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Event: 2269

Key Event Title

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

Increased, Sterol Regulatory Element Binding Protein 2 (SREBP2) protein expression

Short name

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Increased, SREBP2 protein expression

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Biological Context

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Level of Biological Organization
Cellular

Cell term

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Cell term
eukaryotic cell

Organ term

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 circulating total protein level	sterol regulatory element-binding protein 2	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
Activation, Pregnane-X receptor leads to increased plasma LDL cholesterol via synthesis	KeyEvent	John Frisch (send email)	Under development: Not open for comment. Do not cite
Activation, Pregnane-X receptor leads to increased plasma LDL cholesterol via PCSK9	KeyEvent	John Frisch (send email)	Under development: Not open for comment. Do not cite

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
mammals	mammals	High	NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Life stage	Evidence
All life stages	Moderate

Sex Applicability

An indication of the the relevant sex for this KE. More help

Term	Evidence
Unspecific	High

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

Sterol Regulatory Element Binding Transcription Protein 2 (SREBP2) is synthesized as an inactive precursor protein, with inactive form located in the endoplasmic reticulum membrane (Horton et al. 2002). SREBP2 has an important role in lipid synthesis regulation. At low cholesterol levels, insulin-induced gene 1 (INSIG1) has lower binding affinity for SREBP cleavage-activating protein (SCAP), allowing free SCAP to bind to Coat Protein Complex II (COPII; Ouyang et al. 2020). The SCAP-COPII complex enables Sterol Regulatory Element Binding Proteins (SREBPs) to move through the endoplasmic reticulum to the Golgi, where membrane-bound transcription factor site-1-protease (S1P) and site-2-protease (S2P) enable proteolytic processing that allows SREBPs to enter the nucleus (Yabe et al. 2022; Yang et al. 2022). In the nucleus, SREBP2 increases gene expression for enzymes involved in the mevalonate pathway of cholesterol synthesis (Sakakura et al. 2001; Ouyang et al. 2020; Itkonen et al., 2023) including not only rate-limited enzymes including 3-hydroxy-3-methylglutarylcoenzyme (HMGCR) (Sakakura et al. 2001; Itkonen et al. 2023) but many enzymes in the pathway: mevalonate kinase, mevalonate pyrophosphate decarboxylase, isopentenyl phosphate isomerase, geranylgeranyl pyrophosphate synthase, farnesyl pyrophosphate synthase, squalene synthase, squalene epoxidase, lanosterol synthase, lanosterol demethylase, and 7-dehydro-cholesterol reductase (Sakakura et al. 2001; Horton et al. 2002). At high cholesterol levels, INSIG1 binds to SCAP, competitively inhibiting the ability of SCAP to bind to COPII (Ouyang et al. 2020). SREBPs are retained in the endoplasmic reticulum rather than being transferred to the Golgi, reducing levels of cholesterol synthesis (Ouyang et al. 2020; Itkonen et al., 2023).

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

Real time PCR can be used to measure SREBP2 transcript abundance, which is an indirect – and only semi-quantitative indicator of SREBP2 protein abundance. SREBP2 protein can be measured via Western blotting or enzyme immunoassay.

Domain of Applicability

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

Life Stage: All life stages.

Sex: Applies to both males and females.

Taxonomic: Primarily studied in humans and laboratory rodents.

References

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

Horton, J.D., Goldstein, J.L., and Brown, M.S. 2002. SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver. The Journal of Clinical Investigation (109)9: 1125-1131.

Itkonen, A., Hakkola, J., and Rysa, J. 2023. Adverse outcome pathway for pregnane X receptor‑induced hypercholesterolemia. Archives of Toxicology 97: 2861–2877. Ouyang, S., Mo, Z., Sun, S., Yin, K., and Lv, Y. 2020. Emerging role of Insig-1 in lipid metabolism and lipid disorders. Clinica Chimica Acta 508: 206–212.

Sakakura, Y., Shimano, H., Sone, H., Takahashi, A., Inoue, K., Toyshima, H., Suzuki, S. and Yamada, N. 2001. Sterol regulatory element-binding proteins induce an entire pathway of cholesterol synthesis. Biochemical and Biophysical Research Communications 286: 176–183.

Yabe, D., Brown, M.S., and Goldstein, J.L. 2002. Insig-2, a second endoplasmic reticulum protein that binds SCAP and blocks export of sterol regulatory element-binding proteins. Proceedings of the National Academy of Sciences 99(20): 12753–12758.

Yang, T., Espenshade, P.J., Wright, M.E., Yabe, D., Gong, Y., Aebersold, R., Goldstein, J.L., and Brown, M.S. 2002. Crucial step in cholesterol homeostasis: sterols promote binding of SCAP to INSIG-1, a membrane protein that facilitates retention of SREBPs in ER. Cell 110: 489–500.

NOTE: Italics indicate edits from John Frisch October 2024.