Upstream eventDecreased, PPARalpha transactivation of gene expression
Decreased, Mitochondrial Fatty Acid Beta Oxidation
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Antagonist binding to PPARα leading to body-weight loss||adjacent||High||Not Specified|
Life Stage Applicability
|Not Otherwise Specified||Not Specified|
Key Event Relationship Description
PPARα is a transcriptional regulator for a variety of genes that facilitate systemic energy homeostasis (Kersten 2014, Evans et al 2004, Desvergne and Wahli 1999). The KE “PPARalpha transactivation of gene expression, Decreased” results in the KE, “Mitochondrial Fatty Acid Beta Oxidation, Decreased” by inhibiting expression of the enzymes involved in mitochondrial fatty acid metabolism (Kersten 2014, Brandt et al. 1998; Mascaro et al. 1998, Aoyama et al. 1998, Gulick et al. 1994, Sanderson et al. 2008). A robust literature-base is available for mitochondrial fatty acid beta-oxidation including broad investigation of key enzymes (Brandt et al. 1998; Mascaro et al. 1998, Kersten 2014, Sanderson et al. 2008, Aoyama et al. 1998) and detailed examination of metabolic flux (Aoyama et al. 1998, Badmann et al. 2007, Potthoff et al. 2009), thus the KER received relatively high scores (see weight of evidence section on main page https://aopkb.org/aopwiki/index.php/Aop:6).
Evidence Supporting this KER
The KER for the KE, “decreased PPARα transactivation of gene expression” -> the KE, “decreased mitochondrial fatty acid beta-oxidation” is firmly established in peer-reviewed literature (Brandt et al. 1998; Mascaro et al. 1998, Kersten 2014, Sanderson et al. 2008, Aoyama et al. 1998, Aoyama et al. 1998, Badmann et al. 2007, Potthoff et al. 2009), therefore it received the score of “strong”.
Biological plausibility of this KER is strong given the supporting relationships cited in the literature described in the previous bullets above.
Include consideration of temporal concordance here
Blocking PPARα signaling has been shown to inhibit expression of transcripts / enzymes involved in both peroxisomal and mitochondrial beta-oxidation causing impaired fatty acid catabolism, fatty acid accumulation in the liver and impaired cellular energy state during fasting events (Badman et al 2007, Kersten et al 1999).
Uncertainties and Inconsistencies
The KER between the KE, “decreased PPARα transactivation of gene expression” -> the KE “decreased mitochondrial fatty acid beta-oxidation” is well supported by the literature (see references above). Few uncertainties remain, and few inconsistencies have been reported.
Quantitative Understanding of the Linkage
Is it known how much change in the first event is needed to impact the second? Are there known modulators of the response-response relationships? Are there models or extrapolation approaches that help describe those relationships?
A large body of research demonstrated that PPARα nuclear signaling directly controls transcriptional expression for genes catalyzing mitochondrial beta-oxidation of short, medium and long chain fatty acids (<20C) (as reviewed in Kersten 2014, Evans et al 2004, Desvergne and Wahli 1999, Sanderson et al 2010). The majority of the research described in these reviews was established using gene knock outs, so there is not much dose-response information available describing the KER between the KE, “decreased PPARα transactivation of gene expression” -> the KE “decreased mitochondrial fatty acid beta-oxidation”.
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
The relationships described herein have been primarily established in human and rodent models.
Aoyama, T., Peters, J.M., Iritani, N., Nakajima, T., Furihata, K., Hashimoto, T., et al., 1998. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). Journal of Biological Chemistry 273:5678e5684.
Badman MK, Pissios P, Kennedy AR, Koukos G, Flier JS, Maratos-Flier E: Hepatic fibroblast growth factor 21 is regulated by PPARalpha and is a key mediator of hepatic lipid metabolism in ketotic states. Cell metabolism 2007, 5(6):426-437.
Brandt JM, Djouadi F, Kelly DP: Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor alpha. J Biol Chem 1998, 273(37):23786-23792.
Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine Reviews 20(5): 649-688. Evans RM, Barish GD, Wang YX: PPARs and the complex journey to obesity. Nat Med 2004, 10(4):355-361.
Evans RM, Barish GD, Wang YX. 2004. Ppars and the complex journey to obesity. Nat Med 10:355-361.
Gulick T, Cresci S, Caira T, Moore DD, Kelly DP (1994) The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proceedings of the National Academy of Sciences USA , 91(23):11012-11016.
Kersten S. 2014. Integrated physiology and systems biology of PPARalpha. Molecular Metabolism 2014, 3(4):354-371.
Mascaró C, Acosta E, Ortiz JA, Marrero PF, Hegardt FG, Haro D: Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator-activated receptor. J Biol Chem 1998, 273(15):8560-8563.
Potthoff MJ, Inagaki T, Satapati S, Ding X, He T, Goetz R, Mohammadi M, Finck BN, Mangelsdorf DJ, Kliewer SA et al: FGF21 induces PGC-1α and regulates carbohydrate and fatty acid metabolism during the adaptive starvation response. Proceedings of the National Academy of Sciences 2009, 106(26):10853-10858.
Sanderson LM, Boekschoten MV, Desvergne B, Muller M, Kersten S (2010) Transcriptional profiling reveals divergent roles of PPARalpha and PPARbeta/delta in regulation of gene expression in mouse liver. Physiological Genomics 41:42e52.