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StAR (Steroidogenic acute regulatory protein) - Deep Define

Updated: Aug 15

Evidence-Based. Scientifically Reviewed by Michael Sharpe, MSc and Dr. Michael Tamber, MD.


This article is part of the Deep Define series. These articles provide an in-depth definition and explanation of complex topics that may require further explanation to understand fully.

StAR (STARD1), or steroidogenic acute regulatory protein, is a transport protein that controls cholesterol transfer inside the mitochondria, which is the rate-limiting step in steroid hormone synthesis.


It's mostly found in steroid-producing cells, such as theca and luteal cells in the ovary, Leydig cells in the testis, and adrenal cortex cell types.


It is greatly involved in the production of steroids and hormones, such as testosterone, etc.



Effects on the Body

The lack of functioning StAR in humans and mice drastically decreases steroid production, although it does not completely eradicate it. Steroids include all steroid hormones, such as testosterone, DHT, etc.


Other effects on the body are not yet fully understood, though they include the following.


  • Bile Acid Production: StAR may potentially transport cholesterol to sterol 27-hydroxylase, a second mitochondrial enzyme. It might be necessary for the initial step in one of the two routes for the liver to produce bile acids.

  • Inflammation: The presence of StAR in the immune cell called a macrophage has also been shown to induce the creation of 27-hydroxycholesterol. 27-hydroxycholesterol may be effective on its own in preventing the formation of inflammatory factors linked to cardiovascular disease. Though a link between StAR and heart disease is not yet clear.

  • Myocardial Infarction: StAR expression was detected in cardiac fibroblasts after myocardial infarction. The anti-apoptotic impact of StAR on fibroblasts may enable them to survive the early stress of an infarct, differentiate, and function in tissue repair.



Function

Cholesterol must be transported from the outer mitochondrial membrane to the inner mitochondrial membrane, where the cholesterol side chain is cleaved by the cytochrome P450scc enzyme (CYP11A1), which is the first enzymatic step in all steroid production.


The lipophilic cholesterol cannot traverse the aqueous phase between these two membranes unless particular proteins aid in the process.


Several proteins have been postulated in the past to aid this transfer, including:

  • sterol carrier protein 2 (SCP2)

  • steroidogenic activator polypeptide (SAP)

  • peripheral benzodiazepine receptor (PBR or translocator protein, TSPO)

  • steroidogenic acute regulatory protein (StAR, or STARD1)


It is now clear that the activity of StAR is the primary mediator in this process.


StAR seems to work from the exterior of the mitochondria, and its entrance inside the mitochondria appears to stop its action, hence the mechanism by which it induces cholesterol transport is unknown. Several theories have been proposed.


Some include StAR acting as a shuttle to transport cholesterol. While StAR may bind cholesterol, the large number of cholesterol molecules transferred by the protein suggests that it must function as a cholesterol channel rather than a shuttle.


Another theory is that it causes cholesterol to be pushed into the inner membrane from the outside membrane (cholesterol desorption). StAR may also facilitate cholesterol import by promoting the establishment of contact areas between the outer and inner mitochondrial membranes.


Another theory proposes that StAR works in tandem with PBR to enhance contact site formation by forcing Cl to exit the mitochondria. However, proof of a StAR-PBR interaction has yet to be discovered.



Its Affects

StAR is a mitochondrial protein that is quickly produced when the cell is stimulated to create steroid hormones.


Hormones such as the following increase its synthesis depending on the cell type.


  • Luteinising hormone (LH)

  • Angiotensin converting hormone (ACTH)

  • Angiotensin II


StAR is generated at the cellular level in response to the activation of the cAMP second messenger pathway, while other systems may be engaged even if cAMP is not.


It has been discovered in all organs capable of producing steroids, including the adrenal cortex, gonads, brain, and nonhuman placenta. The human placenta is one known exception.


Substances that inhibit StAR action may disturb the endocrine system, causing changes in steroid hormone levels and fertility. Some of those substances are listed below.


  • Alcohol

  • DEHP (di(2- ethylhexyl) phthalate, a plasticiser)

  • DBP (Dibutyl phthalate, a plasticiser)

  • Permethrin (also known as Nix, a medication and an insecticide)

  • Cypermethrin (CP, a synthetic pyrethroid used as an insecticide)

  • DES (Diethylstilbestrol, also known as stilbestrol or stilboestrol, a nonsteroidal estrogen medication)

  • Arsenite

  • BPA (Bisphenol A, used for making polycarbonates and epoxy resin)



About Deep Define

Deep Define is a type of article on this website that provides detailed in-depth information for the scientific-minded people among us. These articles provide information about complex subjects that may require extra explanation to fully understand. See more of Deep Define.

 

References

This section contains links to research, studies, and sources of information for this article, as well as authors, contributors, etc. All sources, along with the article and facts, are subjected to a series of quality, reliability, and relevance checks.

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This evidence based definition and explanation of StAR (steroidogenic acute regulatory protein) features 19 references, listed below.


