AVINIMENT OF HEALTH & ROMAINA
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Published in final edited form as: Adv Biol Regul. 2026 January ; 99: 101131. doi:10.1016/j.jbior.2025.101131.
Potential endogenous lipid ligands for the nuclear receptor transcription factor Steroidogenic Factor-1
Alexis N. Campbella, Raymond D. Blinda,b,*
aDepartment of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN, 37232, USA
bDepartment of Medicine, Division of Diabetes, Endocrinology & Metabolism, Vanderbilt University Medical Center, Nashville, TN, 37232, USA
Abstract
Nuclear receptors are lipid-regulated transcription factors that respond to the changing metabolic and signaling requirements of animal cells and tissues. Steroidogenic Factor 1 (SF-1, NR5A1) is a nuclear receptor and master regulator of steroidogenic gene expression. SF-1 is required for development and adult function of steroidogenic tissues, hyperactivation of SF-1 associates with adrenocortical carcinoma, while hypomorphic loss-of-function polymorphisms associate with disorders of sexual development. Many of these physiological functions of SF-1 are broadly understood, however the identity of the endogenous regulatory lipid ligands for SF-1 have yet to be well established, preventing progress on therapeutic development for human diseases, such as adrenocortical carcinoma. Several signaling lipids have been put forth as potential regulatory ligands of SF-1, including sphingosine, lyso-sphingomyelin, sphingomyelin, ceramide and several phosphoinositide species including PI(4,5)P2 and PI(3,4,5)P3. Here, we review the evidence linking the ability of these potential phospholipid ligands to regulate SF-1 mediated gene expression in metazoan cells, and discuss how lipid ligands regulate SF-1 from a structural perspective.
Keywords
Nuclear hormone receptor ligand; Receptor-mediated transcriptional activation; X-ray crystallography and crystal structures; Phosphatidylinositol and sphingolipid receptor
This is an open access article under the CC BY-NC license (https://creativecommons.org/licenses/by-nc/4.0/).
`Corresponding author. Department of Medicine, Division of Diabetes, Endocrinology & Metabolism, Vanderbilt University Medical Center, Nashville, TN, 37232, USA., ray.blind@vanderbilt.edu (R.D. Blind).
Declaration of competing interest
The authors declare they have no significant financial interests.
CRediT authorship contribution statement
Alexis N. Campbell: Writing - review & editing, Writing - original draft, Project administration, Methodology, Investigation, Formal analysis, Conceptualization. Raymond D. Blind: Writing - review & editing, Visualization, Validation, Supervision, Project administration, Investigation, Funding acquisition, Formal analysis, Conceptualization.
1. Introduction
Steroidogenic Factor-1 (SF-1, NR5A1) is a ligand-regulated, DNA-binding transcription factor within the NR5A subclass of the nuclear receptor superfamily (Lala et al., 1992). SF-1 is a master regulator of gene expression, controlling the expression of steroidogenic enzymes in the gonads and adrenals (Jeyasuria et al., 2004; Luo et al., 1994) of all animals examined to date. SF-1 is essential for the development and adult function of steroidogenic tissues (Grgurevic et al., 2008; Jeyasuria et al., 2004; Luo et al., 1994; Sadovsky et al., 1995) and overexpression of SF-1 has been linked to several pathological human diseases, but mainly adrenocortical carcinoma (Doghman et al., 2007, 2009; Duregon et al., 2013; Ehrlund et al., 2012; Kaneko et al., 2008; Kiiveri et al., 2005; Lalli, 2010; Muzzi et al., 2022; Nakamura et al., 2015; Relav et al., 2023) and endometriosis (Bulun et al., 2009; Lu et al., 2015; Noël et al., 2010; Tian et al., 2009; Xue et al., 2007, 2011). Developmental loss of SF-1 expression or SF-1 function associates with differences in sexual development (Buonocore et al., 2019; Knarston et al., 2019; Luo et al., 1994), adrenal and gonadal loss of function and (Buonocore et al., 2019; Buonocore and Achermann, 2020; Ferraz-de-Souza et al., 2011; Suntharalingham et al., 2015) disease (Bland et al., 2004; Michelle L. Bland et al., 2000; M. L. Bland et al., 2000; Buaas et al., 2012; Luo et al., 1994; Sadovsky et al., 1995; Xing et al., 2017). Understanding the molecular underpinnings and detailed regulatory mechanisms of SF-1 is a key step in the development of drugs capable of targeting SF-1, and thus the development of new therapeutics that can help treat these human diseases (Doghman et al., 2009).
