Upstream eventDecreased, PPARalpha transactivation of gene expression
Fatty Acid Beta Oxidation, Decreased
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||High|
Life Stage Applicability
|Adult, reproductively mature||High|
Key Event Relationship Description
PPARα acts as a positive transcriptional regulator for many of the genes involved in peroxisomal and mitochondrial fatty acid beta oxidation as well as genes involved in the pre- and post-processing of fatty acids in peroxisomal pathways (Desvergne and Wahili 1999, Kersten 2014). Inhibition of PPARα transactivation (KE1) results in decreased transcriptional expression for genes that catalyze the peroxisomal and mitochondrial fatty acid beta oxidation pathways (Desvergne and Wahili 1999, Kersten 2014, Dreyer et al. 1992, Lazarow 1978) by inhibiting expression of the enzymes involved in fatty acid metabolism. The processes involved in both peroxisomal and mitochondrial fatty acid beta-oxidation, are well described in the literature including good coverage of the gene products that catalyze the metabolic reactions (Kersten 2014) with reasonable characterization of metabolic flux (Mannaerts and Van Veldhoven 1993, Desvergne and Wahli 1999), thus the WOE scores for KER were in the medium to medium-high range.
Evidence Supporting this KER
PPARα acts as a positive transcriptional regulator for many of the genes involved in both peroxisomal and mitochondrial fatty acid beta oxidation as well as genes involved in the pre- and post-processing of fatty acids in both pathways (Desvergne and Wahili 1999, Kersten 2014), hence the KER for the KE, “decreased PPARα transactivation of gene expression” -> the KE “decreased fatty acid beta oxidation” received the score of “strong”. Peroxisomal fatty acid beta oxidation 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 downstream KE, “mitochondrial fatty acid beta-oxidation” (as reviewed in Kersten et al. 2014 and Desvergne and Wahli 1999). Mitochondrial processing of fatty acids involves: (1) Import of short, medium and long chain fatty acids (<C20) acyl-CoAs into the mitochondrial, (2) beta-oxidation catalyzed by the length-specific acyl-CoA hydrogenases, (3) release acetyl-CoAs from the hydrocarbon chain and, (4) conversion of unsaturated and 2-methylated acetyl-CoAs into intermediates for beta-oxidation (Brandt et al 1998, Gulick et al 1994, Mascaro et al 1998, Sanderson et al 2008, Aoyama et al 1998, Kersten et al 2014).
Biological plausibility of this KER is strong given the supporting relationships cited in the literature described in the previous bullets above.
PPARα knock out nullifies downstream expression of transcripts for genes involved in both peroxisomal and mitochondrial beta-oxidation of fatty acids (Kersten et al 2014).
Uncertainties and Inconsistencies
The KER relationship between the KE, “decreased PPARα transactivation of gene expression” and the KE, “decreased 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
A large body of research demonstrated that PPARα nuclear signaling directly controls transcriptional expression for genes catalyzing peroxisomal beta-oxidation of very long chain fatty acids (>20C), mitochondrial beta-oxidation of short, medium and long chain fatty acids (<20C), and ketogenesis (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 KE, “decreased PPARα transactivation of gene expression” -> the KE, “decreased fatty acid beta oxidation”.
Rapid Molecular Interactions.
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 although the processes are fundamental in biology and likely broadly conserved.
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.
Brandt, J.M., Djouadi, F., Kelly, D.P., 1998. Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor alpha. Journal of Biological Chemistry 273:23786e23792.
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.
Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W (1992) Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell 68(5):879-887.
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, D.D., Kelly, D.P., 1994. The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proceedings of the National Academy of Sciences of the United States of America 91:11012e11016.
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.
Mascaro, C., Acosta, E., Ortiz, J.A., Marrero, P.F., Hegardt, F.G., Haro, D., 1998. Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator-activated receptor. Journal of Biological Chemistry 273:8560e8563.
Sanderson, L.M., de Groot, P.J., Hooiveld, G.J., Koppen, A., Kalkhoven, E., Muller, M., et al., 2008. Effect of synthetic dietary triglycerides: a novel research paradigm for nutrigenomics. PLoS One 3:e1681.