Activation of the orphan nuclear receptor steroidogenic factor 1 by oxysterols

Lala, Deepak S.; Syka, Peter; Lazarchik, Steven B.; Mangelsdorf, David J.; Parker, Keith L.; Heyman, Richard A.

doi:10.1073/pnas.94.10.4895

Cited by 180 publications

(100 citation statements)

References 33 publications

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“…This is an attractive hypothesis since our data indicates that lipoproteins regulate StAR via the transcription factor SF-1, and oxysterols have been reported to be a ligand for both SF-1 as well as another orphan nuclear receptor, LXR (38,39). Furthermore, a recent report suggests that oxysterols are able to regulate StAR transcription in nonsteroid producing cells (20).…”

Section: Discussionmentioning

confidence: 91%

Lipoproteins Regulate Expression of the Steroidogenic Acute Regulatory Protein (StAR) in Mouse Adrenocortical Cells

Reyland¹,

Evans²,

White³

2000

Journal of Biological Chemistry

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The production of hormones in steroidogenic tissues is dependent upon the availability of free cholesterol at the inner mitochondrial membrane, the site of the cholesterol side chain cleavage. In adrenocortical cells, adrenocorticotropin (ACTH) 1 stimulates hydrolysis of cholesteryl esters in lipid droplets, and transport of free cholesterol to mitochondria for use in steroid synthesis (1, 2). How free cholesterol in the outer mitochondrial membrane is transferred to the P450-cholesterol side chain cleavage (P450-SCC) complex on the inner mitochondrial membrane is unclear, and the existence of a hormonally regulated, labile protein which facilitates this transfer had been predicted for many years (1, 3). The recently discovered steroidogenic acute regulatory protein (StAR) is a 30-kDa mitochondrial protein which has many of the characteristics of this regulator (3,4). StAR has been demonstrated to promote movement of cholesterol from the outer to the inner mitochondrial membrane where P450-SCC catalyzes the first, and rate-limiting, enzymatic step in steroid synthesis (5, 6). In addition, expression of StAR promotes steroidogenesis, and directly facilitates the transfer of cholesterol and other sterols in reconstituted mitochondria (7-9). Perhaps the most convincing evidence that StAR is critical for this process in vivo is the observation by Miller and others (10, 11) that mutations in the StAR gene cause congenital lipoid adrenal hypoplasia. In this autosomal recessive disorder, gonadal and adrenal steroid production are blocked at the level of cholesterol side chain cleavage, resulting in a massive accumulation of cholesterol in the adrenal glands (10). Likewise, mice in which the StAR gene is disrupted have a severe reduction in corticosterone synthesis and accumulate massive lipid deposits in their adrenal cortex (12).Expression of StAR is acutely regulated in response to hormonal stimulation by a process which does not require de novo protein synthesis (5). Phosphorylation of StAR has also been demonstrated to regulate its steroidogenic activity (13). cAMPdependent protein kinase (PKA), as well as the transcription factors steroidogenic factor-1 (SF-1) and C/EBP␤, are required for basal transcription of StAR (14 -19). Other reports demonstrate that StAR transcription can be regulated by oxysterols (20) and agents known to increase cellular calcium can also regulate StAR transcription (21). Since the net result of ACTH stimulation is an increase in free cholesterol at the outer mitochondrial membrane, the current studies were undertaken to ask if the expression of StAR is regulated directly by lipoproteins, the major source of cholesterol for steroid synthesis in adrenocortical cells. Our studies demonstrate that lipoproteins regulate StAR expression by a mechanism that is dependent on cAMP-dependent protein kinase, and the transcription factor SF-1. The regulation of StAR expression by cholesterol may represent a positive feedback circuit designed to maintain maximal output of steroid hormone. * This work ...

