AOP Title
NR1I3 (CAR) suppression leading to hepatic steatosis
Short name: NR1I3 suppression to steatosis
Authors
Michelle Angrish, 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 7/2/2016.
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Abstract
Background (optional)
Summary of the AOP
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Molecular Initiating Event
Key Events
Event
|
Support for Essentiality
|
SREBF1, Activation |
Moderate
|
ChREBP, Activation |
Moderate
|
De Novo FA synthesis, Increased |
Strong
|
Fatty acid uptake, Increased |
Strong
|
Triglyceride formation, Increased |
Moderate
|
CD36, Up Regulation |
Strong
|
SCD-1, Up Regulation |
Strong
|
FAS, Up Regulation |
Strong
|
Mitochondrial fatty acid beta-oxidation, Inhibition |
|
Fatty acid, Accumulation |
|
Acetyl-CoA carboxylase-1 (ACC-1), Up Regulation |
Strong
|
Adverse Outcome
Relationships Among Key Events and the Adverse Outcome
Event
|
Description
|
Triggers
|
Weight of Evidence
|
Quantitative Understanding
|
Constitutive androstane receptor, NR1l3, Suppression |
Directly Leads to |
LXR, Activation |
Strong |
Strong
|
Constitutive androstane receptor, NR1l3, Suppression |
Directly Leads to |
PPARγ, Activation |
Strong |
Strong
|
LXR, Activation |
Directly Leads to |
SREBF1, Activation |
Strong |
Strong
|
LXR, Activation |
Directly Leads to |
ChREBP, Activation |
Strong |
Strong
|
ChREBP, Activation |
Directly Leads to |
De Novo FA synthesis, Increased |
Strong |
Strong
|
Triglyceride formation, Increased |
Directly Leads to |
Liver Steatosis, Increased |
Strong |
Strong
|
PPARγ, Activation |
Directly Leads to |
SREBF1, Activation |
Moderate |
Moderate
|
PPARγ, Activation |
Directly Leads to |
Fatty acid uptake, Increased |
Moderate |
Moderate
|
SREBF1, Activation |
Directly Leads to |
SCD-1, Up Regulation |
Strong |
Strong
|
LXR, Activation |
Directly Leads to |
CD36, Up Regulation |
Strong |
Strong
|
LXR, Activation |
Directly Leads to |
FAS, Up Regulation |
Strong |
Strong
|
LXR, Activation |
Directly Leads to |
SCD-1, Up Regulation |
Strong |
Strong
|
FAS, Up Regulation |
Directly Leads to |
De Novo FA synthesis, Increased |
Strong |
Strong
|
SCD-1, Up Regulation |
Directly Leads to |
Triglyceride formation, Increased |
Strong |
Strong
|
CD36, Up Regulation |
Directly Leads to |
Fatty acid uptake, Increased |
Strong |
Strong
|
LXR, Activation |
Indirectly Leads to |
PPAR alpha, Inhibition |
|
|
PPAR alpha, Inhibition |
Directly Leads to |
Mitochondrial fatty acid beta-oxidation, Inhibition |
Strong |
|
De Novo FA synthesis, Increased |
Directly Leads to |
Fatty acid, Accumulation |
Strong |
|
Fatty acid uptake, Increased |
Directly Leads to |
Fatty acid, Accumulation |
Strong |
|
Fatty acid, Accumulation |
Directly Leads to |
Triglyceride formation, Increased |
|
|
Fatty acid, Accumulation |
Directly Leads to |
Liver Steatosis, Increased |
|
|
Mitochondrial fatty acid beta-oxidation, Inhibition |
Directly Leads to |
Fatty acid, Accumulation |
|
|
LXR, Activation |
Directly Leads to |
Acetyl-CoA carboxylase-1 (ACC-1), Up Regulation |
Strong |
|
Acetyl-CoA carboxylase-1 (ACC-1), Up Regulation |
Indirectly Leads to |
De Novo FA synthesis, Increased |
Strong |
|
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Life Stage Applicability
Life Stage
|
Evidence
|
Links
|
Taxonomic Applicability
Name
|
Scientific Name
|
Evidence
|
Links
|
human, mouse, rat |
|
Moderate |
|
Sex Applicability
Graphical Representation
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Overall Assessment of the AOP
Domain of Applicability
Life Stage Applicability,
Taxonomic Applicability,
Sex Applicability
Elaborate on the domains of applicability listed in the summary section above. Specifically, provide the literature supporting, or excluding, certain domains.
Essentiality of the Key Events
Molecular Initiating Event Summary,
Key Event Summary
Provide an overall assessment of the essentiality for the key events in the AOP. Support calls for individual key events can be included in the molecular initiating event, key event, and adverse outcome tables above.
Weight of Evidence Summary
Summary Table
Provide an overall summary of the weight of evidence based on the evaluations of the individual linkages from the Key Event Relationship pages.
Quantitative Considerations
Summary Table
Provide an overall discussion of the quantitative information available for this AOP. Support calls for the individual relationships can be included in the Key Event Relationship table above.
Considerations for Potential Applications of the AOP (optional)
References