Blocking BRE expression in Leydig cells inhibits steroidogenesis by down-regulating 3β-hydroxysteroid dehydrogenase

Abstract

Conversion of cholesterol to biologically active steroids is a multi-step enzymatic process. Along with some important enzymes, like cholesterol side-chain cleavage enzyme (P450scc) and 3 -hydroxysteroid dehydrogenase/ isomerase (3 -HSD), several proteins play key role in steroidogenesis. The role of steroidogenic acute regulatory (StAR) protein is well established. A novel protein, BRE, found mainly in brain, adrenals and gonads, was highly expressed in hyperplastic rat adrenals with impaired steroidogenesis, suggesting its regulation by pituitary hormones. To further elucidate its role in steroidogenic tissues, mouse Leydig tumor cells (mLTC-1) were transfected with BRE antisense probes. Morphologically the BRE antisense cells exhibited large cytoplasmic lipid droplets and failed to shrink in response to human chorionic gonadotropin. Although cAMP production, along with StAR and P450scc mRNA expression, was unaffected in BRE antisense clones, progesterone and testosterone yields were significantly decreased, while pregnenolone was increased in response to human chorionic gonadotropin stimulation or in the presence of 22(R)OH-cholesterol. Furthermore, whereas exogenous progesterone was readily converted to testosterone, pregnenolone was not, suggesting impairment of pregnenolone-to-progesterone conversion, a step metabolized by 3 -HSD. That steroidogenesis was compromised at the 3 -HSD step was further confirmed by the reduced expression of 3 -HSD type I (3ß-HSDI) mRNA in BRE antisense cells compared with controls. Our results suggest that BRE influences steroidogenesis through its effects on 3 -HSD action, probably affecting its transcription.

Genome-wide association study provides strong evidence of genes affecting the reproductive performance of Nellore beef cows

“…In S1 Table, window 71-72Mb of BTA11 harbors the FOSL2 gene related to endometrial decidualization [27], RBKS associated with oocyte maturation [28], and BRE associated with steroidogenesis in the ovary and maintenance of placental function [29]. The subsequent window of BTA11 (72-73Mb) harbors important genes previously reported to be associated with reproductive events, such as SLC30A3 [30] and CAD [31] described as estrogen receptors, CIB4 associated with male sheep fecundity [32], EMILIN1 associated with placentation and trophoblast invasion in the uterine wall [33], TCF23 which plays an important role in endometrial decidualization [34], UCN associated with steroidogenesis and maintenance of placental function which is expressed in mature mouse spermatozoa and rat epididymis [35, 36, 37], and IFT172 , PREB and SNX17 which are associated with neural development [38, 39, 40, 41].…”

Thermal Proteome Profiling Reveals Distinct Target Selectivity for Differentially Oxidized Oxysterols

“…Among them, BRISC and BRCA1-A complex member 2 (BRE) are known to be involved in the defective synthesis of steroid hormones and accumulation of large quantities of cholesterol under stress or under the influence of steroid hormones. 29 The two targets most stabilized by 7-KC were associated with lysosomal functions (SI Table S1). E3 ubiquitin-protein ligase RNF167 and Ragulator complex protein LAMTOR4 are both localized in lysosomes, where they perform ubiquitin protein ligase activity and regulation of TOR signaling activity, respectively (see Figure 3A for associated melting curves).…”

“…Importantly, destabilized proteins were considered as putative targets (SI Table S1). Among them, BRISC and BRCA1-A complex member 2 (BRE) are known to be involved in the defective synthesis of steroid hormones and accumulation of large quantities of cholesterol under stress or under the influence of steroid hormones …”

Comparative Proteomics: An Approach to Elucidating the Function of a Novel Gene Called BRE

“…Since NF-B is known to induce the survival pathway associated with TNF receptor, it is likely that BRE can modulate the cell death process. The expression of the BRE gene has been investigated in various biological models including adrenal glands (Miao et al, 2001), testis (Miao et al, 2005) and hepatocellular carcinoma cells (Chan et al, 2008), but the function of BRE has still not been clarified -the protein structure of BRE do not have identifiable functional domain. It has been suggested the BRE contained 2 ubiquitinconjugating enzyme family-like regions (Hu et al, 2011).…”