Steroidogenic acute regulatory protein

Last updated

steroidogenic acute regulatory protein
Identifiers
SymbolStAR
NCBI gene 6770
HGNC 11359
OMIM 600617
RefSeq NM_000349
UniProt P49675
Other data
Locus Chr. 8 p11.2
Search for
Structures Swiss-model
Domains InterPro

The steroidogenic acute regulatory protein, commonly referred to as StAR (STARD1), is a transport protein that regulates cholesterol transfer within the mitochondria, which is the rate-limiting step in the production of steroid hormones. It is primarily present in steroid-producing cells, including theca cells and luteal cells in the ovary, Leydig cells in the testis and cell types in the adrenal cortex.

Contents

Function

Cholesterol needs to be transferred from the outer mitochondrial membrane to the inner membrane where cytochrome P450scc enzyme (CYP11A1) cleaves the cholesterol side chain, which is the first enzymatic step in all steroid synthesis. The aqueous phase between these two membranes cannot be crossed by the lipophilic cholesterol, unless certain proteins assist in this process. A number of proteins have historically been proposed to facilitate this transfer including: sterol carrier protein 2 (SCP2), steroidogenic activator polypeptide (SAP), peripheral benzodiazepine receptor (PBR or translocator protein, TSPO), and StAR. It is now clear that this process is primarily mediated by the action of StAR.

The mechanism by which StAR causes cholesterol movement remains unclear as it appears to act from the outside of the mitochondria and its entry into the mitochondria ends its function. Various hypotheses have been advanced. Some involve StAR transferring cholesterol itself like a shuttle. [1] [2] While StAR may bind cholesterol itself, [3] the exorbitant number of cholesterol molecules that the protein transfers would indicate that it would have to act as a cholesterol channel instead of a shuttle. Another notion is that it causes cholesterol to be kicked out of the outer membrane to the inner (cholesterol desorption). [4] StAR may also promote the formation of contact sites between the outer and inner mitochondrial membranes to allow cholesterol influx. Another suggests that StAR acts in conjunction with PBR, causing the movement of Cl− out of the mitochondria to facilitate contact site formation. However, evidence for an interaction between StAR and PBR remains elusive.

Structure

In humans, the gene for StAR is located on chromosome 8p11.23 [5] and the protein has 285 amino acids. The signal sequence of StAR that targets it to the mitochondria is clipped off in two steps with import into the mitochondria. Phosphorylation at the serine at position 195 increases its activity. [6]

The domain of StAR important for promoting cholesterol transfer is the StAR-related transfer domain (START domain). StAR is the prototypic member of the START domain family of proteins and is thus also known as STARD1 for "START domain-containing protein 1". [7] It is hypothesized that the START domain forms a pocket in StAR that binds single cholesterol molecules for delivery to P450scc.

The closest homolog to StAR is MLN64 (STARD3). [8] Together they comprise the StarD1/D3 subfamily of START domain-containing proteins.

Production

StAR is a mitochondrial protein that is rapidly synthesized in response to stimulation of the cell to produce steroid. Hormones that stimulate its production depend on the cell type and include luteinizing hormone (LH), ACTH and angiotensin II.

At the cellular level, StAR is synthesized typically in response to activation of the cAMP second messenger system, although other systems can be involved even independently of cAMP. [9]

StAR has thus far been found in all tissues that can produce steroids, including the adrenal cortex, the gonads, the brain and the nonhuman placenta. [10] One known exception is the human placenta.

Substances that suppress StAR activity, like those listed below, can cause endocrine disrupting effects, including altered steroid hormone levels and fertility.

  1. Alcohol [11]
  2. DEHP [12] and DBP [ citation needed ][ unreliable source? ]
  3. Permethrin [13] and cypermethrin [14]
  4. DES and arsenite [15]
  5. BPA

Pathology

Mutations in the gene for StAR cause lipoid congenital adrenal hyperplasia (lipoid CAH), in which patients produce little steroid and can die shortly after birth. [10] Mutations that less severely affect the function of StAR result in nonclassic lipoid CAH or familial glucocorticoid deficiency type 3. [16] [17] All known mutations disrupt StAR function by altering its START domain. In the case of StAR mutation, the phenotype does not present until birth since human placental steroidogenesis is independent of StAR.

