asso- Up to now, only one non-synonymous SNP, namely rs2066479 ciations with HSD17B1 SNPs were found. In multiethnic women (G/A: Gly289Ser), was analysed for HSD17B3. The A-allele of the from the US (Feigelson et al., 2001) and in Malaysian women (Wu SNP associated with a higher prostate cancer risk in Italian men et al., 2003) the A-allele of the SNP rs605059 (A/G: Gly312Ser) (Margiotti et al., 2002), but the SNP did not show any association was claimed to be a high-risk allele. This observation could not with polycystic ovary syndrome in Caucasian or African women be demonstrated in a later study from the same author with much (Moghrabi et al., 1998). more participants, including only US citizens of Caucasian origin (Feigelson et al., 2006). However, haplotype analysis including four 5.4. HSD17B4 SNPs of HSD17B1 was performed in this latter study and two com- mon haplotypes might be associated to estrogen receptor-negative As prognosis factor in different cancers 17beta-HSD4 was breast tumors. Some studies concerning HSD17B1 polymorphisms described up to now only on the level of expression (English et al., do not observe overall association with breast cancer but asso- 2000, 1999; Rasiah et al., in press). On the genomic level HSD17B4 ciation to other phenotypes. In one study the AA allele in SNP SNPs were solely identified in the context of D-bifunctional pro- rs605059 correlated with higher serum estradiol concentrations tein (D-BP) deficiency. Four single SNPs, 1269A/G (L423L), 317G/A in lean women (Setiawan et al., 2004) and in another study a 12 bp (R106H), 1531T/C (W511R), 1675A/G (I559V), found in different deletion in 5 flanking area of HSD17B1 was shown to only influence families, in which some members suffered from the disease, could recurrence rate of breast cancer (Kristensen et al., 2001). Several not be associated with functional gene defects (Paton and Pollard, studies could not show any connection between HSD17B1 SNPs and 2000; Suzuki et al., 1997; van Grunsven et al., 1999). Anyhow, in one breast cancer (Hefler et al., 2004; Mannermaa et al., 1994; Plourde patient with mild symptoms of D-BP deficiency the combination of et al., 2008b). two amino acid exchanges, c.317G/A (R106H) + c.1675A/G (I559V), In Chinese women the AG- and AA-alleles of SNP rs605059 was observed, while no other severe mutation in the HSD17B4 gene (A/G: S312G) of HSD17B1 seem to prevent endometrial cancer and could be found. An association of this double mutation with impair- soy intake might add to this protection (Dai et al., 2007) while in ment of beta-oxidation was discussed but a proof is still pending another study with US women no association of HSD17B1 SNPs to (Paton and Pollard, 2000). endometrial cancer was seen (Setiawan et al., 2004). Interestingly, the A-allele was reported to be associated in Japanese women with 5.5. AKR1C3 a higher risk of endometriosis (Tsuchiya et al., 2005). Surprisingly, HSD17B1 polymorphisms might play a role in Polymorphisms in the gene AKR1C3 coding for 17beta-HSD5 prostate cancer risk prediction. In a study with a large number of seem to be most penetrant to the human phenotypes. However, multiethnic men no overall association of haplotypes of four com- the outcomes of association studies remain controversial. mon SNPs in HSD17B1 (rs676387 (C/A), rs605059 (A/G), rs598126 The SNP rs3763676 (5’-71 A/G; near SP1/SP3 binding site) of (G/A), rs2010750 (C/T)) with prostate cancer were observed but AKR1C3 was described to associate with PCOS in a case–control two subgroups, Latinos and Japanese Americans, showing the hap- study with multiethnic women. The G-alleles in the PCOS patients lotype CAGC had a lower prostate cancer risk (Kraft et al., 2005). were significantly more frequent than in the controls with an odds In non-Hispanic Caucasian men the minor allele of HSD17B1 SNP ratio of 1.66 (Qin et al., 2006). A trend of higher testosterone lev- rs605059 (A/G) was more frequent among sporadic prostate can- els was as well observed in subjects homozygous for the G-allele. cer cases than among controls, anyhow, no significant association These both findings could not be replicated by another study in could be detected (Cunningham et al., 2007). which non-Hispanic white US women were analysed. This latter An Australian ovarian cancer study with cases and controls of study included the SNP mentioned above, and four additional SNPs Caucasian origin showed no association between ovarian cancer (rs12529 C/G, Q5H; rs17396032 A/G intron 1; rs2518049 A/G intron and HSD17B1 as well as HSD17B4 polymorphisms (Beesley et al., 1; rs1937841 A/G intron 4) as well as haplotype analysis of these 2007). (Goodarzi et al., 2008). Apart from cancer, HSD17B1 polymorphisms were also found In a case–control study including familiar as well as sporadic to be related to other phenotypes like vasomotor symptoms (VMS) non-familiar prostate cancer cases of non-Hispanic Caucasian men, (Crandall et al., 2006), depression and some cognitive function in where only a suggestive association between a HSD17B1 SNP and Chinese women (Kravitz et al., 2006b). One study analysed the asso- sporadic prostate cancer could be seen (see above), the synonymous ciation of three HSD17B1 SNPs, rs2830 (A/G), rs592389 (T/G), and SNP rs7741 c.90G/A (P30P) in the AKR1C3 gene showed as well rs615942 (G/T), with the metabolic syndrome and diabetes in a only suggestive but no significant association with familiar prostate group of multiethnic women (Lo et al., 2006). The odds ratio of cancer (Cunningham et al., 2007). In another study five novel poly- having diabetes among Caucasian women who were homozygous morphisms in the AKR1C3 gene were analysed in connection to for the HSD17B1 polymorphisms were 4- to 7-fold greater com- serum testosterone. One of the SNPs, an A/G substitution in exon 2 pared with women who were heterozygous for these SNPs. On the that confers an E77G change, occurred in 4.8% in Caucasians but was other hand, the three 17beta-HSD1 gene polymorphisms were not completely absent in Orientals. For carriers of the G77 allele a sig- associated with the metabolic syndrome in any racial/ethnic group nificantly lower serum testosterone level was observed (Jakobsson (Lo et al., 2006). et al., 2007). G. Moeller, J. Adamski / Molecular and Cellular Endocrinology 301 (2009) 7–19 15

