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Event: 1972

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increased, Steroidogenic acute regulatory protein (StAR)

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. More help
Increased, Steroidogenic acute regulatory protein (StAR)
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Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
steroid hormone secreting cell

Organ term

The location/biological environment in which the event takes place.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Organ term
reproductive organ

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signaling by that receptor).  Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description.  To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons.  If a desired term does not exist, a new term request may be made via Term Requests.  Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
increased luteinizing hormone level StAR-related lipid transfer protein 3 increased
increased luteinizing hormone level StAR-related lipid transfer protein 4 increased
increased luteinizing hormone level StAR-related lipid transfer protein 5 increased
increased luteinizing hormone level StAR-related lipid transfer protein 6 increased

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Hypothalamic estrogen receptors inhibition leading to ovarian cancer KeyEvent Kalyan Gayen (send email) Under development: Not open for comment. Do not cite Under Development

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KE.In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mice Mus sp. High NCBI
rat Rattus norvegicus High NCBI
Monkey Monkey Low NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Adult, reproductively mature High

Sex Applicability

An indication of the the relevant sex for this KE. More help
Term Evidence
Female High
Male Low

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. More help

Biological state: Steroidogenic acute regulatory protein (StAR) plays important role in luteal steroidogenesis(Christenson and Devoto, 2003). Steroidogenic acute regulatory protein (StAR) controls the transport of cholesterol from the outer to inner mitochondrial membrane(Stocco, 2000). There are several pathways involved for the transport of cholesterol from different subcellular pools into the inner mitochondria(Martin et al., 2016).

Biological compartments: Cholesterol is one type of lipid which is crystalline solid with yellow colour.  It is biosynthesized by animal cells and is an essential structural component of animal cell membranes (Hanukoglu, 1992). It is the precursor molecule for the synthesis all steroid hormones(Payne and Hales, 2004).  Cytochrome P450 enzymes are present in most tissues of the body, and play important roles in hormone synthesis in mitochondria using cholesterol as precursor(Poderoso et al., 2013).

General role in biology:  It is been reported that high  in cholesterol levels in mitochondrial resulted several diseases like cancer, neurodegenerative diseases, steatohepatitis ischemia, and influence disease (Martin et al., 2016). The alteration in mitochondrial cholesterol import may change the cholesterol concentrations that may lead to proper mitochondrial function along with biophysical properties of mitochondrial membranes. In absence of StAR protein, cholesterol transport into the mitochondria did not occurs leading to  no conversion of progesterone from cholesterol precursors doesn’t occur(Kiriakidou et al., 1996; Pescador et al., 1996). All Steroidogenic acute regulatory protein (StAR) promoters contain steroidogenic factor 1 binding sites which is responsible for sex hormones regulation(Manna et al., 2002).

One of the important function of the steroid hormones is maintaining reproductive capacity. For this purpose, steroidogenic cells must move large amounts of cholesterol from the outer mitochondrial membrane to the inner membrane. In the granulosa cells, this cholesterol is ultimately converted to progesterone. The initial transport of cholesterol across the mitochondrial membrane requires Steroidogenic Acute Regulatory (StAR) protein. Expression of StAR protein in preovulatory cells of the developing follicle is low. The dramatic upregulation of StAR protein expression within the dominant follicle is found after the luteinizing hormone (LH) surge. This upregulation allows the corpus luteum to produce substantial amounts of progesterone to maintain the reproductive capacity in human/animal (Men et al., 2017; Stocco, 2000).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA). Do not provide detailed protocols. More help

StAR protein is measure by quantitative real time PCR (qRT-PCR):

For qRT-PCR analyses, cDNA is synthesized using reagent kit in a 20-μl reaction containing 0.5 μg of total RNA collected from human ovarian granulosa tumor cell line ( KGN cells ), mouse Leydig cells. qPCR is performed in a 25-μl reaction containing 0.5 to 1.5 μl of cDNA using fluorescein in real-time PCR detection systems. PCR was performed by initial denaturation at 95°C for 5 minutes, followed by 40 cycles of 30 seconds at 95°C, 30 seconds at 60°C, and 30 seconds at 72°C. The threshold cycle values of each sample are used to calculate mRNA levels. The PCR primers for the indicated human and mouse genes are as follows (Men et al., 2017).

Human H19 forward: 5′-GCACCTTGGACATCTGGAGT

Human H19 reverse: 5′-TTCTTTCCAGCCCTAGCTCA

Human StAR forward: 5′-GGCATCCTTAGCAACCAAGA

Human StAR reverse: 5′-TCTCCTTGACATTGGGGTTC

Mouse StAR forward: 5′-TTGGGCATACTCAACAACCA

Mouse StAR reverse: 5′-GAAACACCTTGCCCACATCT

Indirect immunohistochemistry for the detection of Steroidogenic Acute Regulatory Protein (StAR):

