API

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Event: 2271

Key Event Title

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

Increased, plasma low-density lipoprotein (LDL) cholesterol

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, plasma LDL cholesterol
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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
Tissue

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
blood plasma

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 LDL cholesterol level low-density lipoprotein cholesterol 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 AdverseOutcome 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 AdverseOutcome 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

Low-density lipoprotein (LDL) cholesterol is a type of cholesterol in which high levels can build up in the arteries and form plaques, while high-density lipoprotein (HDL) cholesterol helps counteract high cholesterol levels by transporting cholesterol to the liver.  Individuals with high levels of plasma low-density lipoprotein (LDL) cholesterol displaying hypercholesterolemia are at greater risk of cardiovascular events (Lalanne et al. 2005; Lambert et al. 2006). 

Cholesterol levels reflect the net of biosynthesis, uptake, efflux, transport, storage, utilization, and excretion processes (Duan et al. 2022).  Biosynthesis of cholesterol involves a number of precursor molecules and enzymes (Sakakura et al. 2001; Itkonen et al. 2023), with high cholesterol levels acting as a negative feedback on additional cholesterol synthesis (Itkonen et al. 2023; MacFarlaine et al. 2014).  Diet is a primary source of cholesterol, with increased intake of saturated fat demonstrated to increase levels of low-density lipoprotein (LDL) cholesterol (Sacks et al. 2017).  Livers with hepatocytes with more low-density lipoprotein receptors (LDLR) have increased uptake of low-density lipoprotein (LDL) cholesterol from plasma (Benjannet et al. 2004; Lalanne et al. 2005).

 

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

A variety of methods are available to assess low-density lipoprotein (LDL) cholesterol levels, including gradient gel electrophoresis, high-performance liquid chromatography, enzyme immunoassays, and estimation from calculations based on triglyceride and cholesterol levels (Islam et al. 2022).

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.  

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. More help

References

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

Benjannet, S., Rhainds, D., Essalmani, R., Mayne, J., Wickham, L., Jin, W., Asselin, M.-C., Hemelin, J., Varret, M., Allrd, D., Trillard, M., Abifadel, M., Tebon, T., Attie, A.D., Rader, D.J., Boileau, C., Brissette, L., Chretien, M., Prat, A., and Seidah, N.G.  2004. NARC-1/PCSK9 and its natural mutants: Zymogen cleavage and effects on the low density lipoprotein (LDL) receptor and LDL cholesterol.   The Journal of Biological Chemistry.  279(47): 48865–48875.

Duan, Y., Gong, K., Xu, S., Zhang, F., Meng, X., and Han, J.  2022.  Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics.  Signal Transduction and Targeted Therapy 7: 265.

Itkonen, A., Hakkola, J., and Rysa, J.  2023.  Adverse outcome pathway for pregnane X receptor‑induced hypercholesterolemia.  Archives of Toxicology 97: 2861–2877. Islam, S.M.T., Osa-Andrews, B., Jones, P.M., Muthukumar, A.R., Hasim, I., and Cao, J.  2022. Methods of low-density lipoprotein-cholesterol measurement: analytical and clinical applications. The Journal of the International Federation of Clinical Chemistry and Laboratory Medicine 33(4): 282-294.

Lalanne, F., Lambert, G., Amar, M.J.A., Chetiveaux, M., Zair, Y., Jarnoux, A.-L., Ouguerram, K., Friburg, J., Seidah, N.G., Brewer, Jr., H.B., Krempf, M., and Costet, P.  2005.  Wild-type PCSK9 inhibits LDL clearance but does not affect apoB-containing lipoprotein production in mouse and cultured cells.  Journal of Lipid Research 46: 1312–1319.

Lambert, G., Jarnoux, A.-J., Pineau, T., Pape, O., Chetiveaux, M., Laboisse, C., Krempf, M., and Costet, P.  2006.  Fasting induces hyperlipidemia in mice overexpressing Proprotein Convertase Subtilisin Kexin Type 9: Lack of modulation of very-low-density lipoprotein hepatic output by the low-density lipoprotein receptor.  Endocrinology 147(10): 4985–4995.

MacFarlaine, M.R., Liang, G., and Engelking, L.J.  2014.  Insig proteins mediate feedback inhibition of cholesterol synthesis in the intestine.  The Journal of Biological Chemistry 289(4): 2148-2156.

Sacks, F.M., Lichtenstein, A.H., Wu, J.H.Y., Appel, L.J., Creager, M.A., Kris-Etherton, P.M., Miller, M., Rimm, E.B., Rudel, L.L., Robinson, J.G., Stone, N.J., and Van Horn, L.V.  2017.  Dietary fats and cardiovascular disease: A presidential advisory from the American Heart Association.  Circulation 136: e1–e23.

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.

NOTE: Italics indicate edits from John Frisch October 2024.