The non-synonymous SNP rs12529 (H5Q) has been associated follow several rules for that including specificity and kinetic prefer- with increased lung cancer risk in a Chinese population, with the ences checked over a wide spectrum of substrates (Meier et al., in strongest association among individuals exposed to smoky coals press). Therefore, before names are given in the future, genomic (Lan et al., 2004). A Spanish bladder cancer study with cases and annotation of the enzymes should be reported, and enzymatic controls of Caucasian origin looked at the association of 24 SNPs activity with various substrates and tissues should be carefully in the AKR1C3 gene with urothelial carcinomas. The most signifi- proven by experimental evidence to optimally classify the enzymes cant finding based on a test for trend was an inverse association and prevent confusions. A new nomenclature for the family of SDR with risk for two highly correlated SNPs, rs1937845 in the pro- enzymes (Persson et al., in press), where most of the 17beta-HSDs moter and rs12529 (C/G, H5Q) in exon 1 where heterozygote and belong to, will additionally provide more clarity on biological func- homozygote variant genotypes compared to the common homozy- tion. gote showed odds ratios of 0.86 and 0.74, respectively. Beside this, a number of more SNPs analysed in this study showed associa- References tion with bladder cancer, some indicating higher, some lower risk (Figueroa et al., 2008). Adamski, J., Husen, B., Marks, F., Jungblut, P.W., 1992. Purification and properties To elucidate the risk of developing leukaemia in childhood the of oestradiol 17 beta-dehydrogenase extracted from cytoplasmic vesicles of porcine endometrial cells. Biochem. J. 288 (Part 2), 375–381. SNP rs12529 (C/G, Q5H), three tag SNPs (rs2245191 G/T intron 1, Adamski, J., Normand, T., Leenders, F., Monte, D., Begue, A., Stehelin, D., Jung- rs10508293 intron 4, and rs3209896 G/A exon 9), and one multi- blut, P.W, de Launoit, Y., 1995. Molecular cloning of a novel widely expressed marker (rs2245191, rs10508293, and rs3209896) were looked at in a human 80 kDa 17 beta-hydroxysteroid dehydrogenase IV. Biochem. J. 311 (Pt 2), 437–443. case–control study with Han Chinese participants from Taiwan. The Aziz, N., Maxwell, M.M., St Jacques, B., Brenner, B.M., 1993. Downregulation of Ke 6, SNP rs10508293 on intron 4 was found to be significantly associated a novel gene encoded within the major histocompatibility complex, in murine with childhood leukaemia. Further, the maternal methylenete- polycystic kidney disease. Mol. Cell Biol. 13, 1847–1853. Baes, M., Huyghe, S., Carmeliet, P., Declercq, P.E., Collen, D., Mannaerts, G.P., Van trahydrofolate reductase A1298C polymorphism was found to be Veldhoven, P.P., 2000. Inactivation of the peroxisomal multifunctional protein-2 an effect modifier (Liu et al., 2008). in mice impedes the degradation of not only 2-methyl-branched fatty acids and bile acid intermediates but also of very long chain fatty acids. J. Biol. Chem. 275, 5.6. HSD17B6 16329–16336. Beesley, J., Jordan, S.J., Spurdle, A.B., Song, H., Ramus, S.J., Kjaer, S.K., Hogdall, E., DiCioccio, R.A., McGuire, V., Whittemore, A.S., Gayther, S.A., Pharoah, P.D., Webb, In a case–control studies with Caucasian women from West- P.M., Chenevix-Trench, G., 2007. Association between single-nucleotide poly- ern Australia 6 non-coding SNPs in the HSD17B6 gene (rs2277339 morphisms in hormone metabolism and DNA repair genes and epithelial ovarian cancer: results from two Australian studies and an additional validation set. (T/G) 5 of promoter, rs7967600 (C/T) 5 -UTR, s898611 (A/G) 5 -UTR, Cancer Epidemiol. Biomarkers Prev. 16, 2557–2565. rs12227117 (C/T) 5 -UTR, rs10459246 (G/T) intron 2, rs1870673 Belyaeva, O.V., Chetyrkin, S.V., Clark, A.L., Kostereva, N.V., SantaCruz, K.S., Chronwall, (C/T) 17.7 kb 3 downstream) were analysed in connection to poly- B.M., Kedishvili, N.Y., 2007. Role of microsomal retinol/sterol dehydrogenase-like short-chain dehydrogenases/reductases in the oxidation and epimerization of cystic ovary syndrome (Jones et al., 2006). Only SNP rs898611 (A/G) 3alpha-hydroxysteroids in human tissues. Endocrinology 148, 2148–2156. showed an association with PCOS. The GG allele appears signifi- Biswas, M.G., Russell, D.W., 1997. Expression cloning and characterization of oxida- cantly more often in PCOS patients than controls. Inside the PCOS tive 17beta- and 3alpha-hydroxysteroid dehydrogenases from rat and human prostate. J. Biol. Chem. 272, 15959–15966. cohort, further correlations could be drawn between some SNPs or Blanchard, P.G., Luu-The, V., 2007. Differential androgen and estrogen substrates haplotypes (including four SNPs) and key phenotypes of PCOS like specificity in the mouse and primates type 12 17beta-hydroxysteroid dehydro- for example the fasting glucose to insulin ratio or the BMI (Jones et genase. J. Endocrinol. 194, 449–455. al., 2006). Bonner, M.R., Rothman, N., Mumford, J.L., He, X., Shen, M., Welch, R., Yeager, M., Chanock, S., Caporaso, N., Lan, Q., 2005. Green tea consumption, genetic sus- ceptibility, PAH-rich smoky coal, and the risk of lung cancer. Mutat. Res. 582, 5.7. HSD17B7 53–60. Breitling, R., Krazeisen, A., Moller, G., Adamski, J., 2001. 17beta-hydroxysteroid dehy- drogenase type 7–an ancient 3-ketosteroid reductase of cholesterogenesis. Mol. Polymorphisms in the genes HSD17B1, HSD17B7 and HSD17B8 Cell. Endocrinol. 171, 199–204. were analysed in a study with Japanese prostate cancer patients Brereton, P., Suzuki, T., Sasano, H., Li, K., Duarte, C., Obeyesekere, V., Haese- where side effects of estramustine-phosphate intake were evalu- leer, F., Palczewski, K., Smith, I., Komesaroff, P., Krozowski, Z., 2001. Pan1b (17betaHSD11)-enzymatic activity and distribution in the lung. Mol. Cell. ated. Of all SNPs only two in the HSD17B7 gene could be associated. Endocrinol. 171, 111–117. Peripheral oedema occurred more frequently in patients with C/C Breton, R., Housset, D., Mazza, C., Fontecilla-Camps, J.C., 1996. The structure of a genotype of SNP rs2804642 (C/G) than in those with C/G genotype. complex of human 17beta-hydroxysteroid dehydrogenase with estradiol and NADP+ identifies two principal targets for the design of inhibitors. Structure 4, Haplotype analysis showed that appetite loss was associated with 905–915. the G allele of rs2804642 and the T allele of rs1780019 (T/C) (Suzuki Casey, M.L., MacDonald, P.C., Andersson, S., 1994. 17 beta-Hydroxysteroid dehy- et al., 2005). drogenase type 2: chromosomal assignment and progestin regulation of in human endometrium. J. Clin. Invest. 94, 2135–2141. Chai, Z., Brereton, P., Suzuki, T., Sasano, H., Obeyesekere, V., Escher, G., Saffery, 6. Outlook R., Fuller, P., Enriquez, C., Krozowski, Z., 2003. 