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Event: 2270

Key Event Title

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

Increased, cholesterol synthesis enzymes

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, cholesterol synthesis enzymes
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Biological Context

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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
eukaryotic 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

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
cholesterol biosynthetic process 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

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

Cholesterol has a variety of roles in organisms, including as a cellular membrane component that helps maintain structure and fluidity, and a precursor for steroid hormones (Sakakura et al. 2001; Horton et al. 2003; Howe et al. 2017).  The cholesterol synthesis pathway involves a number of precursor molecules and enzymes (Sakakura et al. 2001; Itkonen et al. 2023).

Table 1: List of cholesterol synthesis enzymes with identifier of enzyme (Uniprot, 2024).

Enzyme Identifier
Hydroxymethylglutaryl-CoA synthase EC:2.3.3.10
Hydroxymethylglutaryl-CoA reductase EC:1.1.1.34
Mevalonate kinase EC:2.7.1.36
Phosphomevalonate kinase EC:2.7.4.2
Diphosphomevalonate decarboxylase EC:4.1.1.33
Isopentenyl-diphosphate Delta-isomerase EC:5.3.3.2
Geranylgeranyl diphosphate synthase EC 2.5.1.29
(2E,6E)-farnesyl diphosphate synthase EC:2.5.1.10
Squalene synthase EC:2.5.1.21
Squalene monooxygenase EC:1.14.14.17
Lanosterol synthase EC:5.4.99.7
Sterol 14alpha-demethylase EC:1.14.14.154
Delta(7)-sterol 5(6)-desaturase EC:1.14.19.20
7-dehydrocholesterol reductase EC:1.3.1.21

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 transcript abundance of genes for cholesterol synthesis enzymes, which is an indirect – and only semi-quantitative indicator of protein abundance.  Protein levels for cholesterol synthesis enzymes can be measured via Western blotting or enzyme immunoassay.  Overall assessment for the rate of cholesterol synthesis can be done by stable isotope labeling techniques (deuterium oxide (2H2O) preferred) and measuring the incorporation of deuterium into new cholesterol (Previs et al. 2011).  Focus can also be placed on the rate-limiting step where HMG CoA is converted to Mevalonate by HMG CoA Reductase (Itkonen et al. 2023).

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., Shah, N.A., Warrington, J.A., Anderson, N.N., Park, S.W., Brown, M.S., and Goldstein, J.L.  2003. Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes.  Proceedings of the National Academy of Sciences 100(21): 12027–12032.

Howe, V., Sharpe, L.J., Prabhu, A.V., and Brown, A.J.  2017.  New insights into cellular cholesterol acquisition: promoter analysis of human HMGCR and SQLE, two key control enzymes in cholesterol synthesis.  Biochim Biophys Acta 1862: 647–657.

Itkonen, A., Hakkola, J., and Rysa, J.  2023.  Adverse outcome pathway for pregnane X receptor‑induced hypercholesterolemia.  Archives of Toxicology 97: 2861–2877.

Karpale, M.  Karajamaki, A.J., Kummu, O., Gylling, H., Hyotylainen, T., Oresic, M., Tolonen, A., Hautajarvi, H., Savolainen, M.J., Ala-Korpela, M., Hukkanen, J., and Hakkola, J.  2021.  Activation of pregnane X receptor induces atherogenic lipids and PCSK9 by a SREBP2-mediated mechanism.  British Journal of Pharmacology  178: 2461–2481.

Previs, S.F., Mahsut, A., Kulick, A., Dunn, K., Andrews-Kelly, G., Johnson, C., Bhat, G., Herath, K., Miller, P.L., Wang, S.-P., Azer, K., Xu, J., Johns, D.G., Hubbard, B.K., and Roddy, T.P.  2011. Quantifying cholesterol synthesis in vivo using 2H2O: enabling back-to-back studies in the same subject.  Journal of Lipid Research 52: 1420-1428.

Sakakura, Y., Shimano, H., Sone, H., Takahashi, A., Inoue, N., 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.

The UniProt Consortium.  UniProt: the Universal Protein Knowledgebase in 2024. https://www.uniprot.org/  Accessed December 2024.

NOTE: Italics indicate edits from John Frisch December 2024.