Oxysterols regulate expression of the steroidogenic acute regulatory protein

King, Steven R.; Matassa, Angela A.; White, Elizabeth K.; Walsh, Lance P.; Jo, Youngah; Rao, Rekha; Stocco, Douglas M.; Reyland, Mary E.

doi:10.1677/jme.0.0320507

Cited by 45 publications

(33 citation statements)

References 57 publications

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“…Treatment of transfected cells with IGF-I, FGF, TGFa, IL-1, and CSF-1 had no apparent effects on StARpromoter activity (Fig. 2B), suggesting elements responsive to these factors may lie upstream of this segment or in intronic sequences of the gene (King et al 2004, Manna et al 2006. In contrast, EGF and hCG showed approximately 1$8-and 2$9-fold increase (P!0$05) in StAR-promoter activity over basal respectively.…”

Section: Resultsmentioning

confidence: 95%

“…We did observe that the action of one factor, TGFa, in increasing StAR expression and steroid synthesis was dependent on the ongoing protein synthesis. However, the lack of effect of TGFa (and other specific cAMP-independent factors) on StAR-promoter activity indicates that their effects on the induction of StAR mRNA are independent of an alteration in the rate of StAR gene transcription (Devoto et al 1999, King et al 2004, Manna et al 2006. The marked inhibition of TGFa-induced StAR expression and steroid synthesis by AG1478 provided evidence that TGFa stimulates steroidogenesis via activation of the EGFR and reinforces the idea that TGFa and EGF bind to the same receptor (Saez 1994, Schroeder & Lee 1997.…”

Section: Discussionmentioning

confidence: 99%

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cAMP-independent signaling regulates steroidogenesis in mouse Leydig cells in the absence of StAR phosphorylation

Manna¹,

Chandrala²,

Jo³

et al. 2006

Journal of Molecular Endocrinology

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In the regulation of steroid biosynthesis, a process mediated by the steroidogenic acute regulatory (StAR) protein, both cAMP-dependent and -independent pathways are involved. While the cAMP-dependent regulatory events represent, by far, the most robust increase in steroid synthesis and are well established, the knowledge regarding cAMP-independent mechanisms is lacking. The present investigation was designed to elucidate the potential involvement of the latter in regulating StAR expression and steroidogenesis in mouse Leydig tumor cells (mLTC-1 cells). Treatment of mLTC-1 cells with a number of factors including insulin-like growth factor-I (IGF-I), epidermal growth factor (EGF), fibroblast growth factor, transforming growth factor (TGF)a, interleukin-1 (IL-1), and colony-stimulating factor-1, increased the levels of StAR mRNA, StAR protein, and progesterone to varying degrees and utilized signaling pathways that are not associated with elevations in intracellular cAMP levels. Importantly, phosphorylation of StAR in response to these stimuli was undetectable, which is in marked contrast to observations with human chorionic gonadotropin (hCG), indicating factors that do not alter intracellular cAMP, regulate the steroid biosynthesis in a StAR phosphorylation-independent manner. In addition, the roles for factors involved in cross-talk between the protein kinase pathways, PKA and PKC, were demonstrated. Further characterization of signaling by one such cAMP-independent factor, TGFa, demonstrated that the mechanism, whereby it increased StAR expression and steroid synthesis, was dependent on de novo protein synthesis and mediated via activation of the EGF receptor. TGFa was also able to augment hCG-stimulated cAMP synthesis, StAR protein and StAR phosphorylation, and influence hCG binding and LH receptor mRNA expression. Furthermore, TGFa increased phosphorylation of extracellular signal-regulated kinases 1/2 (ERK1/2) and cAMP-response element-binding protein (CREB), processes inhibited by the mitogen-activated protein kinase/ERK inhibitor U0126 and by expression of non-phosphorylatable CREB-M1 respectively. Inhibition of ERK activity enhanced TGFa-mediated StAR protein expression (but not its phosphorylation) and decreased progesterone synthesis, events correlated with the expression of dosage-sensitive sex reversal, adrenal hypoplasia congenita, critical region on the X chromosome, gene 1 (DAX-1) and scavenger receptor class B type 1 (SR-B1). Collectively, these findings demonstrate that, in mouse Leydig cells, cAMPindependent signaling events regulate steroidogenesis in a StAR phosphorylation-independent manner.

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Section: Resultsmentioning

confidence: 95%

Section: Discussionmentioning

confidence: 99%

cAMP-independent signaling regulates steroidogenesis in mouse Leydig cells in the absence of StAR phosphorylation

Manna¹,

Chandrala²,

Jo³

et al. 2006

Journal of Molecular Endocrinology

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“…44). Oxysterols and lipoproteins have also been identified as chronic regulators of StAR gene and protein expression (45)(46)(47). Using an in vitro reporter assay, King et al (46) concluded that oxysterols regulate StAR in a process thought to be independent of new gene transcription.…”

Section: Discussionmentioning

confidence: 99%

“…Oxysterols and lipoproteins have also been identified as chronic regulators of StAR gene and protein expression (45)(46)(47). Using an in vitro reporter assay, King et al (46) concluded that oxysterols regulate StAR in a process thought to be independent of new gene transcription. In contrast, our data generated both in vivo and in vitro and utilizing a number of independent analyses demonstrate that LXR activation directly mediates expression of StAR mRNA and protein.…”