17 beta-hydroxysteroid dehy- drogenase type XI localizes to human steroidogenic cells. Endocrinology 144, 2084–2091. Although all the enzymes described here were named as 17beta- Chu, L.W., Reichardt, J.K., Hsing, A.W., 2008. Androgens and the molecular epidemi- HSDs, and therewith suggested to be most important in sex steroid ology of prostate cancer. Curr. Opin. Endocrinol. Diabetes Obes. 15, 261–270. metabolism, we now know that many of the enzymes play more Corbould, A.M., Bawden, M.J., Lavranos, T.C., Rodgers, R.J., Judd, S.J., 2002. The effect important roles in other metabolic pathways as for example in of obesity on the ratio of type 3 17beta-hydroxysteroid dehydrogenase mRNA to cytochrome P450 aromatase mRNA in subcutaneous abdominal and intra- fatty acid metabolism. Therefore, 17beta-HSDs contribute to our abdominal adipose tissue of women. Int. J. Obes. Relat. Metab. Disord. 26, knowledge on the metabolome, specifically the lipidome. 165–175. We are awaiting the discovery of more so-called 17beta-HSDs. Crandall, C.J., Crawford, S.L., Gold, E.B., 2006. Vasomotor symptom prevalence is asso- ciated with polymorphisms in sex steroid-metabolizing enzymes and receptors. Indeed, inhibitor studies against estrogenic enzymes suggest the Am. J. Med. 119, S52–60. existence of further 17beta-HSDs as presented in a contribution in Cunningham, J.M., Hebbring, S.J., McDonnell, S.K., Cicek, M.S., Christensen, G.B., the same journal issue (Laplante et al., in press). However, not all Wang, L., Jacobsen, S.J., Cerhan, J.R., Blute, M.L., Schaid, D.J., Thibodeau, S.N., 2007. Evaluation of genetic variations in the androgen and estrogen metabolic path- enzymes converting steroids at position 17 deserve physiologically ways as risk factors for sporadic and familial prostate cancer. Cancer Epidemiol. the name of 17beta-hydroxysteroid dehydrogenases as they have to Biomarkers Prev. 16, 969–978. 16 G. Moeller, J. Adamski / Molecular and Cellular Endocrinology 301 (2009) 7–19

Dai, Q., Xu, W.H., Long, J.R., Courtney, R., Xiang, Y.B., Cai, Q., Cheng, J., Zheng, W., Shu, hermaphroditism caused by mutations of testicular 17 beta-hydroxysteroid X.O., 2007. Interaction of soy and 17beta-HSD1 gene polymorphisms in the risk dehydrogenase 3. Nat. Genet. 7, 34–39. of endometrial cancer. Pharmacogenet. Genomics 17, 161–167. Ghersevich, S.A., Poutanen, M.H., Martikainen, H.K., Vihko, R.K., 1994. Expression Day, J.M., Foster, P.A., Tutill, H.J., Parsons, M.F., Newman, S.P., Chander, S.K., Allan, of 17 beta-hydroxysteroid dehydrogenase in human granulosa cells: correla- G.M., Lawrence, H.R., Vicker, N., Potter, B.V., Reed, M.J., Purohit, A., 2008. 17beta- tion with follicular size, cytochrome P450 aromatase activity and oestradiol hydroxysteroid dehydrogenase Type 1, and not Type 12, is a target for endocrine production. J. Endocrinol. 143, 139–150. therapy of hormone-dependent breast cancer. Int. J. Cancer 122, 1931–1940. Ghosh, D., Pletnev, V.Z., Zhu, D.W., Wawrzak, Z., Duax, W.L., Pangborn, W., Labrie, F., Dieuaide-Noubhani, M., Asselberghs, S., Mannaerts, G.P., Van Veldhoven, P.P., 1997. Lin, S.X., 1995. Structure of human estrogenic 17 beta-hydroxysteroid dehydro- Evidence that multifunctional protein 2, and not multifunctional protein 1, is genase at 2.20 A resolution. Structure 3, 503–513. involved in the peroxisomal beta-oxidation of pristanic acid. Biochem. J. 325 Gnatenko, D.V., Cupit, L.D., Huang, E.C., Dhundale, A., Perrotta, P.L., Bahou, W.F., 2005. (Part 2), 367–373. Platelets express steroidogenic 17beta-hydroxysteroid dehydrogenases. Distinct Dieuaide-Noubhani, M., Novikov, D., Baumgart, E., Vanhooren, J.C., Fransen, M., profiles predict the essential thrombocythemic phenotype. Thromb. Haemost. Goethals, M., Vandekerckhove, J., Van Veldhoven, P.P., Mannaerts, G.P., 1996. Fur- 94, 412–421. ther characterization of the peroxisomal 3-hydroxyacyl-CoA dehydrogenases Goodarzi, M.O., Jones, M.R., Antoine, H.J., Pall, M., Chen, Y.D., Azziz, R., 2008. from rat liver. Relationship between the different dehydrogenases and evi- Nonreplication of the type 5 17beta-hydroxysteroid dehydrogenase gene asso- dence that fatty acids and the C27 bile acids di- and tri-hydroxycoprostanic ciation with polycystic ovary syndrome. J. Clin. Endocrinol. Metab. 93, 300– acids are metabolized by separate multifunctional . Eur. J. Biochem. 240, 303. 660–666. Haapalainen, A.M., van Aalten, D.M., Merilainen, G., Jalonen, J.E., Pirila, P., Wierenga, Du Yan, S., Zhu, Y., Stern, E.D., Hwang, Y.C., Hori, O., Ogawa, S., Frosch, M.P., Connolly R.K., Hiltunen, J.K., Glumoff, T., 2001. Crystal structure of the liganded SCP-2- Jr., E.S., McTaggert, R., Pinsky, D.J., Clarke, S., Stern, D.M., Ramasamy, R., 2000. like domain of human peroxisomal multifunctional enzyme type 2 at 1.75 A Amyloid beta-peptide-binding alcohol dehydrogenase is a component of the resolution. J. Mol. Biol. 313, 1127–1138. cellular response to nutritional stress. J. Biol. Chem. 275, 27100–27109. Haiman, C.A., Bernstein, L., Berg, D., Ingles, S.A., Salane, M., Ursin, G., 2002. Genetic Duan, W.R., Linzer, D.I., Gibori, G., 1996. Cloning and characterization of an ovarian- determinants of mammographic density. Breast Cancer Res. 4, R5. specific protein that associates with the short form of the prolactin receptor. J. Han, Q., Campbell, R.L., Gangloff, A., Huang, Y.W., Lin, S.X., 2000. Dehy- Biol. Chem. 271, 15602–15607. droepiandrosterone and dihydrotestosterone recognition by human estrogenic Dumont, M., Luu-The, V., de Launoit, Y., Labrie, F., 1992. Expression of human 17 beta- 17beta-hydroxysteroid dehydrogenase. C-18/c-19 steroid discrimination and hydroxysteroid dehydrogenase in mammalian cells. J. Steroid Biochem. Mol. Biol. enzyme-induced strain. J. Biol. Chem. 275, 1105–1111. 41, 605–608. He, X.Y., Merz, G., Mehta, P., Schulz, H., Yang, S.Y., 1999. Human brain short chain L- Dunning, A.M., Dowsett, M., Healey, C.S., Tee, L., Luben, R.N., Folkerd, E., Novik, 3-hydroxyacyl coenzyme A dehydrogenase is a single-domain multifunctional K.L., Kelemen, L., Ogata, S., Pharoah, P.D., Easton, D.F., Day, N.E., Ponder, B.A., enzyme. Characterization of a novel 17beta-hydroxysteroid dehydrogenase. J. 2004. Polymorphisms associated with circulating sex hormone levels in post- Biol. Chem. 274, 15014–15019. menopausal women. J. Natl. Cancer Inst. 96, 936–945. He, X.Y., Merz, G., Yang, Y.Z., Mehta, P., Schulz, H., Yang, S.Y., 2001. Characterization English, M.A., Hughes, S.V., Kane, K.F., Langman, M.J., Stewart, P.M., Hewison, M., and localization of human type10 17beta-hydroxysteroid dehydrogenase. Eur. J. 2000. Oestrogen inactivation in the colon: analysis of the expression and regu- Biochem. 268, 4899–4907. lation of 17beta-hydroxysteroid dehydrogenase isozymes in normal colon and He, X.Y., Merz, G., Yang, Y.Z., Pullakart, R., Mehta, P., Schulz, H., Yang, S.Y., 2000. Func- colonic cancer. Br. J. Cancer 83, 550–558. tion of human brain short chain L-3-hydroxyacyl coenzyme A dehydrogenase in English, M.A., Kane, K.F., Cruickshank, N., Langman, M.J., Stewart, P.M., Hewison, M., androgen metabolism. Biochim. Biophys. Acta 1484, 267–277. 