Within the nuclear receptor superfamily, SF-1 is a member of the NR5A sub-class of orphan nuclear receptors, referred to as an orphan as the endogenous ligand for SF-1 has not yet been unequivocally established (Campbell et al., 2023). However, several lines of evidence suggest phospholipids are regulatory ligands for SF-1 (Blind et al., 2014; R. D. Blind et al., 2012; Bryant et al., 2021a; Campbell et al., 2023; Chi et al., 2023; Crowder et al., 2017; Krylova et al., 2005; Mullaney et al., 2010; Musille et al., 2013; Ortlund et al., 2005; Sablin et al., 2009), as SF-1 has an unusually large ligand binding pocket (approximately 1600 A3 in volume) (Krylova et al., 2005) that can accommodate many different types of phospholipid species (Sablin et al., 2009). Indeed, the nature of the SF-1 ligand binding pocket has led to suggestions that SF-1 may be capable of accommodating many different chemically distinct phospholipid ligands (Blind, 2014), although all structural analysis of ligands for SF-1 to date have been phospholipids or synthetic small molecules (Cato et al., 2023; Mays et al., 2020). This review aims to discuss SF-1 ligands of interest discovered by x-ray crystallographic and mass spectrometry analyses, as well as ligands that have been tested for binding and regulation of SF-1 in more hypothesis-driven approaches.
1.1. History of nuclear phospholipids
Extensive evidence demonstrates the presence and functional significance of nuclear phospholipids beyond their interactions with nuclear receptors such as SF-1. Among these, the phosphoinositides constitute a family of signaling phospholipids that act as lipid second messengers regulating a variety of nuclear processes. Phosphoinositides are distinguished by the degree of phosphorylation of the inositol headgroup, which can
carry one to three variable phosphate groups, giving rise to the principal species PI(4)P, PI(4,5)P2, and PI(3,4,5)P3 (commonly referred to as PIP, PIP2, and PIP3, respectively). The phosphorylation of these lipids is mediated by specific kinases, several of which have been shown to localize within the nucleus (Resnick et al., 2005; Tabellini et al., 2003; Visnjic and Banfic, 2007). The nuclear generation of these phosphoinositides is a key component of nuclear phosphoinositide signaling pathways(Cocco et al., 1987; Divecha et al., 1991, 1993; Jones et al., 2006; Shah et al., 2013; Vidalle et al., 2023). These kinases are enriched in nuclear speckles, subnuclear structures rich in pre-messenger RNA (pre-mRNA) processing factors (Boronenkov et al., 1998; S. L. Osborne et al., 2001). Data suggest that the roles of PIP2 and PIP3 in mRNA processing are mediated through their association with these factors(S L Osborne et al., 2001). Notably, depletion of nuclear PIP2 blocks mRNA splicing, an effect that cannot be rescued by exogenous PIP2 addition to isolated nuclear fractions(S L Osborne et al., 2001). This finding supports a model in which PIP2 regulates splicing through its interaction and localization of specific splicing factors, rather than by its presence alone(S. L. Osborne et al., 2001). Similarly, PIP3 has been shown to be required for the localization of the nuclear export factor Aly to nuclear speckles, disruption of PIP3-Aly interactions lead to a reduction in Aly localization to speckles and a consequent decrease in mRNA export efficiency (Okada et al., 2008). Beyond mRNA processing, nuclear phosphoinositide’s have also been implicated in nuclear stress responses and are thought to influence the activity of regulatory proteins that control nuclear actin polymerization and organization (Barlow et al., 2010). Nuclear sphingolipids also have a long history of involvement in nuclear processes (Lucki and Sewer, 2012), thus phospholipids have specific functions within the nuclear compartment, where the nuclear receptor SF-1 is primarily located. This pool of nuclear phospholipids are prime candidates as the physiological ligands that modulate the function of the SF-1 nuclear receptor.
