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Event: 291
Key Event Title
Accumulation, Triglyceride
Short name
Biological Context
Level of Biological Organization |
---|
Cellular |
Cell term
Cell term |
---|
hepatocyte |
Organ term
Key Event Components
Process | Object | Action |
---|---|---|
triglyceride | increased |
Key Event Overview
AOPs Including This Key Event
AOP Name | Role of event in AOP | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|
LXR Activation to Liver Steatosis | KeyEvent | Marina Goumenou (send email) | Not under active development | |
AhR activation to steatosis | KeyEvent | Michelle Angrish (send email) | Under Development: Contributions and Comments Welcome | |
GR activation leading to hepatic steatosis | KeyEvent | Chander K. Negi (send email) | Under Development: Contributions and Comments Welcome | |
PXR activation leads to liver steatosis | KeyEvent | John Frisch (send email) | Under development: Not open for comment. Do not cite | |
LXR activation leads to liver steatosis | KeyEvent | John Frisch (send email) | Under development: Not open for comment. Do not cite |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
Vertebrates | Vertebrates | High | NCBI |
Life Stages
Life stage | Evidence |
---|---|
Adult | High |
Juvenile | Moderate |
Sex Applicability
Term | Evidence |
---|---|
Unspecific | High |
Key Event Description
Triglycerides are important building blocks for a wide variety of compounds found in organisms, with cellular concentrations reflecting the relative rate of influx and efflux, as well as the relative rate of synthesis and breakdown. However, excess accumulation leads to Fatty Liver Cells and steatosis.
In this key event we focus on excessive accumulation of triglycerides in mammalian systems. Four major pathways for triglyceride accumulation are: 1. Increased fatty acid uptake; 2. Increased De Novo FA and Lipid Synthesis; 3. Decreased FA Oxidation; 4. Decreased Lipid Efflux (Angrish et al. 2016). Chemical stressors can increase gene expression of key genes involving these pathways, leading to increased accumulation of triglycerides (Aguayo-Orozco et al. 2018). In addition, excessive dietary compounds of fatty compounds can also increase likelihood of accumulation of triglycerides (Nguyen et al. 2008). Nuclear receptors that have been implicated in causing excessive accumulation of triglycerides leading to steatosis, when overexpressed, include (Mellor et al. 2016): Aryl hydrocarbon receptor (AHR), Constitutive androstane receptor (CAR), Oestrogen receptor (ER), Farnesoid X receptor (FXR), Glucocorticoid receptor (GXR), Liver X receptor (LXR), Peroxisome proliferator-activated receptor (PPAR), Pregnane X receptor (PXR), and Retinoic acid receptor (RAR or RXR).
How It Is Measured or Detected
Concentrations of triglycerides, cholesterols, fatty acids, and related compounds are measured biochemically to assess levels in control versus potentially affected individuals. 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. 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
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
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.
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.
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.