1999. Loss of estrogen inactivation in colonic cancer. J. Clin. Endocrinol. Metab. He, X.Y., Schulz, H., Yang, S.Y., 1998. A human brain L-3-hydroxyacyl-coenzyme A 84, 2080–2085. dehydrogenase is identical to an amyloid beta-peptide-binding protein involved Entchev, E.V., Schwudke, D., Zagoriy, V., Matyash, V., Bogdanova, A., Habermann, B., in Alzheimer’s disease. J. Biol. Chem. 273, 10741–10746. Zhu, L., Shevchenko, A., Kurzchalia, T.V., 2008. LET-767 is required for the pro- He, X.Y., Wegiel, J., Yang, Y.Z., Pullarkat, R., Schulz, H., Yang, S.Y., 2005. Type 10 duction of branched chain and long chain fatty acids in Caenorhabditis elegans. 17beta-hydroxysteroid dehydrogenase catalyzing the oxidation of steroid mod- J. Biol. Chem. 283, 17550–17560. ulators of gamma-aminobutyric acid type A receptors. Mol. Cell. Endocrinol. 229, Feigelson, H.S., Cox, D.G., Cann, H.M., Wacholder, S., Kaaks, R., Henderson, B.E., 111–117. Albanes, D., Altshuler, D., Berglund, G., Berrino, F., Bingham, S., Buring, J.E., Burtt, He, X.Y., Yang, Y.Z., Peehl, D.M., Lauderdale, A., Schulz, H., Yang, S.Y., 2003. Oxidative N.P., Calle, E.E., Chanock, S.J., Clavel-Chapelon, F., Colditz, G., Diver, W.R., Freed- 3alpha-hydroxysteroid dehydrogenase activity of human type 10 17beta- man, M.L., Haiman, C.A., Hankinson, S.E., Hayes, R.B., Hirschhorn, J.N., Hunter, D., hydroxysteroid dehydrogenase. J. Steroid Biochem. Mol. Biol. 87, 191–198. Kolonel, L.N., Kraft, P., LeMarchand, L., Linseisen, J., Modi, W., Navarro, C., Peeters, Hefler, L.A., Tempfer, C.B., Grimm, C., Lebrecht, A., Ulbrich, E., Heinze, G., Leodolter, P.H., Pike, M.C., Riboli, E., Setiawan, V.W., Stram, D.O., Thomas, G., Thun, M.J., S., Schneeberger, C., Mueller, M.W., Muendlein, A., Koelbl, H., 2004. Estrogen- Tjonneland, A., Trichopoulos, D., 2006. Haplotype analysis of the HSD17B1 gene metabolizing gene polymorphisms in the assessment of breast carcinoma risk and risk of breast cancer: a comprehensive approach to multicenter analyses of and fibroadenoma risk in Caucasian women. Cancer 101, 264–269. prospective cohort studies. Cancer Res. 66, 2468–2475. Hoppe, U., Holterhus, P.M., Wunsch, L., Jocham, D., Drechsler, T., Thiele, S., Marschke, Feigelson, H.S., McKean-Cowdin, R., Coetzee, G.A., Stram, D.O., Kolonel, L.N., Hen- C., Hiort, O., 2006. Tissue-specific transcription profiles of sex steroid biosyn- derson, B.E., 2001. Building a multigenic model of breast cancer susceptibility: thesis enzymes and the androgen receptor. J. Mol. Med. 84, 651–659. CYP17 and HSD17B1 are two important candidates. Cancer Res. 61, 785– Horiguchi, Y., Araki, M., Motojima, K., 2008. 17beta-Hydroxysteroid dehydrogenase 789. type 13 is a liver-specific lipid droplet-associated protein. Biochem. Biophys. Res. Figueroa, J.D., Malats, N., Garcia-Closas, M., Real, F.X., Silverman, D., Kogevinas, M., Commun. 370, 235–238. Chanock, S., Welch, R., Dosemeci, M., Lan, Q., Tardon, A., Serra, C., Carrato, A., Huang, X.F., Luu-The, V., 2000. Molecular characterization of a first human 3(alpha– Garcia-Closas, R., Castano-Vinyals, G., Rothman, N., 2008. Bladder cancer risk >beta)-hydroxysteroid epimerase. J. Biol. Chem. 275, 29452–29457. and genetic variation in AKR1C3 and other metabolizing genes. Carcinogenesis. Huang, X.F., Luu-The, V., 2001. Gene structure, chromosomal localization and Fomitcheva, J., Baker, M.E., Anderson, E., Lee, G.Y., Aziz, N., 1998. Characterization of analysis of 3-ketosteroid reductase activity of the human 3(alpha–>beta)- Ke 6, a new 17beta-hydroxysteroid dehydrogenase, and its expression in gonadal hydroxysteroid epimerase. Biochim. Biophys. Acta 1520, 124–130. tissues. J. Biol. Chem. 273, 22664–22671. Huber, A., Bentz, E.K., Schneeberger, C., Huber, J.C., Hefler, L., Tempfer, C., 2005. Ten Froyen, G., Corbett, M., Vandewalle, J., Jarvela, I., Lawrence, O., Meldrum, C., Bauters, polymorphisms of estrogen-metabolizing genes and a family history of colon M., Govaerts, K., Vandeleur, L., Van Esch, H., Chelly, J., Sanlaville, D., van Bokhoven, cancer–an association study of multiple gene-gene interactions. J. Soc. Gynecol. H., Ropers, H.H., Laumonnier, F., Ranieri, E., Schwartz, C.E., Abidi, F., Tarpey, P.S., Investig. 12, e51–e54. Futreal, P.A., Whibley, A., Raymond, F.L., Stratton, M.R., Fryns, J.P., Scott, R., Peippo, Huyghe, S., Mannaerts, G.P., Baes, M., Van Veldhoven, P.P., 2006a. Peroxisomal multi- M., Sipponen, M., Partington, M., Mowat, D., Field, M., Hackett, A., Marynen, P., functional protein-2: the enzyme, the patients and the knockout mouse model. Turner, G., Gecz, J., 2008. Submicroscopic duplications of the hydroxysteroid Biochim. Biophys. Acta 1761, 973–994. dehydrogenase HSD17B10 and the E3 ubiquitin ligase HUWE1 are associated Huyghe, S., Schmalbruch, H., De Gendt, K., Verhoeven, G., Guillou, F., Van Veld- with mental retardation. Am. J. Hum. Genet. 82, 432–443. hoven, P.P., Baes, M., 2006b. Peroxisomal multifunctional protein 2 is essential Fujimoto, Y., Itabe, H., Sakai, J., Makita, M., Noda, J., Mori, M., Higashi, Y., Kojima, S., for lipid homeostasis in Sertoli cells and male fertility in mice. Endocrinology Takano, T., 2004. Identification of major proteins in the lipid droplet-enriched 147, 2228–2236. fraction isolated from the human hepatocyte cell line HuH7. Biochim. Biophys. Huyghe, S., Schmalbruch, H., Hulshagen, L., Veldhoven, P.V., Baes, M., Hartmann, D., Acta 1644, 47–59. 2006c. Peroxisomal multifunctional protein-2 deficiency causes motor deficits Fung, K.M., Samara, E.N., Wong, C., Metwalli, A., Krlin, R., Bane, B., Liu, C.Z., Yang, and glial lesions in the adult central nervous system. Am. J. Pathol. 168, J.T., Pitha, J.V., Culkin, D.J., Kropp, B.P., Penning, T.M., Lin, H.K., 2006. Increased 1321–1334. expression of type 2 3alpha-hydroxysteroid dehydrogenase/type 5 17beta- Jakobsson, J., Palonek, E., Lorentzon, M., Ohlsson, C., Rane, A., Ekstrom, L., 2007. A hydroxysteroid dehydrogenase (AKR1C3) and its relationship with androgen novel polymorphism in the 17beta-hydroxysteroid dehydrogenase type 5 (aldo- receptor in prostate carcinoma. Endocr. Relat. Cancer 13, 169–180. keto reductase 1C3) gene is associated with lower serum testosterone levels in Gangloff, A., Shi, R., Nahoum, V., Lin, S.X., 2003. Pseudo-symmetry of C19 steroids, caucasian men. Pharmacogenomics J. 7, 282–289. alternative binding orientations, and multispecificity in human estrogenic Jansson, A., Carlsson, J., Olsson, A., Storm, P., Margolin, S., Gunnarsson, C., Stenmark- 17beta-hydroxysteroid dehydrogenase. FASEB. J. 17, 274–276. Askmalm, M., Lindblom, A., Persson, B., Stal, O., 2007. A new polymorphism in Geissler, W.M., Davis, D.L., Wu, L., Bradshaw, K.D., Patel, S., Mendonca, B.B., the coding region of exon four in HSD17B2 in relation to risk of sporadic and Elliston, K.O., Wilson, J.D., Russell, D.W., Andersson, S., 1994. Male pseudo- hereditary breast cancer. Breast Cancer Res. Treat. 106, 57–64. G. Moeller, J. Adamski / Molecular and Cellular Endocrinology 301 (2009) 7–19 17