1.2. Crystallographic identification of phospholipid ligands
In early crystallographic structural analysis of the mouse orthologue of SF-1, it was discovered that the canonical ligand-binding pocket of SF-1 was occupied by bacterial phospholipids that co-purified with SF-1 from the E. coli recombinant protein expression system(Krylova et al., 2005; Ortlund et al., 2005; Wang et al., 2005). There were several practically simultaneous publications of the phospholipid binding capacity of SF-1, discovered in parallel, with SF-1 bound in this manner by phosphatidylethanolamine (PDB:1YP0), phosphatidylethanol (PDB:1YOW) and phosphatidylglycerol (PG, PDB:1YMT), showing the phospholipid acyl chains were buried deep within the canonical ligand binding pocket of the SF-1 ligand binding domain (Krylova et al., 2005; Ortlund et al., 2005; Wang et al., 2005). These crystal structures all revealed a large ligand binding pocket of SF-1, which suggested SF-1 has the ability to accommodate a wide variety of different phospholipid species, this was somewhat surprising as the crystal structure of the close SF-1 homolog Liver Receptor Homolog-1 (LRH-1, NR5A2) from mouse showed a far smaller pocket without any associated oxysterol or phospholipid ligand (Sablin et al., 2003). However, the SF-1 binding pocket was large enough to presumably bind any phospholipid, including the phosphatidylinositol phosphates (phosphoinositides). Phosphoinositides are some of the most important signaling lipids, bearing a very large
headgroup relative to phosphatidylethanol or phosphatidylglycerol. Initial studies tested binding of the phosphoinositides showed direct binding to the ligand binding domain of SF-1 (Krylova et al., 2005). Four years later, the structure of SF-1 bound to the non- bacterial phospholipid phosphatidylcholine was solved and compared to the structures of bacterial phospholipids bound to SF-1, showing significant structural changes induced by the different phospholipids to the SF-1 ligand binding domain near the phospholipid binding pocket (Sablin et al., 2009). In those structures two SF-1 surface loops, one between helixes 2 and 3 (L2-3) and another between helices 11 and 12 (L11-12), were poorly ordered in the structure, suggesting those loops remained dynamic despite the presence of a bound phosphatidylcholine (PC) ligand. These data suggested that phospholipids that stabilize these loops might have potential to exert additional regulatory effects on SF-1, and thus on the transcriptional activity of SF-1 in living cells. However, phospholipids that had co-crystalized with SF-1 were unable to induce much crystallographic order in these regions of the SF-1 ligand binding domain.
1.3. Phosphoinositides as SF-1 lipid ligands
In searching for a phospholipid ligand that might bind to SF-1 to induce order in these loops, the phosphoinositides became prime candidates, due to the large and potential stabilizing effect the phosphates in the inositol headgroup might have on the SF-1 loops disordered in other phospholipid-bound SF-1 structures. However despite much effort, these crystals proved very difficult to obtain, it was only upon the removal of the non-ionic detergent CHAPS that SF-1 was able to be crystalized in the presence of these signaling phosphoinositides (Blind et al., 2014). The signaling phosphoinositide lipids PI(4,5)P2 (PIP2) and PI(3,4,5)P3 (PIP3) (Fig. 1) were such prized targets for crystallography and as potential regulatory ligands because 1) they are present in very low abundance in cells, 2) have rapid signaling effects elaborated on below and 3) have well-established biological/functional roles in signaling that extend beyond lipids purely physical properties as structural lipids in membranes (Anderson et al., 1999; Majerus et al., 1990; Poli et al., 2016). The phosphoinositides PIP2 and PIP3 had been shown to directly bind the SF-1 ligand binding domain (Krylova et al., 2005) but no structural or functional details of the interactions with SF-1 had been determined. This led to the strong interest in crystallographic examination of PIP2 and PIP3 bound to SF-1.