1. Kallen CB, Billheimer JT, Summers SA, Stayrook SE, Lewis M, Strauss III JF. Steroidogenic acute regulatory protein (StAR) is a sterol transfer protein. J Biol Chem. (Oct, 1998) ✔

2. Bose HS, Whittal RM, Baldwin MA, Miller WL. The active form of the steroidogenic acute regulatory protein, StAR, appears to be a molten globule. Proc Natl Acad Sci U.S.A. (Jun, 1999) ✔

3. Roostaee A, Barbar E, Lehoux JG, Lavigne P. Cholesterol binding is a prerequisite for the activity of the steroidogenic acute regulatory protein (StAR). Biochem J. (June 2008) ✔

4. Christenson LK, Strauss III JF. Steroidogenic acute regulatory protein: an update on its regulation and mechanism of action. Arch Med Res. (2001) ✔

5. Arakane F, King SR, Du Y, Kallen CB, Walsh LP, Watari H, Stocco DM, Strauss JF. Phosphorylation of steroidogenic acute regulatory protein (StAR) modulates its steroidogenic activity. J Biol Chem. (Dec, 1997) ✔

6. Ponting CP, Aravind L. START: a lipid-binding domain in StAR, HD-ZIP and signalling proteins. Trends Biochem Sci. (Apr, 1999) ✔

7. Alpy F, Tomasetto C. MLN64 and MENTHO, two mediators of endosomal cholesterol transport. Biochem Soc Trans. (Jun, 2006) ✔

8. Stocco DM, Wang X, Jo Y, Manna PR. Multiple Signaling Pathways Regulating Steroidogenesis and Steroidogenic Acute Regulatory Protein Expression: More Complicated than We Thought. Molecular Endocrinology. (Nov, 2005) ✔

9. Bhangoo A, Anhalt H, Ten S, King SR. Phenotypic variations in lipoid congenital adrenal hyperplasia. Pediatr Endocrinol Rev. (Mar, 2006) ✔

10. Srivastava VK, Vijayan E, Hiney JK, Dees WL. Effect of ethanol on follicle stimulating hormone-induced steroidogenic acute regulatory protein (StAR) in cultured rat granulosa cells. Alcohol. (Oct, 2005) ✔

11. Kariyazono Y, Taura J, Hattori Y, Ishii Y, Narimatsu S, Fujimura M, Takeda T, Yamada H. 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. J Tox Sci. (Dec, 2015) ✔

12. Motohashi M, Wempe MF, Mutou T, Okayama Y, Kansaku N, Takahashi H, Ikegami M, Asari M, Wakui S. In utero-exposed di(n-butyl) phthalate induce dose dependent, age-related changes of morphology and testosterone-biosynthesis enzymes/associated proteins of Leydig cell mitochondria in rats. J Tox Sci. (2016) ✔

13. Jin, Yuanxiang; Liu, Jingwen; Wang, Linggang; Chen, Rujia; Zhou, Cheng; Yang, Yuefeng; Liu, Weiping; Fu, Zhengwei. Permethrin exposure during puberty has the potential to enantioselectively induce reproductive toxicity in mice. Enviro Int. (2012) ✔

14. Wang, Hua; Wang, Qun; Zhao, Xian-Feng; Liu, Ping; Meng, Xiu-Hong; Yu, Tao; Ji, Yan-Li; Zhang, Heng; Zhang, Cheng; Zhang, Ying; Xu, De-Xiang. Cypermethrin exposure during puberty disrupts testosterone synthesis via downregulating StAR in mouse testes. Arch Tox. (2009) ✔

15. Hutson JC. Physiologic interactions between macrophages and Leydig cells. Exp. Biol. Med. (Maywood). (Jan, 2006) ✔

16. Hall EA, Ren S, Hylemon PB, Rodriguez-Agudo D, Redford K, Marques D, Kang D, Gil G, Pandak WM. Detection of the steroidogenic acute regulatory protein, StAR, in human liver cells. Biochim Biophys Acta. (Apr, 2005) ✔

17. Ma Y, Ren S, Pandak WM, Li X, Ning Y, Lu C, Zhao F, Yin L. The effects of inflammatory cytokines on steroidogenic acute regulatory protein expression in macrophages. Inflamm Res. (Dec, 2007) ✔

18. Taylor JM, Borthwick F, Bartholomew C, Graham A. Overexpression of steroidogenic acute regulatory protein increases macrophage cholesterol efflux to apolipoprotein AI. Cardiovasc Res. (Jun, 2010) ✔

19. Anuka E, Yivgi-Ohana N, Eimerl S, Garfinkel B, Melamed-Book N, Chepurkol E, Aravot D, Zinman T, Shainberg A, Hochhauser E, Orly J. Infarct-Induced Steroidogenic Acute Regulatory Protein: A Survival Role in Cardiac Fibroblasts. Mol Endocrinol. (Sep, 2013) ✔

Citations with a tick indicate the information is from a trusted source.

 

The information provided in this article is not intended to replace professional medical advice, diagnosis, or treatment. Always seek the guidance of a physician or other competent professional before following advice or taking any supplement. See our terms and conditions.



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