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AOP: 213

Title

A descriptive phrase which references both the Molecular Initiating Event and Adverse Outcome.It should take the form “MIE leading to AO”. For example, “Aromatase inhibition leading to reproductive dysfunction” where Aromatase inhibition is the MIE and reproductive dysfunction the AO. In cases where the MIE is unknown or undefined, the earliest known KE in the chain (i.e., furthest upstream) should be used in lieu of the MIE and it should be made clear that the stated event is a KE and not the MIE. More help

Inhibition of fatty acid beta oxidation leading to nonalcoholic steatohepatitis (NASH)

Short name

A name that succinctly summarises the information from the title. This name should not exceed 90 characters. More help

Inhibition fatty acid beta oxidation leading to nonalcoholic steatohepatisis (NASH)

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Handbook Version v1.0

Graphical Representation

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Click to download graphical representation template Explore AOP in a Third Party Tool

Authors

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Lyle Burgoon, US Army Engineer Research and Development Center

Edward Perkins, US Army Engineer Research and Development Center

Point of Contact

The user responsible for managing the AOP entry in the AOP-KB and controlling write access to the page by defining the contributors as described in the next section. More help

Lyle Burgoon (email point of contact)

Contributors

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Edward Perkins
Lyle Burgoon

Coaches

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OECD Information Table

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OECD Project #	OECD Status	Reviewer's Reports	Journal-format Article	OECD iLibrary Published Version

This AOP was last modified on April 29, 2023 16:02

Revision dates for related pages

Page	Revision Date/Time
Increase, cytosolic fatty acid	November 27, 2017 12:20
N/A, Steatohepatisis	November 27, 2017 13:41
Inhibition, Fatty Acid Beta Oxidation	November 27, 2017 12:15
Increased, Liver Steatosis	May 21, 2024 10:00
Increased, Reactive oxygen species	April 10, 2024 17:33
Increased, Oncotic Necrosis	November 27, 2017 13:31
Inhibition of fatty acid beta oxidation leads to Increase, cytosolic fatty acid	November 13, 2017 12:51
Increase, cytosolic fatty acid leads to Increased, Liver Steatosis	November 14, 2017 10:25
Increased, Liver Steatosis leads to Increased, Reactive oxygen species	November 14, 2017 10:26
Increased, Reactive oxygen species leads to increased, oncotic necrosis	November 14, 2017 10:27
increased, oncotic necrosis leads to steatohepatitis	November 14, 2017 10:28

Abstract

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Non-alcoholic steatohepatitis (NASH) is a significant disease of the liver. NASH presents as steatosis (fatty liver) and hepatitis (liver inflammation). NASH is on a spectrum of liver disease, starting at steatosis and ultimately leading to cirrhosis (liver fibrosis) if chemical exposure and injury continues. This AOP is focused on fatty acid beta oxidation and its contribution as a molecular initiating event in the formation of NASH. Steatosis is ultimately a net increase in fatty acids within hepatocytes. This can be from a net decrease in efflux (e.g., influx >> efflux), a net decrease in overall fatty acid oxidation/metabolism to glucose and intermediates, or a combination of these factors. In this AOP, our MIE is the inhibition of fatty acid beta oxidation (FABO). This leads to an overall increase in fatty acids. These fatty acids undergo lipid peroxidation resulting in fatty acid free radicals. When the reduction potential of the cell is overwhelmed, the free radicals lead to oncotic cell death, and the release of signals that stimulate inflammatory cell infiltration.

AOP Development Strategy

Context

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Steatosis is the condition where an abnormal amount of fat is being stored within the liver. The liver is the site where sugars and fats are converted for the purposes of supplying energy to the rest of the body. The liver will convert glucose to fatty acids and package them as triglycerides for distribution throughout the body via the bloodstream and storage in adipose tissue. The liver also takes in fatty acids and triglycerides, and oxidizes them back to glucose for distribution throughout the body. When the influx/efflux and metabolism of fatty acids is altered, leading to a net increase in cellular fatty acids, the result is steatosis. As steatosis progresses, these fatty acids may lead to oxidative stress that ultimately leads to oncotic necrosis (cell death) and inflammatory cell infiltration (inflammation). This is termed steatohepatitis.