At the cellular level, the lack of StAR results in a pathologic accumulation of lipid within cells, especially noticeable in the adrenal cortex as seen in the mouse model. The testes are undescended and the resident steroidogenic Leydig cells are modestly affected. Early in life, the ovary is spared as it does not express StAR until puberty. After puberty, lipid accumulations and hallmarks of ovarian failure are noted.[ citation needed ]

StAR-independent steroidogenesis

While loss of functional StAR in the human and the mouse catastrophically reduces steroid production, it does not eliminate all of it, indicating the existence of StAR-independent pathways for steroid generation. Aside from the human placenta, these pathways are considered minor for endocrine production.

It is unclear what factors catalyze StAR-independent steroidogenesis. Candidates include oxysterols which can be freely converted to steroid [18] and the ubiquitous MLN64.

New roles

Recent findings suggest that StAR may also traffic cholesterol to a second mitochondrial enzyme, sterol 27-hydroxylase. This enzyme converts cholesterol to 27-hydroxycholesterol. In this way it may be important for the first step in one of the two pathways for the production of bile acids by the liver (the alternative pathway). [19]

Evidence also shows that the presence of StAR in a type of immune cell, the macrophage, where it can stimulate the production of 27-hydroxycholesterol. [20] [21] In this case, 27-hydroxycholesterol may by itself be helpful against the production of inflammatory factors associated with cardiovascular disease. It is important to note that no study has yet found a link between the loss of StAR and problems in bile acid production or increased risk for cardiovascular disease.

Recently StAR was found to be expressed in cardiac fibroblasts in response to ischemic injury due to myocardial infarction. In these cells it has no apparent de novo steroidogenic activity, as evidenced by the lack of the key steroidogenic enzymes cytochrome P450 side chain cleavage (CYP11A1) and 3 beta hydroxysteroid dehydrogenase (3βHSD). StAR was found to have an anti-apoptotic effect on the fibroblasts, which may allow them to survive the initial stress of the infarct, differentiate and function in tissue repair at the infarction site. [22]

History

The StAR protein was first identified, characterized and named by Douglas Stocco at Texas Tech University Health Sciences Center in 1994. [23] The role of this protein in lipoid CAH was confirmed the following year in collaboration with Walter Miller at the University of California, San Francisco. [24] All of this work follows the initial observations of the appearance of this protein and its phosphorylated form coincident with factors that caused steroid production by Nanette Orme-Johnson while at Tufts University. [25]

See also

Related Research Articles

<span class="mw-page-title-main">Adrenal gland</span> Endocrine gland

The adrenal glands are endocrine glands that produce a variety of hormones including adrenaline and the steroids aldosterone and cortisol. They are found above the kidneys. Each gland has an outer cortex which produces steroid hormones and an inner medulla. The adrenal cortex itself is divided into three main zones: the zona glomerulosa, the zona fasciculata and the zona reticularis.

<span class="mw-page-title-main">Adrenal cortex</span> Cortex of the adrenal gland

The adrenal cortex is the outer region and also the largest part of the adrenal gland. It is divided into three separate zones: zona glomerulosa, zona fasciculata and zona reticularis. Each zone is responsible for producing specific hormones. It is also a secondary site of androgen synthesis.

<span class="mw-page-title-main">Steroid hormone</span> Substance with biological function

A steroid hormone is a steroid that acts as a hormone. Steroid hormones can be grouped into two classes: corticosteroids and sex steroids. Within those two classes are five types according to the receptors to which they bind: glucocorticoids and mineralocorticoids and androgens, estrogens, and progestogens. Vitamin D derivatives are a sixth closely related hormone system with homologous receptors. They have some of the characteristics of true steroids as receptor ligands.

<span class="mw-page-title-main">Leydig cell</span> Androgen-producing cell adjacent to the seminiferous tubules of the testicle

Leydig cells, also known as interstitial cells of the testes and interstitial cells of Leydig, are found adjacent to the seminiferous tubules in the testicle and produce testosterone in the presence of luteinizing hormone (LH). They are polyhedral in shape and have a large, prominent nucleus, an eosinophilic cytoplasm, and numerous lipid-filled vesicles.