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Section: Discussionmentioning

confidence: 91%

Lipoproteins Regulate Expression of the Steroidogenic Acute Regulatory Protein (StAR) in Mouse Adrenocortical Cells

Reyland¹,

Evans²,

White³

2000

Journal of Biological Chemistry

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“…Although an oxysterol was reported to activate SF-1 (40), this finding could not be confirmed (41). Alternative modes of regulation for SF-1, including phosphorylation (42,43) and sumoylation (44), have been presented.…”

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confidence: 79%

The crystal structures of human steroidogenic factor-1 and liver receptor homologue-1

Wang¹,

Zhang²,

Marimuthu³

et al. 2005

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

132

134

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Steroidogenic factor-1 (SF-1) and liver receptor homologue-1 (LRH-1) belong to the fushi tarazu factor 1 subfamily of nuclear receptors. SF-1 is an essential factor for sex determination during development and regulates adrenal and gonadal steroidogenesis in the adult, whereas LRH-1 is a critical factor for development of endodermal tissues and regulates cholesterol and bile acid homeostasis. Regulatory ligands are unknown for SF-1 and LRH-1. A reported mouse LRH-1 structure revealed an empty pocket in a region commonly occupied by ligands in the structures of other nuclear receptors, and pocket-filling mutations did not alter the constitutive activity observed. Here we report the crystal structures of the putative ligand-binding domains of human SF-1 at 2.1-Å resolution and human LRH-1 at 2.5-Å resolution. Both structures bind a coactivator-derived peptide at the canonical activationfunction surface, thus adopting the transcriptionally activating conformation. In human LRH-1, coactivator peptide binding also occurs to a second site. We discovered in both structures a phospholipid molecule bound in a pocket of the putative ligand-binding domain. MS analysis of the protein samples used for crystallization indicated that the two proteins associate with a range of phospholipids. Mutations of the pocket-lining residues reduced the transcriptional activities of SF-1 and LRH-1 in mammalian cell transfection assays without affecting their expression levels. These results suggest that human SF-1 and LRH-1 may be ligand-binding receptors, although it remains to be seen if phospholipids or possibly other molecules regulate SF-1 or LRH-1 under physiological conditions.x-ray crystallography ͉ phospholipid ͉ nuclear receptor ͉ steroid ͉ bile S teroidogenic factor-1 (SF-1; AD4BP͞NR5A1) and liver receptor homologue-1 (LRH-1; CPF͞FTF͞NR5A2), expressed in man, are homologues of the fushi tarazu factor-1 of Drosophila (1) and FF1B of fish (2). Together, these factors constitute the NR5A subfamily of nuclear receptors (NRs) (3). SF-1 and LRH-1 function as monomers (4) to regulate genes by binding to similar response elements.SF-1 is expressed in the adrenal, testes, ovary, pituitary, hypothalamus, spleen, and skin and regulates genes that direct biosynthesis of adrenal and gonadal steroids as well as Mullerian hormone and gonadotropins (5, 6). SF-1 is essential for normal adrenal and gonadal development given that SF-1 knockout in mice causes adrenal and gonadal agenesis and impaired gonadotropin expression, resulting in postnatal death due to severe adrenal insufficiency (7,8). SF-1 knockout also causes abnormalities of the ventromedial hypothalamic nucleus, the control center for satiety and feeding, which suggests that SF-1 may have broader roles in the control of metabolism and obesity (9). In humans, partial loss-of-function mutations in SF-1 result in XY sex reversal and adrenal failure (10, 11). Although SF-1 is expressed in the ovary (12), a mutation of SF-1 was observed not to affect ovarian development; thus, SF-1 may no...

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“…high affinity ligands that are essential for AF-2-mediated activation (50,52,53,76,77), a high affinity ligand for SF-1 remains to be identified (78,79). Mutations in the AF-2 domain of SF-1 suppresses protein kinase A-dependent transactivation of the bovine CYP17 gene (80).…”

Section: Trep-132 and Sf-1 Interaction In P450scc Gene Regulationmentioning

confidence: 99%

The Transcriptional Regulating Protein of 132 kDa (TReP-132) Enhances P450scc Gene Transcription through Interaction with Steroidogenic Factor-1 in Human Adrenal Cells

Gizard

Lavallée

Dewitte

et al. 2002

Journal of Biological Chemistry

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Activation of the orphan nuclear receptor steroidogenic factor 1 by oxysterols

Cited by 180 publications

References 33 publications

Lipoproteins Regulate Expression of the Steroidogenic Acute Regulatory Protein (StAR) in Mouse Adrenocortical Cells

Lipoproteins Regulate Expression of the Steroidogenic Acute Regulatory Protein (StAR) in Mouse Adrenocortical Cells

The crystal structures of human steroidogenic factor-1 and liver receptor homologue-1

The Transcriptional Regulating Protein of 132 kDa (TReP-132) Enhances P450scc Gene Transcription through Interaction with Steroidogenic Factor-1 in Human Adrenal Cells

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