Strategy

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Summary of the AOP

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Events:

Molecular Initiating Events (MIE)

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Key Events (KE)

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Adverse Outcomes (AO)

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

Type	Event ID	Title	Short name

MIE

1490

Inhibition, Fatty Acid Beta Oxidation

Inhibition of fatty acid beta oxidation

KE	1305	Increase, cytosolic fatty acid	Increase, cytosolic fatty acid
KE	459	Increased, Liver Steatosis	Increased, Liver Steatosis
KE	1115	Increased, Reactive oxygen species	Increased, Reactive oxygen species
KE	1491	Increased, Oncotic Necrosis	increased, oncotic necrosis

1489

N/A, Steatohepatisis

steatohepatitis

Relationships Between Two Key Events (Including MIEs and AOs)

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Title	Adjacency	Evidence	Quantitative Understanding

Inhibition of fatty acid beta oxidation leads to Increase, cytosolic fatty acid	adjacent	High	High
Increase, cytosolic fatty acid leads to Increased, Liver Steatosis	adjacent	High	High
Increased, Liver Steatosis leads to Increased, Reactive oxygen species	adjacent	High	Low
Increased, Reactive oxygen species leads to increased, oncotic necrosis	adjacent	High	Low
increased, oncotic necrosis leads to steatohepatitis	adjacent	High	Low

Network View

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Prototypical Stressors

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Life Stage Applicability

The life stage for which the AOP is known to be applicable. More help

Life stage	Evidence
All life stages	High

Taxonomic Applicability

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Term	Scientific Term	Evidence	Link
Vertebrates	Vertebrates	High	NCBI

Sex Applicability

The sex for which the AOP is known to be applicable. More help

Sex	Evidence
Unspecific	High

Overall Assessment of the AOP

Addressess the relevant biological domain of applicability (i.e., in terms of taxa, sex, life stage, etc.) and Weight of Evidence (WoE) for the overall AOP as a basis to consider appropriate regulatory application (e.g., priority setting, testing strategies or risk assessment). More help

Overall, the confidence in this AOP is high. Most of the components of fatty acid metabolism are well known biochemical pathways that are well studied. Although components of this AOP occur within cells, the overall diagnosis of this condition is typically at the organ level. The adverse outcome is known to occur in vertebrates in the liver. Steatosis has been used as a regulatory endpoint or potential regulatory endpoint in many assessments from the US EPA.

This AOP begins at inhibition of fatty acid beta-oxidation. This results in an increase in the overall amount of cytosolic fatty acids in the cytoplasm (under certain assumptions mentioned below). To lead to toxicity, the cytoplasm must become a net sink of fatty acids, with the rate of fatty acid deposition being greater than the rate of fatty acid efflux. This increase in cytosolic fatty acids increases the likelihood that reactive oxygen species will have lipids to undergo peroxidation, leading to a cascade of protein and membrane damage once the cellular reduction system is depleted. This damage leads to oncotic necrosis which results in the spillage of cytoplasmic contents, which triggers an inflammatory response. The result is steatohepatitis.

Domain of Applicability

Addressess the relevant biological domain(s) of applicability in terms of sex, life-stage, taxa, and other aspects of biological context. More help

The domain of applicability for this AOP is all sexes in vertebrates at all life stages with a functional liver.

Essentiality of the Key Events

The essentiality of KEs can only be assessed relative to the impact of manipulation of a given KE (e.g., experimentally blocking or exacerbating the event) on the downstream sequence of KEs defined for the AOP. Consequently, evidence supporting essentiality is assembled on the AOP page, rather than on the independent KE pages that are meant to stand-alone as modular units without reference to other KEs in the sequence. The nature of experimental evidence that is relevant to assessing essentiality relates to the impact on downstream KEs and the AO if upstream KEs are prevented or modified. This includes: Direct evidence: directly measured experimental support that blocking or preventing a KE prevents or impacts downstream KEs in the pathway in the expected fashion. Indirect evidence: evidence that modulation or attenuation in the magnitude of impact on a specific KE (increased effect or decreased effect) is associated with corresponding changes (increases or decreases) in the magnitude or frequency of one or more downstream KEs. More help

It has been demonstrated that pharmacological inhibition of fatty acid beta-oxidation is sufficient to cause steatosis (1-4).