<span class="mw-page-title-main">Corpus luteum</span> Temporary endocrine structure in ovaries

The corpus luteum is a temporary endocrine structure in female ovaries involved in the production of relatively high levels of progesterone, and moderate levels of estradiol, and inhibin A. It is the remains of the ovarian follicle that has released a mature ovum during a previous ovulation.

<span class="mw-page-title-main">Lipoid congenital adrenal hyperplasia</span> Medical condition

Lipoid congenital adrenal hyperplasia is an endocrine disorder that is an uncommon and potentially lethal form of congenital adrenal hyperplasia (CAH). It arises from defects in the earliest stages of steroid hormone synthesis: the transport of cholesterol into the mitochondria and the conversion of cholesterol to pregnenolone—the first step in the synthesis of all steroid hormones. Lipoid CAH causes mineralocorticoid deficiency in affected infants and children. Male infants are severely undervirilized causing their external genitalia to look feminine. The adrenals are large and filled with lipid globules derived from cholesterol.

<span class="mw-page-title-main">Glucocorticoid deficiency 1</span> Medical condition

Glucocorticoid deficiency 1 is an adrenocortical failure characterized by low levels of plasma cortisol produced by the adrenal gland despite high levels of plasma ACTH. This is an inherited disorder with several different causes which define the type.

In humans and other animals, the adrenocortical hormones are hormones produced by the adrenal cortex, the outer region of the adrenal gland. These polycyclic steroid hormones have a variety of roles that are crucial for the body's response to stress, and they also regulate other functions in the body. Threats to homeostasis, such as injury, chemical imbalances, infection, or psychological stress, can initiate a stress response. Examples of adrenocortical hormones that are involved in the stress response are aldosterone and cortisol. These hormones also function in regulating the conservation of water by the kidneys and glucose metabolism, respectively.

3β-Hydroxysteroid dehydrogenase/Δ5-4 isomerase (3β-HSD) is an enzyme that catalyzes the biosynthesis of the steroid progesterone from pregnenolone, 17α-hydroxyprogesterone from 17α-hydroxypregnenolone, and androstenedione from dehydroepiandrosterone (DHEA) in the adrenal gland. It is the only enzyme in the adrenal pathway of corticosteroid synthesis that is not a member of the cytochrome P450 family. It is also present in other steroid-producing tissues, including the ovary, testis and placenta. In humans, there are two 3β-HSD isozymes encoded by the HSD3B1 and HSD3B2 genes.

<span class="mw-page-title-main">Cholesterol side-chain cleavage enzyme</span> Mammalian protein found in Homo sapiens

Cholesterol side-chain cleavage enzyme is commonly referred to as P450scc, where "scc" is an abbreviation for side-chain cleavage. P450scc is a mitochondrial enzyme that catalyzes conversion of cholesterol to pregnenolone. This is the first reaction in the process of steroidogenesis in all mammalian tissues that specialize in the production of various steroid hormones.

<span class="mw-page-title-main">Steroid 11β-hydroxylase</span> Protein found in mammals

Steroid 11β-hydroxylase, also known as steroid 11β-monooxygenase, is a steroid hydroxylase found in the zona glomerulosa and zona fasciculata of the adrenal cortex. Named officially the cytochrome P450 11B1, mitochondrial, it is a protein that in humans is encoded by the CYP11B1 gene. The enzyme is involved in the biosynthesis of adrenal corticosteroids by catalyzing the addition of hydroxyl groups during oxidation reactions.

<span class="mw-page-title-main">Translocator protein</span> Human protein

Translocator protein (TSPO) is an 18 kDa protein mainly found on the outer mitochondrial membrane. It was first described as peripheral benzodiazepine receptor (PBR), a secondary binding site for diazepam, but subsequent research has found the receptor to be expressed throughout the body and brain. In humans, the translocator protein is encoded by the TSPO gene. It belongs to a family of tryptophan-rich sensory proteins. Regarding intramitochondrial cholesterol transport, TSPO has been proposed to interact with StAR to transport cholesterol into mitochondria, though evidence is mixed.

<span class="mw-page-title-main">Steroidogenic factor 1</span> Protein-coding gene in humans

The steroidogenic factor 1 (SF-1) protein is a transcription factor involved in sex determination by controlling the activity of genes related to the reproductive glands or gonads and adrenal glands. This protein is encoded by the NR5A1 gene, a member of the nuclear receptor subfamily, located on the long arm of chromosome 9 at position 33.3. It was originally identified as a regulator of genes encoding cytochrome P450 steroid hydroxylases, however, further roles in endocrine function have since been discovered.

