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Relationship: 132
Title
Increase, FA Influx leads to Accumulation, Triglyceride
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
LXR activation leading to hepatic steatosis | adjacent | Not Specified | Marina Goumenou (send email) | Not under active development | ||
Pregnane X Receptor (PXR) activation leads to liver steatosis | adjacent | Moderate | Not Specified | John Frisch (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Sex Applicability
Sex | Evidence |
---|---|
Unspecific | Moderate |
Life Stage Applicability
Term | Evidence |
---|---|
Adult | High |
Juvenile | Moderate |
Key Event Relationship Description
Increased fatty acid influx is a main pathway broadly accepted as a mechanism for accumulation of triglycerides in cells. Chemical stressors or alteration of gene expression levels can trigger increased fatty acid influx, as well as changes to membrane permeability and membrane proteins that facilitate fatty acid transport.
Evidence Collection Strategy
This KER was identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. Support for this KER is referenced in publications cited in the originating work of Landesmann et al. (2012) and Negi et al. (2021).
Evidence Supporting this KER
Biological Plausibility
The biological plausibility linking increased fatty acid influx to accumulation of triglycerides is strong, as a main pathway conserved across taxa.
Empirical Evidence
In empirical studies, the link between increased fatty acid influx and accumulation of triglycerides is generally inferred. Zhou et al. (2006) link accumulation of triglycerides to increased fatty acid influx in the livers of transgenic mice with increased Pregnane X Receptor expression compared to wild-type mice. Increased expression of genes and/or signaling molecules known to facilitate fatty acid influx, and corresponding increases in triglyceride content in cells, are correlated to show evidence that increases are due to increased influx rather than alternative pathways. Angrish et al. (2016) review genes, signaling molecules, and chemical stressors linked to increased fatty acid influx, as well as other pathways leading to accumulation of triglycerides in cells. For a review of membrane proteins facilitating fatty acid influx, see Glatz et al. (2010).
Species |
Duration |
Dose |
Increased FA influx? |
Increased triglyceride? |
Summary |
Citation |
Lab mice (Mus musculus) |
16 hours |
Wild-type versus transgenic-cd36 mice. |
yes |
yes |
Heptatocytes from transgenic-CD36 mice showed increased fatty acid influx than null mice and measured by the fluorescent fatty acid analog BODIPY and correlated increased triglycerides. |
Koonen et al. (2007) |
Lab mice (Mus musculus) |
1 week, 24 hours |
100 mg/kg/day oral or in vitro 20 um efavirenz |
Yes |
Yes |
Hepatocytes exposed to 20 um efavirenz for 24 hours had increased fatty acid influx as measured by palmitic acid uptake and correlated increased triglycerides and cholesterol to mice exposed to 100 mg/kg/day efavirenz for 1 week. |
Gwag et al. (2009) |
Uncertainties and Inconsistencies
Known modulating factors
Quantitative Understanding of the Linkage
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Life Stage: Older individuals are more likely to manifest this adverse outcome pathway (adults > juveniles) due to accumulation of triglycerides.
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
Angrish, M.M., Kaiser, J.P., McQueen, C.A., and Chorley, B.N. 2016. Tipping the balance: Hepatotoxicity and the 4 apical key events of hepatic steatosis. Toxicological Sciences 150(2): 261–268.
Glatz, J.F.C., Joost, J.F., Luiken, P., and Bonen, A. 2010. Membrane fatty acid transporters as regulators of lipid metabolism: Implications for metabolic disease. Physiological Reviews 90: 367–417.
Gwag, T., Meng, Z., Sui, Y., Helsley, R.N., Park, S.-H., Wang, S., Greenberg, R.N., and Zhou, C. 2019. Non-nucleoside reverse transcriptase inhibitor efavirenz activates PXR to induce hypercholesterolemia and hepatic steatosis Journal of Hepatology 70: 930–940.
Koonen, D.P.Y., Jacobs, R.L., Febbraio, M. Young, M.E., Soltys, C.-L.M., Ong, H., Vance, D.E., and Dyck, J.R.B. 2007. Increased hepatic CD36 expression contributes to dyslipidemia associated with diet-induced obesity. Diabetes 56: 2863-2871.
Landesmann, B., Goumenou, M., Munn, S., and Whelan, M. 2012. Description of Prototype Modes-of-Action Related to Repeated Dose Toxicity. European Commission Report EUR 25631, 49 pages. https://op.europa.eu/en/publication-detail/-/publication/d2b09726-8267-42de-8093-8c8981201d65/language-en
Negi, C.K., Bajard, L., Kohoutek, J., and Blaha, L. 2021. An adverse outcome pathway based in vitro characterization of novel flame retardants-induced hepatic steatosis. Environmental Pollution 289: 117855.
Zhou, J., Zhai, Y., Mu, Y., Gong, H., Uppal, H., Toma, D., Ren, S., Evans, R.M., and Xie, W. 2006. A Novel Pregnane X Receptor-mediated and Sterol Regulatory Element-binding Protein-independent Lipogenic Pathway. The Journal of biological chemistry 281(21): 15013–15020.