Steatosis leading to inflammation (termed non-alcoholic steatohepatitis; NASH) is well known. Some hypotheses of how this may occur are discussed in (5). As steatosis is necessary for a diagnosis of NASH, it is essential by definition.

Evidence Assessment

Addressess the biological plausibility, empirical support, and quantitative understanding from each KER in an AOP. More help

NASH is a well-known adverse event that has been well-studied in the toxicology literature, especially in support of pharmaceutical development. The key events involved in NASH are relatively well-studied. There are many forking paths that lead to NASH, with inhibition of fatty acid beta-oxidation being just one. The progression from pre-steatosis to steatohepatitis is reviewed in (6). The key events are generally well-known; however, what is less well-known are the exact molecular key event components that lead from steatosis to activation of the hepatic Kuppfer cells (liver macrophages) which activate hepatitis. However, for the purposes of the AOP, this level of granular knowledge is not required.

Known Modulating Factors

Modulating factors (MFs) may alter the shape of the response-response function that describes the quantitative relationship between two KES, thus having an impact on the progression of the pathway or the severity of the AO.The evidence supporting the influence of various modulating factors is assembled within the individual KERs. More help

Quantitative Understanding

Optional field to provide quantitative weight of evidence descriptors. More help

Based on information available in (2-3) it is possible to estimate the amount of fatty acid beta-oxidation inhibition that is required to lead to steatosis. The quantitative evidence for the steps leading from steatosis to hepatitis are relatively weak. This process is not entirely well-known at the granular, molecular level, and there is a derth of quantitative studies at this time.

Considerations for Potential Applications of the AOP (optional)

Addressess potential applications of an AOP to support regulatory decision-making.This may include, for example, possible utility for test guideline development or refinement, development of integrated testing and assessment approaches, development of (Q)SARs / or chemical profilers to facilitate the grouping of chemicals for subsequent read-across, screening level hazard assessments or even risk assessment. More help

This AOP was developed to support the development of probabilistic AOPs, specifically the AOP Bayesian Network (AOPBN) for Steatosis featured in the BISCT tool (BISCT: Bayesian Inference for Substance and Chemical Toxicity ). The Steatosis AOPBN is intended for use in:

Chemical Screening, when coupled with HTS assays,
Hazard Identification, for risk screening and risk assessment

The AOPBN in BISCT is compatible with data from HTS assays, high content assays (e.g., toxicogenomics), molecular assays, and more traditional assays.

BISCT is open source software, available at GitHub

References

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

Begriche K, Igoudjil A, Pessayre D, Fromenty B. Mitochondrial dysfunction in NASH: causes, consequences and possible means to prevent it. Mitochondrion. 2006 Feb;6(1):1-28. Epub 2006 Jan 5.
E Freneaux, B Fromenty, A Berson, G Labbe, C Degott, P Letteron, D Larrey and D Pessayre. Stereoselective and nonstereoselective effects of ibuprofen enantiomers on mitochondrial beta-oxidation of fatty acids. Journal of Pharmacology and Experimental Therapeutics November 1990, 255 (2) 529-535.
J Geneve, B Hayat-Bonan, G Labbe, C Degott, P Letteron, E Freneaux, T L Dinh, D Larrey and D Pessayre. Inhibition of mitochondrial beta-oxidation of fatty acids by pirprofen. Role in microvesicular steatosis due to this nonsteroidal anti-inflammatory drug. Journal of Pharmacology and Experimental Therapeutics September 1987, 242 (3) 1133-1137.
Seung-Hoi Koo. Nonalcoholic fatty liver disease: molecular mechanisms for the hepatic steatosis. Clin Mol Hepatol. 2013 Sep; 19(3): 210–215.
Herbert Tilg, Alexander R. Moschen. Evolution of inflammation in nonalcoholic fatty liver disease: The multiple parallel hits hypothesis. Hepatology 2010;52:1836-1846.
Satapathy SK, Kuwajima V, Nadelson J, Atiq O, Sanyal AJ. Drug-induced fatty liver disease: An overview of pathogenesis and management. Ann Hepatol. 2015 Nov-Dec;14(6):789-806. doi: 10.5604/16652681.1171749.