<span class="mw-page-title-main">Adrenodoxin reductase</span> Protein-coding gene in the species Homo sapiens

Adrenodoxin reductase, was first isolated from bovine adrenal cortex where it functions as the first enzyme in the mitochondrial P450 systems that catalyze essential steps in steroid hormone biosynthesis. Examination of complete genome sequences revealed that adrenodoxin reductase gene is present in most metazoans and prokaryotes.

<span class="mw-page-title-main">StAR-related transfer domain</span> Lipid-binding protein domain

START is a lipid-binding domain in StAR, HD-ZIP and signalling proteins. The archetypical domain is found in StAR, a mitochondrial protein that is synthesized in steroid-producing cells. StAR initiates steroid production by mediating the delivery of cholesterol to the first enzyme in the steroidogenic pathway. The START domain is critical for this activity, perhaps through the binding of cholesterol. Following the discovery of StAR, 15 START-domain-containing proteins were subsequently identified in vertebrates as well as other that are related.

<span class="mw-page-title-main">Vassilios Papadopoulos</span>

Vassilios Papadopoulos, DPharm, PhD, DSc (hon), born February 18, 1961, in Athens, Greece, is a scholar, researcher, inventor, professor, and university administrator who has served as dean of the USC Alfred E. Mann School of Pharmacy and Pharmaceutical Sciences at the University of Southern California in Los Angeles, California, since 2016. Previously, he was the associate vice president and director of the Biomedical Graduate Research Organization at Georgetown University from 2005 to 2007, and the executive director and chief scientific officer of the Research Institute of the McGill University Health Center from 2007 to 2015.

Walter L. Miller is an American endocrinologist and professor emeritus of pediatrics at the University of California, San Francisco (UCSF). Miller is expert in the field of human steroid biosynthesis and disorders of steroid metabolism. Over the past 40 years Miller's group at UCSF has described molecular basis of several metabolic disorders including, congenital adrenal hyperplasia, pseudo vitamin D dependent rickets, severe, recessive form of Ehlers-Danlos syndrome, 17,20 lyase deficiency caused by CYP17A1 defects, P450scc deficiency caused by CYP11A1 defects, P450 oxidoreductase deficiency.

<span class="mw-page-title-main">Steroidogenic enzyme</span>

Steroidogenic enzymes are enzymes that are involved in steroidogenesis and steroid biosynthesis. They are responsible for the biosynthesis of the steroid hormones, including sex steroids and corticosteroids, as well as neurosteroids, from cholesterol. Steroidogenic enzymes are most highly expressed in classical steroidogenic tissues, such as the testis, ovary, and adrenal cortex, but are also present in other tissues in the body.

<span class="mw-page-title-main">STAR (gene)</span> Protein-coding gene in the species Homo sapiens

Steroidogenic acute regulatory protein is a protein that in humans is encoded by the STAR gene.

<span class="mw-page-title-main">Star related lipid transfer domain containing 3</span>

StAR related lipid transfer domain containing 3(STARD3) is a protein that in humans is encoded by the STARD3 gene. STARD3 also known as metastatic lymph node 64 protein (MLN64) is a late endosomal integral membrane protein involved in cholesterol transport. STARD3 creates membrane contact sites between the endoplasmic reticulum (ER) and late endosomes where it moves cholesterol.