Jansson, A.K., Gunnarsson, C., Cohen, M., Sivik, T., Stal, O., 2006. 17beta- dehydrogenase responsible for estradiol formation in women. Mol. Endocrinol. hydroxysteroid dehydrogenase 14 affects estradiol levels in breast cancer cells 20, 437–443. and is a prognostic marker in estrogen receptor-positive breast cancer. Cancer Mackenzie, S.M., Huda, S.S., Sattar, N., Fraser, R., Connell, J.M., Davies, E., 2008. Res. 66, 11471–11477. Depot-specific steroidogenic gene transcription in human adipose tissue. Clin. Jones, M.R., Italiano, L., Wilson, S.G., Mullin, B.H., Mead, R., Dudbridge, F., Watts, G.F., Endocrinol. (Oxf.). Stuckey, B.G., 2006. Polymorphism in HSD17B6 is associated with key features Maentausta, O., Sormunen, R., Isomaa, V., Lehto, V.P., Jouppila, P., Vihko, R., 1991. of polycystic ovary syndrome. Fertil. Steril. 86, 1438–1446. Immunohistochemical localization of 17 beta-hydroxysteroid dehydrogenase in Kissinger, C.R., Rejto, P.A., Pelletier, L.A., Thomson, J.A., Showalter, R.E., Abreo, M.A., the human endometrium during the menstrual cycle. Lab. Invest. 65, 582–587. Agree, C.S., Margosiak, S., Meng, J.J., Aust, R.M., Vanderpool, D., Li, B., Tempczyk- Mannermaa, A., Peltoketo, H., Winqvist, R., Ponder, B.A., Kiviniemi, H., Easton, D.F., Russell, A., Villafranca, J.E., 2004. Crystal structure of human ABAD/HSD10 with Poutanen, M., Isomaa, V., Vihko, R., 1994. Human familial and sporadic breast a bound inhibitor: implications for design of Alzheimer’s disease therapeutics. cancer: analysis of the coding regions of the 17 beta-hydroxysteroid dehydro- J. Mol. Biol. 342, 943–952. genase 2 gene (EDH17B2) using a single-strand conformation polymorphism Kitawaki, J., Kado, N., Ishihara, H., Koshiba, H., Kitaoka, Y., Honjo, H., 2002. assay. Hum. Genet. 93, 319–324. Endometriosis: the pathophysiology as an estrogen-dependent disease. J. Margiotti, K., Kim, E., Pearce, C.L., Spera, E., Novelli, G., Reichardt, J.K., 2002. Associ- Steroid Biochem. Mol. Biol. 83, 149–155. ation of the G289S single nucleotide polymorphism in the HSD17B3 gene with Koski, K.M., Haapalainen, A.M., Hiltunen, J.K., Glumoff, T., 2005. Crystal structure prostate cancer in Italian men. Prostate 53, 65–68. of 2-enoyl-CoA hydratase 2 from human peroxisomal multifunctional enzyme Marijanovic, Z., Laubner, D., Moller, G., Gege, C., Husen, B., Adamski, J., Breitling, R., type 2. J. Mol. Biol. 345, 1157–1169. 2003. Closing the gap: identification of human 3-ketosteroid reductase, the last Kraft, P., Pharoah, P., Chanock, S.J., Albanes, D., Kolonel, L.N., Hayes, R.B., Altshuler, unknown enzyme of mammalian cholesterol biosynthesis. Mol. Endocrinol. 17, D., Andriole, G., Berg, C., Boeing, H., Burtt, N.P., Bueno-de-Mesquita, B., Calle, 1715–1725. E.E., Cann, H., Canzian, F., Chen, Y.C., Crawford, D.E., Dunning, A.M., Feigelson, Markus, M., Husen, B., Leenders, F., Jungblut, P.W., Hall, P.F., Adamski, J., 1995. The H.S., Freedman, M.L., Gaziano, J.M., Giovannucci, E., Gonzalez, C.A., Haiman, C.A., organelles containing porcine 17beta-estradiol dehydrogenase are peroxisomes. Hallmans, G., Henderson, B.E., Hirschhorn, J.N., Hunter, D.J., Kaaks, R., Key, T., Eur. J. Cell. Biol. 68, 263–267. Le Marchand, L., Ma, J., Overvad, K., Palli, D., Pike, M.C., Riboli, E., Rodriguez, Matsuura, K., Shiraishi, H., Hara, A., Sato, K., Deyashiki, Y., Ninomiya, M., C., Setiawan, W.V., Stampfer, M.J., Stram, D.O., Thomas, G., Thun, M.J., Travis, Sakai, S., 1998. Identification of a principal mRNA species for human R., Trichopoulou, A., Virtamo, J., Wacholder, S., 2005. Genetic variation in the 3alpha-hydroxysteroid dehydrogenase isoform (AKR1C3) that exhibits high HSD17B1 gene and risk of prostate cancer. PLoS Genet. 1, e68. prostaglandin D2 11-ketoreductase activity. J. Biochem. (Tokyo) 124, 940–946. Kravitz, H.M., Janssen, I., Lotrich, F.E., Kado, D.M., Bromberger, J.T., 2006a. Sex steroid Mazza, C., Breton, R., Housset, D., Fontecilla-Camps, J.C., 1998. Unusual charge stabi- hormone gene polymorphisms and depressive symptoms in women at midlife. lization of NADP+ in 17beta-hydroxysteroid dehydrogenase. J. Biol. Chem. 273, Am. J. Med. 119, S87–93. 8145–8152. Kravitz, H.M., Meyer, P.M., Seeman, T.E., Greendale, G.A., Sowers, M.R., 2006b. Cog- Meier, M., Möller, G., Adamski, J., in press. Perspectives in understanding the role of nitive functioning and sex steroid hormone gene polymorphisms in women at human 17beta-hydroxysteroid dehydrogenases in health and disease. Ann. N.Y. midlife. Am. J. Med. 119, S94–S102. Acad. Sci., doi:10.1016/j.cbi.2008.10.036. Krazeisen, A., Breitling, R., Imai, K., Fritz, S., Moller, G., Adamski, J., 1999. Determina- Miettinen, M.M., Mustonen, M.V., Poutanen, M.H., Isomaa, V.V., Vihko, R.K., 1996. tion of cDNA, gene structure and chromosomal localization of the novel human Human 17 beta-hydroxysteroid dehydrogenase type 1 and type 2 isoenzymes 17beta-hydroxysteroid dehydrogenase type 7. FEBS Lett. 460, 373–379. have opposite activities in cultured cells and characteristic cell- and tissue- Kristensen, V.N., Harada, N., Kristensen, T., Borresen-Dale, A.L., 2001. Genetic poly- specific expression. Biochem. J. 314 (Part 3), 839–845. morphism and variability of steroid hormone metabolism: connection with risk Mindnich, R., Deluca, D., Adamski, J., 2004. Identification and characterization of of developing breast neoplasms. Vopr. Onkol. 47, 156–159. 17 beta-hydroxysteroid dehydrogenases in the zebrafish, Danio rerio. Mol. Cell. Lan, Q., Mumford, J.L., Shen, M., Demarini, D.M., Bonner, M.R., He, X., Yeager, M., Endocrinol. 215, 19–30. Welch, R., Chanock, S., Tian, L., Chapman, R.S., Zheng, T., Keohavong, P., Capo- Mindnich, R., Haller, F., Halbach, F., Moeller, G., Hrabe de Angelis, M., Adamski, J., raso, N., Rothman, N., 2004. Oxidative damage-related genes AKR1C3 and OGG1 2005. Androgen metabolism via 17beta-hydroxysteroid dehydrogenase type 3 modulate risks for lung cancer due to exposure to PAH-rich coal combustion in mammalian and non-mammalian vertebrates: comparison of the human and emissions. Carcinogenesis 25, 2177–2181. the zebrafish enzyme. J. Mol. Endocrinol. 