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Event: 807

Key Event Title

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

Decreased, 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
Decreased, 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
cholesterol biosynthetic process cholesterol decreased
cholesterol transport cholesterol decreased
cholesterol transport cholesteryl ester decreased

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
HMGCR inhibition to male fertility KeyEvent Cataia Ives (send email) Under Development: Contributions and Comments Welcome
PPARa Agonism Impairs Fish Reproduction KeyEvent Arthur Author (send email) Open for citation & comment

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
Vertebrates Vertebrates High NCBI

Life Stages

An indication of the the relevant life stage(s) for this KE. More help
Life stage Evidence
Adult High
All life stages Moderate

Sex Applicability

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

Most cholesterol synthesis in vertebrates occurs within the endoplasmic reticulum of hepatic cells. First, acetyl-CoA is converted to HMG-CoA via HMG-CoA synthase. Next, HMG-CoA is converted to mevalonate via HMG-CoA reductase. Several other steps follow, but conversion of HMG-CoA to mevalonate is the rate-limiting step of cholesterol synthesis (Cerqueira et al. 2016; Risley 2002). Consequently, Statin drugs inhibit HMG-CoA reductase to reduce cholesterol (Pahan 2006).

Cholesterol synthesis may also occur to a limited extent in steroidogenic cells where it’s used to produce steroid hormones (Azhar et al., 2007)

Once cholesterol is produced in the liver, it’s transported in the plasma. Hydrophobic lipids like cholesterol, cholesteryl ester (a cholesterol molecule bound to a fatty acid), and triglycerides are transported via lipoprotein complexes. There are different groups of lipoproteins which use different proteins and ratios of lipids including high-density lipoprotein (HDL), low-density (LDL), and very low-density (VLDL).

Cholesterol metabolism KEGG Pathway  ko04979

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

Commerical assay kits are available for measuring cholesterol using either colorimetric or fluorometric detection. Total cholesterol assay kits often include cholesteryl esters in the measurement (Cell Bio LabsThermoFisher). Additional kits are availalbe for measuring the cholesterol in the different lipoprotein complexes (Cell Bio Labs). 

Oil Red O staining can be used for organisms such as zebrafish larvae that are clear, however it stains triglycerides and lipids not just cholesterol (Zhou et al., 2015). 

Plasma cholesterol is a common clinical measurement in humans and the Abell-Kendall technique is the standard chemical determination method (Cox et al. 1990), although there are a wide variety of viable methods.

Domain of Applicability

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

Taxonomic Applicability: Cholesterol is synthesized in plants but acts as a precursor for different products than in animals (Sonawane et al. 2016). Within the animal kingdom most deuterostomes (including vertebrata, cyclostomata, cephalochordate, and echinodermata, but not chordata) possess the genes necessary for cholesterol biosynthesis. However, most protostomes (including arthropoda and nematomorpha) have lost these genes (Zhang et al., 2019). Thus far vertebrates are the primary consideration for this KE.

Lifestage Applicability: Cholesterol can be measured in organisms at all life stages. However, the size of young organisms may limit the ability to collect plasma for cholesterol analysis. Whole-body measurements or pooled samples may be more feasible.

Sex Applicability: Cholesterol measurements are applicable for all sexes

References

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

Al-Habsi, A.A., A. Massarsky, T.W. Moon (2016) “Exposure to gemfibrozil and atorvastatin affects cholesterol metabolism and steroid production in zebrafish (Danio rerio)”, Comparative Biochemistry and Physiology, Part B, Vol. 199, Elsevier, pp. 87-96. http://dx.doi.org/10.1016/j.cbpb.2015.11.009

Azhar, S., E. Reaven (2007) “Regulation of Leydig cell cholesterol metabolism”, in A.H. Payne, M.P. Hardy (eds.) The Leydig Cell in Health and Disease, Humana Press. https://doi.org/10.1007/978-1-59745-453-7

Cox RA, García-Palmieri MR. Cholesterol, Triglycerides, and Associated Lipoproteins. In: Walker HK, Hall WD, Hurst JW, editors. Clinical Methods: The History, Physical, and Laboratory Examinations. 3rd edition. Boston: Butterworths; 1990. Chapter 31. Available from: https://www.ncbi.nlm.nih.gov/books/NBK351/

Dai, W. et al. (2015) "High fat plus high cholesterol diet lead to hepatic steatosis in zebrafish larvae: a novel model for screening anti-hepatic steatosis drugs", Nutrition and Metabolism, Vol. 12(42), Springer Nature. DOI 10.1186/s12986-015-0036-z 

Du, Z.Y. et al. (2008) “Hypolipidaemic effect of fenofibrate and fasting in the herbivorous grass carp (Ctenopharyngodon idella) fed a high-fat diet”, British Journal of Nutrition, Vol. 100, Cambridge University Press, pp. 1200-1212. doi:10.1017/S0007114508986840

Guo, X. et al. (2015) “Effects of lipid-lowering pharmaceutical clofibrate on lipid and lipoprotein metabolism of grass carp (Ctenopharyngodon idellal Val.) fed with the high non-protein energy diets”, Fish Physiology and Biochemistry, Vol. 41, Springer, pp. 331-343. doi: 10.1007/s10695-014-9986-8

Cerqueira, N. M., Oliveira, E. F., Gesto, D. S., Santos-Martins, D., Moreira, C., Moorthy, H. N., ... & Fernandes, P. A. (2016). Cholesterol biosynthesis: a mechanistic overview. Biochemistry55(39), 5483-5506.

Prindiville, J.S. et al. (2011) “The fibrate drug gemfibrozil disrupts lipoprotein metabolism in rainbow trout”, Toxicology and Applied Pharmacology, Vol. 251, Elsevier, pp. 201-238. doi:10.1016/j.taap.2010.12.013

Pahan, K. (2006). Lipid-lowering drugs. Cellular and molecular life sciences CMLS63(10), 1165-1178.

Risley, J. M. (2002). Cholesterol biosynthesis: Lanosterol to cholesterol. Journal of chemical education79(3), 377.

Sonawane, P.D. et al. (2016) “Plant cholesterol biosynthetic pathway overlaps with phytosterol metabolism”, Nature Plants, Vol. 3, Nature Publishing Group, https://doi.org/10.1038/nplants.2016.205

Velasco-Santamaría, Y.M. et al. (2011) “Bezafibrate, a lipid-lowering pharmaceutical, as a potential endocrine disruptor in male zebrafish (Danio rerio)”, Aquatic Toxicology, Vol. 105, Elsevier, pp. 107-118. doi:10.1016/j.aquatox.2011.05.018

Zhang, T. et al. (2019) “Evolution of the cholesterol biosynthesis pathway in animals”, Molecular Biology and Evolution, Vol. 36(11), Oxford University Press, pp. 2548-2556. doi:10.1093/molbev/msz167

Zhou, J. et al. (2015) "Rapid analysis of hypolipidemic drugs in a live zebrafish assay", Journal of Pharmacological and Toxicological Methods, Vol. 72, Elsevier, pp. 47-52. http://dx.doi.org/10.1016/j.vascn.2014.12.002