References

  1. ↑ Kallen CB, Billheimer JT, Summers SA, Stayrook SE, Lewis M, Strauss III JF (October 1998). "Steroidogenic acute regulatory protein (StAR) is a sterol transfer protein". J. Biol. Chem. 273 (41): 26285–8. doi: 10.1074/jbc.273.41.26285 . PMID   9756854.
  2. ↑ Bose HS, Whittal RM, Baldwin MA, Miller WL (June 1999). "The active form of the steroidogenic acute regulatory protein, StAR, appears to be a molten globule". Proc. Natl. Acad. Sci. U.S.A. 96 (13): 7250–5. Bibcode:1999PNAS...96.7250B. doi: 10.1073/pnas.96.13.7250 . PMC   22068 . PMID   10377400.
  3. ↑ Roostaee A, Barbar E, Lehoux JG, Lavigne P (June 2008). "Cholesterol binding is a prerequisite for the activity of the steroidogenic acute regulatory protein (StAR)". Biochem. J. 412 (3): 553–62. doi:10.1042/BJ20071264. PMID   18341481.
  4. ↑ Christenson LK, Strauss III JF (2001). "Steroidogenic acute regulatory protein: an update on its regulation and mechanism of action". Arch. Med. Res. 32 (6): 576–86. doi:10.1016/S0188-4409(01)00338-1. PMID   11750733.
  5. ↑ Williams SV, Platt FM, Hurst CD, Aveyard JS, Taylor CF, Pole JC, Garcia MJ, Knowles MA (2010). "High-resolution analysis of genomic alteration on chromosome arm 8p in urothelial carcinoma". Genes, Chromosomes and Cancer. 49 (7): 642–659. doi:10.1002/gcc.20775. PMID   20461757. S2CID   29971371.
  6. ↑ Arakane F, King SR, Du Y, Kallen CB, Walsh LP, Watari H, Stocco DM, Strauss JF (December 1997). "Phosphorylation of steroidogenic acute regulatory protein (StAR) modulates its steroidogenic activity". J. Biol. Chem. 272 (51): 32656–62. doi: 10.1074/jbc.272.51.32656 . PMID   9405483.
  7. ↑ Ponting CP, Aravind L (April 1999). "START: a lipid-binding domain in StAR, HD-ZIP and signalling proteins". Trends Biochem. Sci. 24 (4): 130–2. doi:10.1016/S0968-0004(99)01362-6. PMID   10322415.
  8. ↑ Alpy F, Tomasetto C (June 2006). "MLN64 and MENTHO, two mediators of endosomal cholesterol transport". Biochem. Soc. Trans. 34 (Pt 3): 343–5. doi:10.1042/BST0340343. PMID   16709157.
  9. ↑ Stocco DM, Wang X, Jo Y, Manna PR (November 2005). "Multiple Signaling Pathways Regulating Steroidogenesis and Steroidogenic Acute Regulatory Protein Expression: More Complicated than We Thought". Molecular Endocrinology. 19 (11): 2647–59. doi: 10.1210/me.2004-0532 . PMID   15831519.
  10. 1 2 Bhangoo A, Anhalt H, Ten S, King SR (March 2006). "Phenotypic variations in lipoid congenital adrenal hyperplasia". Pediatr Endocrinol Rev. 3 (3): 258–71. PMID   16639391.
  11. ↑ Srivastava VK, Vijayan E, Hiney JK, Dees WL (October 2005). "Effect of ethanol on follicle stimulating hormone-induced steroidogenic acute regulatory protein (StAR) in cultured rat granulosa cells". Alcohol. 37 (2): 105–11. doi:10.1016/j.alcohol.2006.01.001. PMID   16584974.
  12. ↑ Kariyazono Y, Taura J, Hattori Y, Ishii Y, Narimatsu S, Fujimura M, Takeda T, Yamada H (December 2015). "Effect of in utero exposure to endocrine disruptors on fetal steroidogenesis governed by the pituitary-gonad axis: a study in rats using different ways of administration". The Journal of Toxicological Sciences. 40 (6): 909–16. doi: 10.2131/jts.40.909 . PMID   26558472.
  13. ↑ Jin Y, Liu J, Wang L, Chen R, Zhou C, Yang Y, Liu W, Fu Z (2012). "Permethrin exposure during puberty has the potential to enantioselectively induce reproductive toxicity in mice". Environment International. 42: 144–151. doi:10.1016/j.envint.2011.05.020. ISSN   0160-4120. PMID   21745691.