35, 305–316. Laplante, Y., Rancourt, C., Poirier, D., in press. Relative involvement of three 17beta- Moeller, G., Adamski, J., 2006. Multifunctionality of human 17beta-hydroxysteroid hydroxysteroid dehydrogenases (types 1, 7 and 12) in the formation of estradiol dehydrogenases. Mol. Cell. Endocrinol. 248, 47–55. in various breast cancer cell lines using selective inhibitors. Mol. Cell. Endocrinol. Moghrabi, N., Hughes, I.A., Dunaif, A., Andersson, S., 1998. Deleterious missense Lenski, C., Kooy, R.F., Reyniers, E., Loessner, D., Wanders, R.J., Winnepenninckx, B., mutations and silent polymorphism in the human 17beta-hydroxysteroid dehy- Hellebrand, H., Engert, S., Schwartz, C.E., Meindl, A., Ramser, J., 2007. The reduced drogenase 3 gene (HSD17B3). J. Clin. Endocrinol. Metab. 83, 2855–2860. expression of the HADH2 protein causes X-linked mental retardation, choreoa- Moon, Y.A., Horton, J.D., 2003. Identification of two mammalian reductases involved thetosis, and abnormal behavior. Am. J. Hum. Genet. 80, 372–377. in the two-carbon fatty acyl elongation cascade. J. Biol. Chem. 278, 7335–7343. Li, K.X., Smith, R.E., Krozowski, Z.S., 1998. Cloning and expression of a novel tissue Motojima, K., 2004. 17beta-hydroxysteroid dehydrogenase type 11 is a major perox- specific 17beta-hydroxysteroid dehydrogenase. Endocr. Res. 24, 663–667. isome proliferator-activated receptor alpha-regulated gene in mouse intestine. Lin, H.K., Jez, J.M., Schlegel, B.P., Peehl, D.M., Pachter, J.A., Penning, T.M., 1997. Eur. J. Biochem. 271, 4141–4146. Expression and characterization of recombinant type 2 3 alpha-hydroxysteroid Nagasaki, S., Suzuki, T., Miki, Y., Akahira, J., Kitada, K., Ishida, T., Handa, H., Ohuchi, N., dehydrogenase (HSD) from human prostate: demonstration of bifunctional Sasano, H., in press. 17␤-hydroxysteroid dehydrogenase type12 in human breast 3 alpha/17 beta-HSD activity and cellular distribution. Mol. Endocrinol. 11, carcinoma: a prognostic factor via potential regulation of fatty acids synthesis. 1971–1984. Cancer Res. Liu, C.Y., Hsu, Y.H., Pan, P.C., Wu, M.T., Ho, C.K., Su, L., Xu, X., Li, Y., Christiani, D.C., 2008. Nokelainen, P., Peltoketo, H., Vihko, R., Vihko, P., 1998. Expression cloning of a novel Maternal and offspring genetic variants of AKR1C3 and the risk of childhood estrogenic mouse 17 beta-hydroxysteroid dehydrogenase/17-ketosteroid reduc- leukemia. Carcinogenesis. tase (m17HSD7), previously described as a prolactin receptor-associated protein Liu, S., Huang, C., Li, D., Ren, W., Zhang, H., Qi, M., Li, X., Yu, L., 2007. Molecular cloning (PRAP) in rat. Mol. Endocrinol. 12, 1048–1059. and expression analysis of a new gene for short-chain dehydrogenase/reductase Ofman, R., Ruiter, J.P., Feenstra, M., Duran, M., Poll-The, B.T., Zschocke, J., 9. Acta Biochim. Pol. 54, 213–218. Ensenauer, R., Lehnert, W., Sass, J.O., Sperl, W., Wanders, R.J., 2003. 2-Methyl- Lo, J.C., Zhao, X., Scuteri, A., Brockwell, S., Sowers, M.R., 2006. The associa- 3-hydroxybutyryl-CoA dehydrogenase deficiency is caused by mutations in the tion of genetic polymorphisms in sex hormone biosynthesis and action with HADH2 gene. Am. J. Hum. Genet. 72, 1300–1307. insulin sensitivity and diabetes mellitus in women at midlife. Am. J. Med. 119, Ohnesorg, T., Adamski, J., 2005. Promoter analyses of human and mouse 17beta- S69–78. hydroxysteroid dehydrogenase type 7. J. Steroid Biochem. Mol. Biol. 94, 259–261. Lukacik, P., Kavanagh, K.L., Oppermann, U., 2006. Structure and function of Ohnesorg, T., Adamski, J., 2006. Analysis of the 5 flanking regions of human and human 17beta-hydroxysteroid dehydrogenases. Mol. Cell. Endocrinol. 248, 61– murine HSD17B7: identification of a cholesterol dependent enhancer region. 71. Mol. Cell. Endocrinol. 248, 164–167. Lukacik, P., Keller, B., Bunkoczi, G., Kavanagh, K.L., Lee, W.H., Adamski, J., Oppermann, Ohnesorg, T., Keller, B., Hrabe de Angelis, M., Adamski, J., 2006. Transcriptional U., 2007. Structural and biochemical characterization of human orphan DHRS10 regulation of human and murine 17beta-hydroxysteroid dehydrogenase type- reveals a novel cytosolic enzyme with steroid dehydrogenase activity. Biochem. 7 confers its participation in cholesterol biosynthesis. J. Mol. Endocrinol. 37, J. 402, 419–427. 185–197. Lustbader, J.W., Cirilli, M., Lin, C., Xu, H.W., Takuma, K., Wang, N., Caspersen, C., Ohno, S., Nishikawa, K., Honda, Y., Nakajin, S., 2008. Expression in E. coli and Chen, X., Pollak, S., Chaney, M., Trinchese, F., Liu, S., Gunn-Moore, F., Lue, L.F., tissue distribution of the human homologue of the mouse Ke 6 gene, 17beta- Walker, D.G., Kuppusamy, P., Zewier, Z.L., Arancio, O., Stern, D., Yan, S.S., Wu, H., hydroxysteroid dehydrogenase type 8. Mol. Cell. Biochem. 309, 209–215. 2004. ABAD directly links Abeta to mitochondrial toxicity in Alzheimer’s disease. Oppermann, U., Filling, C., Hult, M., Shafqat, N., Wu, X., Lindh, M., Shafqat, J., Science 304, 448–452. Nordling, E., Kallberg, Y., Persson, B., Jornvall, H., 2003. Short-chain dehydro- Luu-The, V., Labrie, C., Simard, J., Lachance, Y., Zhao, H.F., Couet, J., Leblanc, G., Labrie, genases/reductases (SDR): the 2002 update. Chem. Biol. Interact. 143–144, F., 1990. Structure of two in tandem human 17 beta-hydroxysteroid dehydroge- 247–253. nase genes. Mol. Endocrinol. 4, 268–275. Paton, B.C., Pollard, A.N., 2000. Molecular changes in the D-bifunctional protein Luu-The, V., Tremblay, P., Labrie, F., 2006. Characterization of type 12 17beta- cDNA sequence in Australasian patients belonging to the bifunctional protein hydroxysteroid dehydrogenase, an isoform of type 3 17beta-hydroxysteroid complementation group. Cell. Biochem. Biophys. 32 (Spring), 247–251. 18 G. Moeller, J. Adamski / Molecular and Cellular Endocrinology 301 (2009) 7–19

