Closing the Gap: Identification of Human 3-Ketosteroid Reductase, the Last Unknown Enzyme of Mammalian Cholesterol Biosynthesis

Marijanovic, Zrinka; Laubner, Daniela; Möller, Gabriele; Gege, Christian; Husen, Bettina; Adamski, Jerzy; Breitling, Rainer

doi:10.1210/me.2002-0436

Cited by 115 publications

(91 citation statements)

References 62 publications

(62 reference statements)

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“…These genes could not be readily assigned to a common functional group. Notably, Hsd17␤7 and Stard4 are involved in synthesis (39) and intracellular transport of cholesterol (40), respectively, and are known to be repressed by elevated sterol levels (41,42).…”

Section: B-e)mentioning

confidence: 99%

Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors

Zelcer

Khanlou

Clare

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

299

223

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Alzheimer's disease (AD) is an age-dependent neurodegenerative disease that causes progressive cognitive impairment. The initiation and progression of AD has been linked to cholesterol metabolism and inflammation, processes that can be modulated by liver x receptors (LXRs). We show here that endogenous LXR signaling impacts the development of AD-related pathology. Genetic loss of either Lxr␣ or Lxr␤ in APP/PS1 transgenic mice results in increased amyloid plaque load. LXRs regulate basal and inducible expression of key cholesterol homeostatic genes in the brain and act as potent inhibitors of inflammatory gene expression. Ligand activation of LXRs attenuates the inflammatory response of primary mixed glial cultures to fibrillar amyloid ␤ peptide (fA␤) in a receptordependent manner. Furthermore, LXRs promote the capacity of microglia to maintain fA␤-stimulated phagocytosis in the setting of inflammation. These results identify endogenous LXR signaling as an important determinant of AD pathogenesis in mice. We propose that LXRs may be tractable targets for the treatment of AD due to their ability to modulate both lipid metabolic and inflammatory gene expression in the brain.T he liver x receptors ␣ and ␤ (LXR␣/NR1H3 and LXR␤/ NR1H2, respectively) are oxysterol-activated nuclear receptors that play an important role in the control of cellular and whole-body cholesterol homeostasis (1-4). LXRs are also potent inhibitors of inflammatory responses in macrophages, pointing to an additional function for LXR signaling in immune regulation (5-11). The function of LXRs in the brain is not well understood. Ligand activation of LXRs promotes cholesterol efflux from glia (12, 13) and primary neurons (14), whereas mice deficient in expression of Lxr␣ and Lxr␤ develop marked accumulation of neutral lipids in the brain (15). Functionally, loss of LXR␤ leads to adult-onset motor neuron degeneration by the age of 7 months (16). The role of LXRs in human neurodegenerative diseases, however, remains largely unknown.Alzheimer's disease (AD) is an age-dependent neurodegenerative disease typified by progressive neuronal loss and cognitive impairment. AD is characterized by extraneuronal deposits of ␤-amyloid (A␤) fibrils (fA␤) (17) and intraneuronal tangles of hyperphosphorylated (18). The identification of rare mutations in the amyloid precursor protein (APP) and in presenilin genes (PS) in human AD is consistent with a central role for A␤ in AD pathogenesis (19). AD is a multifactorial disease, and inflammatory processes and cholesterol metabolism are among several factors that have been linked to its etiology.The AD brain exhibits prominent activation of innate immune responses. For example, elevated levels of inflammatory mediators can be measured in AD brains, and these are postulated to contribute to neuronal loss. The local inflammatory response is mediated by activated microglia and reactive astrocytes that surround the senile plaques (20,21). Interaction of microglia with fA␤ leads to their activation and the release of an arra...

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Section: B-e)mentioning

confidence: 99%

Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors

Zelcer

Khanlou

Clare

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

299

223

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“…However, sequence and promoter analysis indicate that the major role of this enzyme may be as a 3-ketosteroid reductase in cholesterol biosynthesis, reducing zymosterone at the 3 position to form zymosterol (Marijanović et al 2003, Ohnesorg et al 2006. Despite this, a recent study has indicate that 17b-HSD7, along with 17b-HSD1, 17b-HSD5 and other steroidogenic enzymes, is significantly up-regulated in ovarian tissue of patients with ovarian endometriosis (Šmuc et al 2007).…”