Section: Discussionmentioning

confidence: 99%

Liver X receptors regulate adrenal cholesterol balance

Cummins

Volle

Zhang³

et al. 2006

Journal of Clinical Investigation

151

122

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Cholesterol is the obligate precursor to adrenal steroids but is cytotoxic at high concentrations. Here, we show the role of the liver X receptors (LXRα and LXRβ) in preventing accumulation of free cholesterol in mouse adrenal glands by controlling expression of genes involved in all aspects of cholesterol utilization, including the steroidogenic acute regulatory protein, StAR, a novel LXR target. Under chronic dietary stress, adrenal glands from Lxrαβ −/− mice accumulated free cholesterol. In contrast, wild-type animals maintained cholesterol homeostasis through basal expression of genes involved in cholesterol efflux and storage (ABC transporter A1 [ABCA1], apoE, SREBP-1c) while preventing steroidogenic gene (StAR) expression. Upon treatment with an LXR agonist that mimics activation by oxysterols, expression of these target genes was increased. Basally, Lxrαβ -/-mice exhibited a marked decrease in ABCA1 and a derepression of StAR expression, causing a net decrease in cholesterol efflux and an increase in steroidogenesis. These changes occurred under conditions that prevented the acute stress response and resulted in a phenotype more specific to the loss of LXRα, including hypercorticosteronemia, cholesterol ester accumulation, and adrenomegaly. These results imply LXRα provides a safety valve to limit free cholesterol levels as a basal protective mechanism in the adrenal gland, where cholesterol is under constant flux. IntroductionThe adrenal cortex is responsible for synthesizing glucocorticoid hormones that are essential for survival under stress. This endocrine pathway is acutely regulated by the hypothalamicpituitary-adrenal axis in response to stress through the release of ACTH from the anterior pituitary. ACTH signals the adrenal gland to increase the expression of a cascade of enzymes required for the conversion of cholesterol into biologically active glucocorticoids. The initial and rate-limiting step in this cascade is mediated by the steroidogenic acute regulatory protein (StAR) that transfers cholesterol from the outer to the inner mitochondrial membrane (1, 2). Inside the mitochondria, cytochrome P450 11A1 (CYP11A1) cleaves the cholesterol side chain to form pregnenolone (3), which can be further converted by a series of enzymes (e.g., type I 3β-hydroxysteroid dehydrogenase/D 5 -D 4 -isomerase) to all steroid hormones produced by the adrenal cortex. Because the stress response is intended to be of limited duration, tight regulation of this system is maintained by the negative feedback of circulating glucocorticoids on the hypothalamus and pituitary that decreases ACTH secretion and ultimately turn off glucocorticoid production (4, 5).

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“…This is partly explained by the notion that hyperplasia of Leydig cells in infants is less manifested than that of the theca cells in adult patients (10,12). Intriguingly, testicular macrophages have the potential to provide 25-hydroxycholesterol as a direct substrate for P450 side-chain cleavage enzyme in an alternate pathway for steroidogenesis, which bypasses the STAR-dependent delivery of cholesterol into the inner mitochondrial membrane (15,16). Thus, potential steroidogenic cooperation may also occur between the macrophages and the ovarian theca cells that, similar to the testicular Leydig cells, make androgens as well.…”

Section: Discussionmentioning

confidence: 99%

Gonadal macrophage infiltration in congenital lipoid adrenal hyperplasia

Ishii

Fukuzawa

Satô

et al. 2016

European Journal of Endocrinology

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Objective: Congenital lipoid adrenal hyperplasia (lipoid CAH) results in impairment of adrenal and gonadal steroidogenesis caused by STAR mutations. Our previous study revealed upregulation of genes associated with inflammatory or immune response and macrophage infiltration in the adrenal cortex of Star-knockout mice. This study aimed at investigating macrophage infiltration in the gonads from human patients with lipoid CAH. Design: This study includes seven patients with lipoid CAH who underwent gonadectomy: two XX women (age, 22 and 40 years) and five XY boys (1 year). Two women with ovarian cysts (32 and 40 years) and six boys with autopsy or tumor (1 year) were examined as controls. Immunohistochemical analysis of their gonads was performed to determine steroidogenic cells by NR5A1 or CYP17A1 and macrophages by IBA1 or CD68. Results: An increased number of macrophages infiltrated into the ovaries of lipoid CAH and consisted of two subpopulations: one scattered within and around a layer of theca cells of maturing follicles and the other massively aggregated in the stroma. Abundant cytoplasmic lipid droplets were observed not only in the theca cells but also in the stromal macrophages. There was no significant difference in the number of macrophages in the testicular interstitium between lipoid CAH (95% confidence interval (95% CI: 19.3-47.7 per 0.2 mm 2 ) and controls (95% CI:13.3-25.8 per 0.2 mm 2 ) (P = 0.10).Conclusions: These results demonstrate that macrophages infiltrate the ovaries of lipoid CAH, where the theca cells and the stromal macrophages have abundant cytoplasmic lipid droplets.

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Oxysterols regulate expression of the steroidogenic acute regulatory protein

Cited by 45 publications

References 57 publications

cAMP-independent signaling regulates steroidogenesis in mouse Leydig cells in the absence of StAR phosphorylation

cAMP-independent signaling regulates steroidogenesis in mouse Leydig cells in the absence of StAR phosphorylation

Liver X receptors regulate adrenal cholesterol balance

Gonadal macrophage infiltration in congenital lipoid adrenal hyperplasia

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