  14. ↑ Wang H, Wang Q, Zhao XF, Liu P, Meng XH, Yu T, Ji YL, Zhang H, Zhang C, Zhang Y, Xu DX (2009). "Cypermethrin exposure during puberty disrupts testosterone synthesis via downregulating StAR in mouse testes". Archives of Toxicology. 84 (1): 53–61. doi:10.1007/s00204-009-0479-y. ISSN   0340-5761. PMID   19862501. S2CID   22210562.
  15. ↑ Clark BJ, Cochrum RK (2007). "The Steroidogenic Acute Regulatory Protein as a Target of Endocrine Disruption in Male Reproduction". Drug Metabolism Reviews. 39 (2–3): 353–370. doi:10.1080/03602530701519151. PMID   17786626. S2CID   26531354.
  16. ↑ Baker BY, Lin L, Kim CJ, Raza J, Smith CP, Miller WL, Achermann JC (December 2006). "Nonclassic congenital lipoid adrenal hyperplasia: a new disorder of the steroidogenic acute regulatory protein with very late presentation and normal male genitalia". J. Clin. Endocrinol. Metab. 91 (12): 4781–5. doi:10.1210/jc.2006-1565. PMC   1865081 . PMID   16968793.
  17. ↑ Metherell LA, Naville D, Halaby G, Begeot M, Huebner A, Nürnberg G, Nürnberg P, Green J, Tomlinson JW, Krone NP, Lin L, Racine M, Berney DM, Achermann JC, Arlt W, Clark AJ (October 2009). "Nonclassic lipoid congenital adrenal hyperplasia masquerading as familial glucocorticoid deficiency". J. Clin. Endocrinol. Metab. 94 (10): 3865–3871. doi:10.1210/jc.2009-0467. PMC   2860769 . PMID   19773404.
  18. ↑ Hutson JC (January 2006). "Physiologic interactions between macrophages and Leydig cells". Exp. Biol. Med. (Maywood). 231 (1): 1–7. doi:10.1177/153537020623100101. PMID   16380639. S2CID   43006988.
  19. ↑ Hall EA, Ren S, Hylemon PB, Rodriguez-Agudo D, Redford K, Marques D, Kang D, Gil G, Pandak WM (April 2005). "Detection of the steroidogenic acute regulatory protein, StAR, in human liver cells". Biochim Biophys Acta. 1733 (2–3): 111–119. doi:10.1016/j.bbalip.2005.01.004. PMID   15863358.
  20. ↑ Ma Y, Ren S, Pandak WM, Li X, Ning Y, Lu C, Zhao F, Yin L (December 2007). "The effects of inflammatory cytokines on steroidogenic acute regulatory protein expression in macrophages". Inflamm Res. 56 (12): 495–501. doi:10.1007/s00011-007-6133-3. PMID   18210233. S2CID   21308251.
  21. ↑ Taylor JM, Borthwick F, Bartholomew C, Graham A (June 2010). "Overexpression of steroidogenic acute regulatory protein increases macrophage cholesterol efflux to apolipoprotein AI". Cardiovasc Res. 86 (3): 526–534. doi:10.1093/cvr/cvq015. PMID   20083572.
  22. ↑ Anuka E, Yivgi-Ohana N, Eimerl S, Garfinkel B, Melamed-Book N, Chepurkol E, Aravot D, Zinman T, Shainberg A, Hochhauser E, Orly J (September 2013). "Infarct-Induced Steroidogenic Acute Regulatory Protein: A Survival Role in Cardiac Fibroblasts". Mol Endocrinol. 27 (9): 1502–1517. doi:10.1210/me.2013-1006. PMC   5415234 . PMID   23831818.
  23. ↑ Clark BJ, Wells J, King SR, Stocco DM (November 1994). "The purification, cloning, and expression of a novel luteinizing hormone-induced mitochondrial protein in MA-10 mouse Leydig tumor cells. Characterization of the steroidogenic acute regulatory protein (StAR)". J Biol Chem. 269 (45): 28314–28322. doi: 10.1016/S0021-9258(18)46930-X . PMID   7961770.
  24. ↑ Lin D, Sugawara T, Strauss III JF, Clark BJ, Stocco DM, Saenger P, Rogol A, Miller WL (March 1995). "Role of steroidogenic acute regulatory protein in adrenal and gonadal steroidogenesis". Science. 267 (5205): 1828–1831. Bibcode:1995Sci...267.1828L. doi:10.1126/science.7892608. PMID   7892608.
  25. ↑ Krueger RJ, Orme-Johnson NR (August 1983). "Acute adrenocorticotropic hormone stimulation of adrenal corticosteroidogenesis". J Biol Chem. 258 (16): 10159–10167. doi: 10.1016/S0021-9258(17)44619-9 . PMID   6309771.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.