Section: B-hsdsmentioning

confidence: 99%

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

Day¹,

Tutill²,

Purohit³

et al. 2008

Endocrine Related Cancer

114

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Abstract17b-Hydroxysteroid dehydrogenases (17b-HSDs) are enzymes that are responsible for reduction or oxidation of hormones, fatty acids and bile acids in vivo, regulating the amount of the active form that is available to bind to its cognate receptor. All require NAD(P)(H) for activity. Fifteen 17b-HSDs have been identified to date, and with one exception, 17b-HSD type 5 (17b-HSD5), an aldo-keto reductase, they are all short-chain dehydrogenases/reductases, although overall homology between the enzymes is low. Although named as 17b-HSDs, reflecting the major redox activity at the 17b-position of the steroid, the activities of these 15 enzymes vary, with several of the 17b-HSDs able to reduce and/or oxidise multiple substrates at various positions. These activities are involved in the progression of a number of diseases, including those related to steroid metabolism. Despite the success of inhibitors of steroidogenic enzymes in the clinic, such as those of aromatase and steroid sulphatase, the development of inhibitors of 17b-HSDs is at a relatively early stage, as at present none have yet reached clinical trials. However, many groups are now working on inhibitors specific for several of these enzymes for the treatment of steroid-dependent diseases, including breast and prostate cancer, and endometriosis, with demonstrable efficacy in in vivo disease models. In this review, the recent advances in the validation of these enzymes as targets for the treatment of these diseases, with emphasis on 17b-HSD1, 3 and 5, the development of specific inhibitors, the models used for their evaluation, and their progress towards the clinic will be discussed.

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“…It is noteworthy that human type 7 17b-HSD, in addition to its ability to catalyze the transformation of E 1 into E 2 , also possesses 3-ketoreductase activity able to transform dihydroxy testosterone (DHT) into 5a-androstane-3b,17b-diol (3b-diol; Torn et al 2003, Liu et al 2005) and zymosterone into zymosterol, an important step in the cholesterol biosynthetic pathway (Marijanovic et al 2003).…”

Section: Introductionmentioning

confidence: 99%

Differential androgen and estrogen substrates specificity in the mouse and primates type 12 17β-hydroxysteroid dehydrogenase

Blanchard¹,

Luu‐The²

2007

Journal of Endocrinology

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Recently, we have shown that human and monkey type 12 17b-hydroxysteroid dehydrogenases (17b-HSD12) are estrogen-specific enzymes catalyzing the transformation of estrone (E 1 ) into estradiol (E 2 ). To further characterize this novel steroidogenic enzyme in an animal model, we have isolated a cDNA fragment encoding mouse 17b-HSD12 and characterized its enzymatic activity. Using human embryonic kidney cells (HEK)-293 cells stably expressing mouse 17b-HSD12, we found that in contrast with the human and monkey enzymes, which are specific for the transformation of E 1 to E 2 , mouse 17b-HSD12 also catalyzes the transformation of 4-androstenedione into testosterone (T), dehydroepiandrosterone (DHEA) into 5-androstene-3b,17b-diol (5-diol), as well as androsterone into 5a-androstane-3a,17b-diol (3a-diol). Previously, we have shown that the specificity of human and monkey 17b-HSD12s for C18-steroid is due to the presence of a bulky phenylalanine (F) at position 234 creating steric hindrance, preventing the entrance of C19-steroids into the active site. To determine whether the smaller size of the corresponding leucine (L) in the mouse sequence is responsible for the entrance of androgenic substrates, we performed site-directed mutagenesis to substitute Leu 234 for Phe in the mouse enzyme. In agreement with our hypothesis, the mutated enzyme has a highly reduced ability to metabolize androgens. mRNA quantification in several mouse tissues using real-time PCR shows that mouse 17b-HSD12 mRNA is highly expressed in the female clitoral gland, male preputial gland, as well as in retroperitoneal fat and adrenal of both sexes. The differential androgenic/estrogenic substrate specificity of type 12 17b-HSD in the mouse and primates seems to agree with the observation that androgen and estrogen in the mouse are provided almost exclusively by gonads, while in primates an important part of these steroid hormones are produced locally from adrenal precursors.

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Closing the Gap: Identification of Human 3-Ketosteroid Reductase, the Last Unknown Enzyme of Mammalian Cholesterol Biosynthesis

Cited by 115 publications

References 62 publications

Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors

Attenuation of neuroinflammation and Alzheimer's disease pathology by liver x receptors

Design and validation of specific inhibitors of 17 -hydroxysteroid dehydrogenases for therapeutic application in breast and prostate cancer, and in endometriosis

Differential androgen and estrogen substrates specificity in the mouse and primates type 12 17β-hydroxysteroid dehydrogenase

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