Ovarian or peritoneal tissues from the human patients are collected. Ovarian or peritoneal tissues from the patient are fixed using 10% paraformaldehyde. Tissues are embedded in paraffin. Serial sections of 5 µm are made using microtome. Tissue sections are prepared by microwave heating in 10× citrate buffer, pH 6.0, for 10 min. Tissues are rinsed three times in 20 mM phosphate buffered saline (PBS), pH 7.2, for 10 min each, before incubation with 1:200 dilutions of polyclonal anti-human StAR antibodies at 37°C for 60 min. Tissue sections were washed three times in 20 mM PBS, pH 7.2, for 2 min each, before incubation with a 1:1000 dilution of secondary mouse– anti-rabbit antibody at 37°C for 30 min. Indirect immunohistochemistry kits were used according to the manufacturer’s instructions to visualize StAR protein stained tissue under microscope and image collected. A pathological image analysis system is used to measure mean optical density (MOD) analysis under high-magnification (×400) microscopy. The MOD, which reflected the positive staining intensity, and the positive staining ratio (area %) of every positively stained area, are measured. The area % is calculated as ([the area of positive staining]/[total nuclear area in the field of view]) × 100. The MOD and area % are used to calculate the expression index, EI (%) = MOD × area %(Tian et al., 2009).

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

In Granulosa cells

References

List of the literature that was cited for this KE description. More help

Baker, B. Y., Epand, R. F., Epand, R. M., & Miller, W. L. (2007). Cholesterol binding does not predict activity of the steroidogenic acute regulatory protein, StAR. J Biol Chem, 282(14), 10223-32. doi:S0021-9258(19)57693-1 [pii]

Chaffin, C., Dissen, G., & Stouffer, R. (2000). Hormonal regulation of steroidogenic enzyme expression in granulosa cells during the peri-ovulatory interval in monkeys. Molecular human reproduction, 6(1), 11-18.

Christenson, L. K., & Devoto, L. (2003). Cholesterol transport and steroidogenesis by the corpus luteum. Reproductive Biology and Endocrinology, 1(1), 1-9.

Hanukoglu, I. (1992). Steroidogenic enzymes: structure, function, and role in regulation of steroid hormone biosynthesis. The Journal of steroid biochemistry and molecular biology, 43(8), 779-804.

Hasegawa, T., Zhao, L., Caron, K. M., Majdic, G., Suzuki, T., Shizawa, S., et al. (2000). Developmental roles of the steroidogenic acute regulatory protein (StAR) as revealed by StAR knockout mice. Mol Endocrinol, 14(9), 1462-71. doi:10.1210/mend.14.9.0515.

Kiriakidou, M., Mcallister, J. M., Sugawara, T., & Strauss 3rd, J. (1996). Expression of steroidogenic acute regulatory protein (StAR) in the human ovary. The Journal of Clinical Endocrinology & Metabolism, 81(11), 4122-4128.

Manna, P. R., Dyson, M. T., Eubank, D. W., Clark, B. J., Lalli, E., Sassone-Corsi, P., et al. (2002). Regulation of steroidogenesis and the steroidogenic acute regulatory protein by a member of the cAMP response-element binding protein family. Molecular Endocrinology, 16(1), 184-199.

Martin, L. A., Kennedy, B. E., & Karten, B. (2016). Mitochondrial cholesterol: mechanisms of import and effects on mitochondrial function. Journal of bioenergetics and biomembranes, 48(2), 137-151.

Men, Y., Fan, Y., Shen, Y., Lu, L., & Kallen, A. N. (2017). The Steroidogenic Acute Regulatory Protein (StAR) Is Regulated by the H19/let-7 Axis. Endocrinology, 158(2), 402-409. doi:10.1210/en.2016-1340.

Payne, A. H., & Hales, D. B. (2004). Overview of steroidogenic enzymes in the pathway from cholesterol to active steroid hormones. Endocrine reviews, 25(6), 947-970.

Pescador, N., Soumano, K., Stocco, D. M., Price, C. A., & Murphy, B. D. (1996). Steroidogenic acute regulatory protein in bovine corpora lutea. Biology of reproduction, 55(2), 485-491.

Poderoso, C., Duarte, A., Cooke, M., Orlando, U., Gottifredi, V., Solano, A. R., et al. (2013). The spatial and temporal regulation of the hormonal signal. Role of mitochondria in the formation of a protein complex required for the activation of cholesterol transport and steroids synthesis. Molecular and cellular endocrinology, 371(1-2), 26-33.

Sreerangaraja Urs, D. B., Wu, W.-H., Komrskova, K., Postlerova, P., Lin, Y.-F., Tzeng, C.-R., et al. (2020). Mitochondrial function in modulating human granulosa cell steroidogenesis and female fertility. International journal of molecular sciences, 21(10), 3592.

Stocco, D. (2000). The role of the StAR protein in steroidogenesis: challenges for the future. Journal of Endocrinology, 164(3), 247-253.

Tian, Y., Kong, B., Zhu, W., Su, S., & Kan, Y. (2009). Expression of steroidogenic factor 1 (SF-1) and steroidogenic acute regulatory protein (StAR) in endometriosis is associated with endometriosis severity. J Int Med Res, 37(5), 1389-95. doi:10.1177/147323000903700513.