Aop:60

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Status

This is a legacy representation of this AOP. Please see the current version here:

https://aopwiki.org/aops/60


AOP Title

NR1I2 (Pregnane X Receptor, PXR) activation leading to hepatic steatosis
Short name: PXR activation to steatosis

Authors

Michelle Angrish and Brian Chorley

Status

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OECD Project 1.29: A catalog of putative AOPs that will enhance the utility of US EPA Toxcast high throughput screening data for hazard identification Under development: Do not distribute or cite.

This AOP page was last modified on 12/11/2016.

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Abstract

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Summary of the AOP

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Molecular Initiating Event

Molecular Initiating Event Support for Essentiality
PXR/SXR, Activation

Key Events

Event Support for Essentiality
FoxA2, Inhibition Strong
Mitochondrial fatty acid beta-oxidation, Decreased Strong
CPT1A, Down Regulation Strong
HMGCS2, Down Regulation Moderate
SCD-1, Up Regulation Strong
CD36, Up Regulation Strong
Hepatic Triglycerides, Increased Strong
FA Influx, Increased Strong
Hepatic FA, Accumulation Strong
Ketogenesis, Decreased Moderate

Adverse Outcome

Adverse Outcome
Liver Steatosis, Increased

Relationships Among Key Events and the Adverse Outcome

Event Description Triggers Weight of Evidence Quantitative Understanding
SCD-1, Up Regulation Directly Leads to Hepatic Triglycerides, Increased Strong
Hepatic Triglycerides, Increased Directly Leads to Liver Steatosis, Increased Strong
CD36, Up Regulation Directly Leads to FA Influx, Increased Strong
FA Influx, Increased Indirectly Leads to Hepatic Triglycerides, Increased Strong
FA Influx, Increased Directly Leads to Hepatic FA, Accumulation Strong
Mitochondrial fatty acid beta-oxidation, Decreased Directly Leads to Hepatic FA, Accumulation Strong
HMGCS2, Down Regulation Directly Leads to Ketogenesis, Decreased Strong
PXR/SXR, Activation Directly Leads to FoxA2, Inhibition Strong
CPT1A, Down Regulation Directly Leads to Mitochondrial fatty acid beta-oxidation, Decreased Strong
PXR/SXR, Activation Directly Leads to CD36, Up Regulation Weak
PXR/SXR, Activation Directly Leads to SCD-1, Up Regulation Weak
Ketogenesis, Decreased Indirectly Leads to Hepatic FA, Accumulation Moderate
FoxA2, Inhibition Directly Leads to HMGCS2, Down Regulation Strong
Hepatic FA, Accumulation Directly Leads to Liver Steatosis, Increased Strong
FoxA2, Inhibition Directly Leads to CPT1A, Down Regulation Strong

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Life Stage Applicability

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Taxonomic Applicability

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Sex Applicability

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Overall Assessment of the AOP

Domain of Applicability

Life Stage Applicability, Taxonomic Applicability, Sex Applicability
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Essentiality of the Key Events

Molecular Initiating Event Summary, Key Event Summary
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Weight of Evidence Summary

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Quantitative Considerations

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Considerations for Potential Applications of the AOP (optional)

References