The phosphoinositide lipids PIP2 and PIP3 have high signaling capacity in many biological systems. Specific associations between SF-1 functional regulation to the levels of phosphoinositides in cells have been made, elevated levels of PIP3 in cells generated by rapid and ligand-specific GPCR activation (GPER or GPR30) associated with an increase in endogenous SF-1 target gene transcriptional activation (B. C. C. Lin et al., 2009). Further analyses showed that when compared to other phosphoinositide species, PIP3 interacts with SF-1 with the best affinity, and the eventual crystal structures revealed that both PIP3 and PIP2 significantly stabilized the flexible loops in SF-1, compared to similar, but not exactly matched structures of SF-1 bound by phospholipids that co-purify with SF-1 from the bacterial expression system (Blind et al., 2014). The stabilizing influence of PIP3 on SF-1 structure is consistent with PIP3 bound to SF-1 in the nucleus and activating SF-1- mediated transcriptional activity (Blind et al., 2012; Lin et al., 2009). Together, these studies
suggested PIP2 and PIP3 could be potential endogenous ligands for SF-1, as cellular PIP3 accumulation associated with SF-1 regulation, both structurally in vitro using the purified SF-1 ligand binding domain (Blind et al., 2014) and functionally in living human cell lines examining endogenous transcripts known to be directly regulated by SF-1(Blind et al., 2012; Lin et al., 2009; Seacrist and Blind, 2018). Further, recent evidence in Tet-inducible SF-1293 cells suggests that antibodies directed against PIP2 detect induction of wild-type SF-1 (Chi et al., 2023). Strongly suggesting this signal is detecting PIP2 bound to SF-1, a pocket mutant of SF-1 was previously established to lacks any detectable phospholipid binding by mass spectrometry (Krylova et al., 2005), induction of this pocket mutant SF-1 did not produce a nuclear PIP2-antibody signal, suggesting SF-1 is bound by nuclear PIP2, at least in this 293 Tet-inducible system (Chi et al., 2023).
The structural analysis of SF-1 bound to PIP3 and PIP2 focused on contacts made between the headgroup of the phosphoinositides at the opening mouth of the ligand binding pocket (Blind et al., 2014). A natural question to ask next is how the acyl chain composition of phosphoinositides might regulate the structure and function of SF-1. Bryant et al. provided both functional and structural evidence that the acyl chain composition of PIP3 induced alterations in SF-1(Bryant et al., 2021a), when di-palmitoyl and di-oleyl PIP3 were used for comparison (Fig. 2). Importantly, these two studies used intentionally matched SF-1 protein sequences, as well as identical coregulator peptide sequences for the crystallography, such that the only variable between the two structures would be the acyl chain composition of the PIP3 bound to SF-1, apart from differences in the crystallization conditions required for each complex. In direct binding assays to human SF-1, PIP3 with varying chain compositions of C16:0/16:0 (dipalmitoyl) and C18:1/18:1 (dioleoyl), it was observed that dioleoyl PIP3 bound with the best affinity to SF-1 (Bryant et al., 2021a), suggesting the C18:1/18:1 acyl chains would generate more order in the crystal structure. However, the crystal structures of SF-1 bound to dipalmitoyl PIP3 vs. dioleoyl PIP3 reveal the latter induced more disorder in the SF-1 protein, despite binding with better affinity (Bryant et al., 2021a). This was surprising, given that small molecules that bind with better affinity (lower Kd) often induce more order in crystallographic analyses than small molecules that bind with weaker affinity (higher Kd). The C18:1/18:1 acyl chain composition induced disorder in the loop region between helix 2 and 3 of SF-1 (L2-3). That L2-3 loop had previously been linked to several clinical disorders in which SF-1 has lost function, suggesting that acyl chain composition might be able to regulate SF-1 functions linked to L2-3 (Bryant et al., 2021a).