Pelletier, G., Luu-The, V., El-Alfy, M., Li, S., Labrie, F., 2001. Immunoelectron Setiawan, V.W., Hankinson, S.E., Colditz, G.A., Hunter, D.J., De Vivo, I., 2004. HSD17B1 microscopic localization of 3beta-hydroxysteroid dehydrogenase and type 5 gene polymorphisms and risk of endometrial and breast cancer. Cancer Epi- 17beta-hydroxysteroid dehydrogenase in the human prostate and mammary demiol. Biomarkers Prev. 13, 213–219. gland. J. Mol. Endocrinol. 26, 11–19. Shafqat, N., Marschall, H.U., Filling, C., Nordling, E., Wu, X.Q., Bjork, L., Thy- Pelletier, G., Luu-The, V., Li, S., Labrie, F., 2005. Localization of Type 8 17{beta}- berg, J., Martensson, E., Salim, S., Jornvall, H., Oppermann, U., 2003. hydroxysteroid Dehydrogenase mRNA in Mouse Tissues as Studied by In Situ Expanded substrate screenings of human and Drosophila type 10 17beta- Hybridization. J. Histochem. Cytochem.. hydroxysteroid dehydrogenases (HSDs) reveal multiple specificities in bile Penning, T.M., Burczynski, M.E., Jez, J.M., Hung, C.F., Lin, H.K., Ma, H., Moore, M., acid and steroid hormone metabolism: characterization of multifunctional Palackal, N., Ratnam, K., 2000. Human 3alpha-hydroxysteroid dehydrogenase 3alpha/7alpha/7beta/17beta/20beta/21-HSD. Biochem. J. 376, 49–60. isoforms (AKR1C1-AKR1C4) of the aldo-keto reductase superfamily: functional Shehu, A., Mao, J., Gibori, G.B., Halperin, J., Le, J., Devi, Y.S., Merrill, B., Kiyokawa, H., plasticity and tissue distribution reveals roles in the inactivation and formation Gibori, G., 2008. Hsd17b7 (PRAP/17{beta}-hydroxysteroid dehydrogenase Type of male and female sex hormones. Biochem. J. 351, 67–77. 7) gene plays a crucial role in embryonic development and fetal survival. Mol. Persson, B., Adamski, J., Bray, J., Bruford, B., Dellaporta, S.L., Gonzalez Duarte, Endocrinol.. R., Jörnvall, H., Kallberg, Y., Kavanagh, K.L., Kedishvili, N., E., M., Orchard, Shen, Z., Peng, Z., Sun, Y., Vaananen, H.K., Poutanen, M., 2008. Overexpression of S., Penning, T.M., Thornton, J., Oppermann, U., in press. The short-chain Human Hydroxysteroid (17beta) Dehydrogenase 2 Induces Disturbance in Skele- dehydrogenase/reductase (SDR) nomenclature initiative. Chem. Biol. Interact., tal Development in Young Male Mice. J. Bone Miner. Res.. doi:10.1016/j.cbi.2008.10.04. Shi, R., Lin, S.X., 2004. Cofactor hydrogen bonding onto the protein main chain is Petry, C.J., Ong, K.K., Wingate, D.L., de Zegher, F., Ibanez, L., Dunger, D.B., 2007. Lack conserved in the short chain dehydrogenase/reductase family and contributes of association between common polymorphisms in the 17beta-hydroxysteroid to nicotinamide orientation. J. Biol. Chem. 279, 16778–16785. dehydrogenase type V gene (HSD17B5) and precocious pubarche. J. Steroid Song, D., Liu, G., Luu-The, V., Zhao, D., Wang, L., Zhang, H., Xueling, G., Li, S., Desy, L., Biochem. Mol. Biol. 105, 176–180. Labrie, F., Pelletier, G., 2006. Expression of aromatase and 17beta-hydroxysteroid Pletnev, V.Z., Duax, W.L., 2005. Rational proteomics IV: modeling the primary func- dehydrogenase types 1, 7 and 12 in breast cancer. An immunocytochemical tion of the mammalian 17beta-hydroxysteroid dehydrogenase type 8. J. Steroid study. J. Steroid Biochem. Mol. Biol. 101, 136–144. Biochem. Mol. Biol. 94, 327–335. Sowers, M.R., Jannausch, M.L., McConnell, D.S., Kardia, S.R., Randolph Jr., J.F., 2006. Plourde, M., Manhes, C., Leblanc, G., Durocher, F., Dumont, M., Sinilnikova, O., Simard, Menstrual cycle markers of ovarian aging and sex steroid hormone genotypes. J., 2008a. Mutation analysis and characterization of HSD17B2 sequence variants Am. J. Med. 119, S31–43. in breast cancer cases from French Canadian families with high risk of breast Steckelbroeck, S., Jin, Y., Gopishetty, S., Oyesanmi, B., Penning, T.M., 2004. Human and ovarian cancer. J. Mol. Endocrinol. 40, 161–172. cytosolic 3alpha-hydroxysteroid dehydrogenases of the aldo-keto reductase Plourde, M., Samson, C., Durocher, F., Sinilnokova, O., Simard, J., 2008b. Characteriza- superfamily display significant 3beta-hydroxysteroid dehydrogenase activity: tion of HSD17B1 sequence variants in breast cancer cases from French Canadian implications for steroid hormone metabolism and action. J. Biol. Chem. 279, families with high risk of breast and ovarian cancer. J. Steroid Biochem. Mol. Biol. 10784–10795. 109, 115–128. Steckelbroeck, S., Stoffel-Wagner, B., Reichelt, R., Schramm, J., Bidlingmaier, F., Poutanen, M., Isomaa, V., Lehto, V.P., Vihko, R., 1992. Immunological analysis of Siekmann, L., Klingmuller, D., 1999. Characterization of 17beta-hydroxysteroid 17 beta-hydroxysteroid dehydrogenase in benign and malignant human breast dehydrogenase activity in brain tissue: testosterone formation in the human tissue. Int. J. Cancer 50, 386–390. temporal lobe. J. Neuroendocrinol. 11, 457–464. Puranen, T., Poutanen, M., Ghosh, D., Vihko, P., Vihko, R., 1997. Characterization of Subramanian, A., Salhab, M., Mokbel, K., 2008. Oestrogen producing enzymes and structural and functional properties of human 17 beta-hydroxysteroid dehydro- mammary carcinogenesis: a review. Breast Cancer Res. Treat. 111, 191–202. genase type 1 using recombinant enzymes and site-directed mutagenesis. Mol. Suzuki, M., Muto, S., Hara, K., Ozeki, T., Yamada, Y., Kadowaki, T., Tomita, K., Endocrinol. 11, 77–86. Kameyama, S., Kitamura, T., 2005. Single-nucleotide polymorphisms in the Qin, K., Ehrmann, D.A., Cox, N., Refetoff, S., Rosenfield, R.L., 2006. Identification of 17beta-hydroxysteroid dehydrogenase genes might predict the risk of side- a functional polymorphism of the human type 5 17beta-hydroxysteroid dehy- effects of estramustine phosphate sodium in prostate cancer patients. Int. J. Urol. drogenase gene associated with polycystic ovary syndrome. J. Clin. Endocrinol. 12, 166–172. Metab. 91, 270–276. Suzuki, T., Miki, Y., Moriya, T., Akahira, J., Hirakawa, H., Ohuchi, N., Sasano, H., 2007. In Qiu, W., Campbell, R.L., Gangloff, A., Dupuis, P., Boivin, R.P., Tremblay, M.R., Poirier, situ production of sex steroids in human breast carcinoma. Med. Mol. Morphol. D., Lin, S.X., 2002. A concerted, rational design of type 1 17beta-hydroxysteroid 40, 121–127. dehydrogenase inhibitors: estradiol-adenosine hybrids with high affinity. FASEB Suzuki, T., Sasano, H., Andersson, S., Mason, J.I., 2000. 3beta-hydroxysteroid J. 16, 1829–1831. dehydrogenase/delta5–>4-isomerase activity associated with the human Qiu, W., Zhou, M., Labrie, F., Lin, S.X., 2004. Crystal structures of the multispecific 17beta-hydroxysteroid dehydrogenase type 2 isoform. J. Clin. Endocrinol. Metab. 17beta-hydroxysteroid dehydrogenase type 5: critical androgen regulation in 85, 3669–3672. human peripheral tissues. Mol. Endocrinol. 18, 1798–1807. Suzuki, Y., Jiang, L.L., Souri, M., Miyazawa, S., Fukuda, S., Zhang, Z., Une, M., Shi- Quinkler, M., Sinha, B., Tomlinson, J.W., Bujalska, I.J., Stewart, P.M., Arlt, W., 2004. mozawa, N., Kondo, N., Orii, T., Hashimoto, T., 1997. D-3-hydroxyacyl-CoA Androgen generation in adipose tissue in women with simple obesity—a site- dehydratase/D-3-hydroxyacyl-CoA dehydrogenase bifunctional protein defi- specific role for 17beta-hydroxysteroid dehydrogenase type 5. J. Endocrinol. 183, ciency: a newly identified peroxisomal disorder. Am. J. Hum. Genet. 61, 331–342. 1153–1162. Rantakari, P., Strauss, L., Kiviranta, R., Lagerbohm, H., Paviala, J., Holopainen, I., Vainio, Tieu, K., Perier, C., Vila, M., Caspersen, C., Zhang, H.P., Teismann, P., Jackson-Lewis, V., S., Pakarinen, P., Poutanen, M., 2008. Placenta defects and embryonic lethality Stern, D.M., Yan, S.D., Przedborski, S., 2004. L-3-hydroxyacyl-CoA dehydrogenase resulting from disruption of mouse hydroxysteroid (17-beta) dehydrogenase 2 II protects in a model of Parkinson’s disease. Ann. Neurol. 