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Decreased, Peroxisomal Fatty Acid Beta Oxidation of Fatty Acids leads to Decreased, Mitochondrial Fatty Acid Beta Oxidation
Key Event Relationship Overview
AOPs Referencing Relationship
Life Stage Applicability
|Not Otherwise Specified||Not Specified|
Key Event Relationship Description
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 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). Mitochondrial beta-oxidation catabolizes short, medium and long chain fatty acids (<C20) into acetyl-CoA and ATP. The production of acetyl-CoA monomers is important as they 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). Acetyl-CoA is also a fundamental units of energy storage via gluconeogenesis (Nelson and Cox, 2000B) and lipogenesis (Nelson and Cox, 2000C).
Evidence Supporting this KER
The KE, “peroxisomal fatty acid beta oxidation of fatty acids” reactions shorten very long chain fatty acids from dietary sources releasing acetyl-CoA subunits (a primary metabolic fuel source) and shortened-chain fatty acids that can subsequently be catabolized in the KE, “mitochondrial fatty acid beta oxidation” (as reviewed in Kersten et al. 2014 and Desvergne and Wahli 1999). Although the KER for these KEs is firmly established, the KE, “mitochondrial fatty acid beta oxidation” is not dependent on the KE, “peroxisomal fatty acid beta oxidation of fatty acids” given that the latter occur using short, medium and long chain fatty acids from diet or when released from adipose tissue (Desvergne and Wahli 1999, Evans et al. 2004), hence the “Moderates” score for weight of evidence and quantitative understanding.
Biological plausibility of this KER is strong given the supporting relationships cited in the literature described in the previous bullets above.
Uncertainties and Inconsistencies
The degree to which the KE, “peroxisomal fatty acid beta oxidation of fatty acids” contributes to the KE, “mitochondrial fatty acid beta oxidation” under a broad range of nutrient levels and types is not well characterized.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The evidence provided is primarily derived from human and rodent models.
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.