Key Event Overview
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AOPs Including This Key Event
|AOP Name||Event Type||Essentiality|
|Antagonist binding to PPARalpha leading to starvation-like body-weight loss||KE||Moderate|
|Homo sapiens||Homo sapiens||Strong||NCBI|
|Mus musculus||Mus musculus||Strong||NCBI|
|Rattus rattus||Rattus rattus||Strong||NCBI|
Level of Biological Organization
How this Key Event works
Peroxisomes participate in a variety of lipid metabolic pathways including the beta-oxidation of very long-straight chain (<20 C in length) or branched –chain acyl-CoAs (Lazarow 1978, Kersten 2014). The peroxisomal beta-oxidation pathway is not directly coupled to the electron transport chain and oxidative phosporylation, therefore the first oxidation reaction loses energy to heat (H2O2 production) while in the second step, energy is captured in the metabolically accessible form of high-energy electrons in NADH (Mannaerts and Van Veldhoven 1993, Desvergne and Wahli 1999). The peroxisomal beta-oxidation pathway provides fatty acid chain shortening where two carbons are removed in each round of oxidation in the form of acetyl-CoA (Desvergne and Wahli 1999). The acetyl-CoA monomers serve as fundamental units for metabolic energy production (ATP) via the citric acid cycle followed by electron-transport chain mediated oxidative phosphorylation (Nelson and Cox, 2000A) as well as serve as the fundamental units for energy storage via gluconeogenesis (Nelson and Cox, 2000B) and lipogenesis (Nelson and Cox, 2000C). The shortened chain fatty acids (<20C) can then be transported to the mitochondria to undergo mitochondrial beta-oxidation for complete metabolism of the carbon substrate for cellular energy production (Desvergne and Wahli 1999).
How it is Measured or Detected
Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?
Spectroscopic analysis of the characteristic absorption bands for fatty acid substrates and fatty acid beta oxidation products were examined for peroxisomal fractions purified from rat livers by differential and of equilibrium density centrifugation (Lazarow 1978). Additionally, NAD reduction assays were conducted for acyl-CoA substrates with varying chain lengths where increased oxidation was observed for substrates with long chain length relative to short chain acyl-CoAs (Lazarow 1978).
Evidence Supporting Taxonomic Applicability
Human (as reviewed in Kersten 2014 and Desvergne and Wahli 1999). Rat (as measured by Lazarow 1978). Mouse (as reviewed in Kersten 2014 and Desvergne and Wahli 1999).
Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine Reviews 20(5): 649-688.
Kersten S. 2014. Integrated physiology and systems biology of PPARalpha. Molecular Metabolism 2014, 3(4):354-371.
Lazarow PB: Rat liver peroxisomes catalyze the beta oxidation of fatty acids. J Biol Chem 1978, 253(5):1522-1528.
Mannaerts GP, Van Veldhoven PP 1993 Metabolic role of mammalian peroxisomes. In: Gibson G, Lake B (eds) Peroxisomes: Biology and Importance in Toxicology and Medicine. Taylor & Francis, London, pp 19–62.
Nelson DL, Cox MM 2000A. The Citric Acid Cycle. Lehninger Principles of Biochemistry. 3rd Edition. Worth Publishers. New York, NY. p567-592.
Nelson DL, Cox MM 2000B. Carbohydrate Biosynthesis. Lehninger Principles of Biochemistry. 3rd Edition. Worth Publishers. New York, NY. p722-764.
Nelson DL, Cox MM 2000C. Lipid Biosynthesis. Lehninger Principles of Biochemistry. 3rd Edition. Worth Publishers. New York, NY. p770-814.