56, 51–60. gene. Mol. Endocrinol. 22, 665–675. Torn, S., Nokelainen, P., Kurkela, R., Pulkka, A., Menjivar, M., Ghosh, S., Coca-Prados, Rasiah, K.K., Gardiner-Garden, M., Padilla, E.J., Möller, G., Kench, J.G., Alles, C., Eggle- M., Peltoketo, H., Isomaa, V., Vihko, P., 2003. Production, purification, and ton, S.A., Stricker, P.D., Adamski, J., Sutherland, R.L., Henshall, S.M., Hayes, V.M., functional analysis of recombinant human and mouse 17beta-hydroxysteroid 2009. HSD17B4 overexpression, an independent biomarker of poor patient out- dehydrogenase type 7. Biochem. Biophys. Res. Commun. 305, 37–45. come in prostate cancer. Mol. Cell. Endocrinol. Travis, R.C., Churchman, M., Edwards, S.A., Smith, G., Verkasalo, P.K., Wolf, C.R., Ren, Y., Xu, H.W., Davey, F., Taylor, M., Aiton, J., Coote, P., Fang, F., Yao, J., Chen, D., Wolf, H., Key, T.J., 2004. No association of polymorphisms in CYP17, CYP19, and Chen, J.X., Yan, S.D., Gunn-Moore, F.J., 2008. Endophilin I expression is increased HSD17-B1 with plasma estradiol concentrations in 1,090 British women. Cancer in the brains of Alzheimer disease patients. J. Biol. Chem. 283, 5685–5691. Epidemiol. Biomarkers Prev. 13, 2282–2284. Risk, M., Shehu, A., Mao, J., Stocco, C.O., Goldsmith, L.T., Bowen-Shauver, J.M., Gibori, Tsuchiya, M., Nakao, H., Katoh, T., Sasaki, H., Hiroshima, M., Tanaka, T., Matsunaga, T., G., 2005. Cloning and characterization of a 5 regulatory region of the pro- Hanaoka, T., Tsugane, S., Ikenoue, T., 2005. Association between endometrio- lactin receptor-associated protein/17{beta} hydroxysteroid dehydrogenase 7 sis and genetic polymorphisms of the estradiol-synthesizing enzyme genes gene. Endocrinology 146, 2807–2816. HSD17B1 and CYP19. Hum. Reprod. 20, 974–978. Sakurai, N., Miki, Y., Suzuki, T., Watanabe, K., Narita, T., Ando, K., Yung, T.M., Aoki, van Grunsven, E.G., Mooijer, P.A., Aubourg, P., Wanders, R.J., 1999. Enoyl-CoA D., Sasano, H., Handa, H., 2006. Systemic distribution and tissue localizations of hydratase deficiency: identification of a new type of D-bifunctional protein human 17beta-hydroxysteroid dehydrogenase type 12. J. Steroid Biochem. Mol. deficiency. Hum. Mol. Genet. 8, 1509–1516. Biol. 99, 174–181. van Grunsven, E.G., van Berkel, E., Ijlst, L., Vreken, P., de Klerk, J.B., Adamski, J., Saloniemi, T., Lamminen, T., Huhtinen, K., Welsh, M., Saunders, P., Kujari, H., Lemonde, H., Clayton, P.T., Cuebas, D.A., Wanders, R.J., 1998. Peroxisomal D- Poutanen, M., 2007. Activation of androgens by hydroxysteroid (17beta) dehy- hydroxyacyl-CoA dehydrogenase deficiency: resolution of the enzyme defect drogenase 1 in vivo as a cause of prenatal masculinization and ovarian benign and its molecular basis in bifunctional protein deficiency. Proc. Natl. Acad. Sci. serous cystadenomas. Mol. Endocrinol. 21, 2627–2636. U.S.A. 95, 2128–2133. Sasano, H., Suzuki, T., Miki, Y., Moriya, T., 2008. Intracrinology of estrogens and Van Veldhoven, P.P., Croes, K., Asselberghs, S., Herdewijn, P., Mannaerts, G.P., 1996. androgens in breast carcinoma. J. Steroid Biochem. Mol. Biol. 108, 181–185. Peroxisomal beta-oxidation of 2-methyl-branched acyl-CoA esters: stereospe- Sawicki, M.W., Erman, M., Puranen, T., Vihko, P., Ghosh, D., 1999. Structure of the cific recognition of the 2S-methyl compounds by trihydroxycoprostanoyl-CoA ternary complex of human 17beta-hydroxysteroid dehydrogenase type 1 with 3- oxidase and pristanoyl-CoA oxidase. FEBS Lett. 388, 80–84. hydroxyestra-1,3,5,7-tetraen-17-one (equilin) and NADP+. Proc. Natl. Acad. Sci. Villar, J., Celay, J., Alonso, M.M., Rotinen, M., de Miguel, C., Migliaccio, M., Encio, U.S.A. 96, 840–845. I., 2007. Transcriptional regulation of the human type 8 17beta-hydroxysteroid Seth, G., McIvor, R.S., Hu, W.S., 2005. 17beta-Hydroxysteroid dehydrogenase type 7 dehydrogenase gene by C/EBPbeta. J. Steroid Biochem. Mol. Biol. 105, (Hsd17b7) reverts cholesterol auxotrophy in NS0 cells. J. Biotechnol.. 131–139. G. Moeller, J. Adamski / Molecular and Cellular Endocrinology 301 (2009) 7–19 19

Wu, A.H., Seow, A., Arakawa, K., Van Den Berg, D., Lee, H.P., Yu, M.C., 2003. HSD17B1 Yao, J., Taylor, M., Davey, F., Ren, Y., Aiton, J., Coote, P., Fang, F., Chen, J.X., Yan, and CYP17 polymorphisms and breast cancer risk among Chinese women in S.D., Gunn-Moore, F.J., 2007. Interaction of amyloid binding alcohol dehy- Singapore. Int. J. Cancer 104, 450–457. drogenase/Abeta mediates up-regulation of peroxiredoxin II in the brains of Wu, L., Einstein, M., Geissler, W.M., Chan, H.K., Elliston, K.O., Andersson, S., 1993. Alzheimer’s disease patients and a transgenic Alzheimer’s disease mouse model. Expression cloning and characterization of human 17 beta-hydroxysteroid dehy- Mol. Cell. Neurosci. 35, 377–382. drogenase type 2, a microsomal enzyme possessing 20 alpha-hydroxysteroid Yokoi, Y., Horiguchi, Y., Araki, M., Motojima, K., 2007. Regulated expression by PPAR- dehydrogenase activity. J. Biol. Chem. 268, 12964–12969. alpha and unique localization of 17beta-hydroxysteroid dehydrogenase type 11 Yan, S.D., Fu, J., Soto, C., Chen, X., Zhu, H., Al-Mohanna, F., Collison, K., Zhu, A., Stern, E., protein in mouse intestine and liver. FEBS J. 274, 4837–4847. Saido, T., Tohyama, M., Ogawa, S., Roher, A., Stern, D., 1997. An intracellular pro- Zhang, K.Q., Salzman, S.A., Reding, D.J., Suarez, B.K., Catalona, W.J., Burmester, J.K., tein that binds amyloid-beta peptide and mediates neurotoxicity in Alzheimer’s 2003. Genetics of prostate cancer. Clin. Med. Res. 1, 21–28. disease. Nature 389, 689–695. Zhongyi, S., Rantakari, P., Lamminen, T., Toppari, J., Poutanen, M., 2007. Transgenic Yan, S.D., Stern, D.M., 2005. Mitochondrial dysfunction and Alzheimer’s disease: role male mice expressing human hydroxysteroid dehydrogenase 2 indicate a role of amyloid-beta peptide alcohol dehydrogenase (ABAD). Int. J. Exp. Pathol. 86, for the enzyme independent of its action on sex steroids. Endocrinology 148, 161–171. 3827–3836. Yan, Y., Liu, Y., Sorci, M., Belfort, G., Lustbader, J.W., Yan, S.S., Wang, C., 2007. Sur- Zhu, D.W., Lee, X., Breton, R., Ghosh, D., Pangborn, W., Daux, W.L., Lin, S.X., 1993. Crys- face plasmon resonance and nuclear magnetic resonance studies of ABAD-Abeta tallization and preliminary X-ray diffraction analysis of the complex of human interaction. Biochemistry 46, 1724–1731. placental 17 beta-hydroxysteroid dehydrogenase with NADP+. J. Mol. Biol. 234, Yang, S.Y., He, X.Y., Miller, D., 2007. HSD17B10: a gene involved in cognitive function 242–244. through metabolism of isoleucine and neuroactive steroids. Mol. Genet. Metab. 92, 36–42.