1.4. Order and disorder induced by phosphoinositides
The activation function-2 (AF2) region of nuclear receptors generally mediates the response to ligand binding the ligand binding site by translating ligand binding information to helix 12 (Blind et al., 2012), which forms a new interaction surface for transcription co-regulators that often bear an LXXLL motif. Along with disorders in the L2-3 region, the AF2 region of SF-1 was also more disordered in the dioleoyl-PIP3-bound structure compared to the dipalmitoyl-bound structure (Bryant et al., 2021a). The AF2 region of SF-1 is an important regulatory binding site for a variety of transcriptional co-activators and co-repressors. As both structures were bound with different acyl-chain compositions of the same PIP3 headgroup, and the identical co-activator peptide representing PGC1a, the
potential functional consequences of the acyl chain composition of the phospholipid ligand could be analyzed with minimal interference from other aspects of the structures. PGC1a peptide recruitment analyses showed that compared to dipalmitoyl PIP3, dioleoyl PIP3 induced weaker binding of the co-activator peptide to SF-1 (Bryant et al., 2021a). These data suggest that dioleoyl PIP3 binding significantly disrupts the structural integrity of SF-1 relative to dipalmitoyl, as examined by a controlled crystallography experiment. Further, dioleoyl PIP3 disrupts the binding of PGC1-a peptide interaction with SF-1 compared to di-palmitoyl PIP3, suggesting a more repressive role for the dioleyl PIP3 ligand on SF-1 function.
The study of just these two lipids crystallographically in a well-controlled manner begs further exploration of similar studies of the acyl chain compositions that might be more relevant to mammals, the most obvious being C18:0/20:4. This particular acyl chain composition dominates the distribution in phosphoinositides, but it is unclear why C18:0/20:4 in particular is so highly enriched in the total cellular pool of all phosphoinositides (Barneda et al., 2019). Interestingly, the phosphoinositide C18:0/20:4 PI(4,5)P2 binds to SF-1 with the best affinity (lowest Kd) in comparison to all other PIP2 species studied, when only PIP2 headgroups are compared to each other, i.e., when the degree of headgroup phosphorylation is held constant (Bryant et al., 2021a). This acyl chain composition is also known as “stearoyl arachidonoyl” (C18:0/20:4) and is the most abundant in human cells, so although this acyl chaing composition is likely to be of high biological relevance, attempts by our lab to co-crystalize SF-1 with any stearoyl arachidonoyl species have not generated diffraction-quality crystals. In mammals, phosphoinositides with stearoyl arachidonoyl acyl chain composition represent approximately 70 % of all mammalian phosphatidylinositol species that have been measured (Barneda et al., 2019). It is not typical for one particular acyl chain composition to be so highly enriched with one headgroup, but it suggests there are biological underpinnings to the enrichment. Unfortunately, the biological relevance of why this particular species is so enriched in phosphoinositides is unclear. However, with evidence that stearoyl arachidonoyl phospholipids bind with a higher affinity in vitro when compared to other acyl chain compositions, a currently untested hypothesis is that this acyl chain composition in some way modulates phosphatidylinositol interactions with proteins that bind via the acyl chains, such as the SF-1 and the close homolog Liver Receptor Homolog-1 (LRH-1, NR5A2) (Barneda et al., 2019; Bryant et al., 2021b). Regardless of that potential, the data thus far suggest the acyl chain composition of phosphoinositides regulates SF-1 protein structure and function, warranting further investigation into the most highly abundant phosphatidylinositol species detected in metazoan cells, C18:0/20:4.
1.5. Sphingolipids as SF-1 ligands
This review has thus far focused on ligands of SF-1 that have been discovered or analyzed by crystallography; however, no structure of any sphingolipid bound to SF-1 has been reported, despite strong mass spectrometry evidence suggesting sphingolipids specifically associate with SF-1, and can act as regulatory ligands (Li et al., 2007; Natasha C Lucki et al., 2012; N. C. Lucki et al., 2012; Ozbay et al., 2004; Urs et al., 2007). Lipidomic analyses of sphingolipids associated with SF-1 immunopurified from human H295R adrenocortical
carcinoma cells suggested that most species of sphingolipids could be detected associated with SF-1, although to varying degrees (Urs et al., 2006). The most abundant sphingolipid species that associated with SF-1 were sphingosine and lyso-sphingomyelin (Urs et al., 2006), two mono-acylated sphingolipids. Functional analysis of SF-1 after sphingosine was added to the media of human adrenocortical carcinoma (H295R) cells growing in culture, suggested the sphingosine treatment associates with repressed SF-1 activity, at least in a luciferase reporter assay driven by the CYP17A1 promoter. Recall SF-1 is a master regulator of steroidogenic enzyme gene expression, including the endogenous CYP17A1 gene (Sewer et al., 2002; Sewer and Waterman, 2003). SF-1 regulation of CYP17A1 transcripts also occurs via the cAMP/PKA signaling pathway, which enhances binding of SF-1 to the proximal promoter region of CYP17A1 (Dammer et al., 2007). In work from Marion Sewer’s lab, it was shown that limiting production of sphingosine in cells significantly increased the abundance of CYP17A1 transcripts (Urs et al., 2006). This observation was further connected to the observed decrease in SF-1 activity by looking at the effects sphingosine has on co-activator recruitment to SF-1. In monitoring CYP17 transcription in the presence of SF-1 with one of its co-activators SRC-1 it was found that additional CYP17 transcripts accumulated in the presence of SRC-1 overexpression, and that increase in transcript abundance could be attenuated by the addition of sphingosine to the cell culture medium (Urs et al., 2006). This suggests that sphingosine has an antagonistic effect on the recruitment of co-activator SRC-1 to SF-1, which thus decreases the activity of SF-1 leading to a drop in the transcription of CYP17. These data link nuclear sphingolipids to SF-1 function in cells.
