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Event: 115

Key Event Title

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

Increase, FA Influx

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
Increase, FA Influx
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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
hepatocyte

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
positive regulation of fatty acid transport fatty acid 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
LXR Activation to Liver Steatosis KeyEvent Undefined (send email) Not under active development
PXR activation leads to liver steatosis 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
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
Juvenile 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

Fat influx to the liver is usually increased under condition like obesity. Free fatty acids (FFA) increase in blood leads to an increase of FFA uptake in the liver. Especially the long chain fatty acids (LCFAs) are translocated across the plasma membrane, reassembled to triglycerides and stored in lipid droplets causing hepatic steatosis [1].

CD36 has consistently been shown to be expressed at the plasma membrane and to enhance LCFA uptake upon over-expression [2], [3].

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

Increases in fatty acid influx are generally measured by increases in triglycerides, fatty acids, cholesterols, and similar compounds in cells.  In addition, assessment is generally made for plasma membrane stability and/or gene expression increases with genes associated with influx, to associate the increase in fatty acid compounds with influx rather than other pathways (ex. synthesis).

Concentrations of triglycerides, cholesterols, fatty acids, and related compounds are measured biochemically to assess levels in control versus potentially affected individuals; common techniques include high throughput enzymatic analyses, analytical ultracentrifuging, gradient gel electrophoresis, Nuclear Magnetic Resonance, lipidomics, and other direct assessment techniques (Schaefer et al. 2016; Yang and Han 2016).  Analysis is often performed to look at gene expression levels to see which pathway(s) have increased expression levels, to attribute plausibility to changes in influx, eflux, synthesis, and/or breakdown pathways (Nguyen et al. 2008; Mellor et al. 2016, Aguayo-Orozco et al. 2018).  Assessment of cellular components including mitochondria and membrane integrity can also be used as evidence of alteration of normal function within cells.

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: Older individuals are more likely to manifest this key event  (adults > juveniles) due to increased opportunity to increase fatty acid influx.

Sex: Applies to both males and females.

Taxonomic: Appears to be present broadly in vertebrates, with most representative studies in mammals (humans, lab mice, lab rats).

References

List of the literature that was cited for this KE description. More help
  1. ↑ Amacher 2011 - Amacher D.E., The mechanistic basis for the induction of hepatic steatosis by xenobiotics, Expert Opinion on Drug Metabolism and Toxicology, 7 (No 8), 949-965, 2011
  2. ↑ Baranowski 2008 - Baranowski, Biological role of liver X receptors, Journal of Physiology and Pharmacology, 59 (Suppl 7), 31–55, 2008
  3. ↑ Su & Abumrad 2009 - Su X., Abumrad N.A., Cellular fatty acid uptake: a pathway under construction. Trends Endocrinol. Metab., 20 (No 2), 72-77, 2009

Aguayo-Orozco, A.A., Bois, F.Y., Brunak, S., and Taboureau, O.  2018.  Analysis of Time-Series Gene Expression Data to Explore Mechanisms of Chemical-Induced Hepatic Steatosis Toxicity.  Frontiers in Genetics 9(Article 396): 1-15.

Mellor, C.L., Steinmetz, F.P., and Cronin, T.D.  2016.  The identification of nuclear receptors associated with hepatic steatosis to develop and extend adverse outcome pathways.  Critical Reviews in Toxicology, 46(2): 138-152.

Nguyen, P., Leray, V., Diez, M., Serisier, S., Le Bloc’h, J., Siliart, B., and Dumon, H.  2008.  Liver lipid metabolism.  Journal of Animal Physiology and Animal Nutrition 92: 272–283.

Schaefer EJ, Tsunoda F, Diffenderfer M, Polisecki, E., Thai, N., and Astalos, B. The Measurement of Lipids, Lipoproteins, Apolipoproteins, Fatty Acids, and Sterols, and Next Generation Sequencing for the Diagnosis and Treatment of Lipid Disorders. [Updated 2016 Mar 29]. In: Feingold KR, Anawalt B, Blackman MR, et al., editors. Endotext [Internet]. South Dartmouth (MA): MDText.com, Inc.; 2000-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK355892/

Yang, K. and Han, X.  2016.  Lipidomics: Techniques, applications, and outcomes related to biomedical sciences.  Trends in Biochemical Sciences 2016 November ; 41(11): 954–969.

NOTE: Italics symbolize edits from John Frisch