While no crystallographic structural analysis of sphingosine-bound SF-1 has been reported thus far, there is strong evidence that sphingosine, like phospholipids, interacts with SF-1 through the canonical SF-1 ligand binding pocket. Mutations within the ligand binding pocket were sufficient to decrease association of SF-1 with sphingosine by mass spectrometry, so it is likely that sphingosine serves as a regulatory ligand of SF-1 (Urs et al., 2006). While functional studies to this point have focused on sphingosine, the initial lipidomic studies suggested that other sphingolipids may also serve as potential ligands for SF-1, and in fact lyso sphingomyelin was found as abundantly associated with SF-1 as sphingosine (Urs et al., 2006). Further, more abundant lipids such as sphingomyelin and ceramide were less enriched in SF-1 immunoprecipitates, suggesting that either SF-1 has very high selective affinity for sphingosine and lyso-sphingomyelin, or cell compartmentalization effectively enhances low affinity sphingolipid interactions with SF-1. Regardless, structural analysis will be needed to show how sphingolipids elicit their functional effects on SF-1, and how sphingolipids such as sphingomyelin and ceramide act to differentially regulate SF-1 through the same structural mechanisms used by glycerolipids, such as PIP2.
2. Conclusions
While the search for endogenous ligands for SF-1 has been ongoing, several ligands have presented substantial promise as endogenous nuclear lipids that regulate SF-1(Lucki and Sewer, 2012). The large size of the canonical ligand binding pocket of SF-1 suggests multiple, biologically significant lipid ligands may interact with SF-1 and the close homolog
LRH-1 (Campbell et al., 2023). The x-ray crystallographic evidence suggests glycerolipids regulate SF-1 function and are not just structural cofactors; however future studies will be needed to determine the most biologically relevant glycerol-phospholipid and/or sphingolipid ligands of SF-1. In the case of sphingolipids, there are no reports of X-ray crystallographic structural analyses of SF-1 bound to any sphingolipid, yet strong biological evidence connects various sphingolipids to SF-1 as ligands, at least in adrenal cancer cell lines. Future exploration of sphingolipids as SF-1 ligands could benefit from a broader exploration of other classes of sphingolipids, such as lyso-sphingomyelin, sphingomyelin and ceramide, all of which are found associated with SF-1, but it is unclear what the structural consequences these sphingolipids interactions are at the molecular level. The search for ligands for SF-1 thus as much yet to be uncovered, continued work on elucidating lipid-dependent regulation of SF-1 will be greatly helpful in understanding how best to target SF-1 for the development of SF-1 antagonists that could help treat conditions such as endometriosis and adrenocortical carcinoma, both human diseases with great unmet clinical need.
Acknowledgements
The authors would like to thank James C. Poland, PhD and Mong Na Claire Loi for critical reading of the manuscript. This work was supported by R35 GM156389 to R.D.B. and T32 training grant support on the Vanderbilt Molecular Biophysics Training Program (MBTP) on GM008320 to A.N.C.
Data availability
No data was used for the research described in the article.
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