Upstream eventDecreased, PPARalpha transactivation of gene expression
Decreased, Peroxisomal Fatty Acid Beta Oxidation of Fatty Acids
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Directness||Weight of Evidence||Quantitative Understanding|
|Antagonist binding to PPARα leading to body-weight loss||directly leads to||Strong||Strong|
Life Stage Applicability
|Not Otherwise Specified||Not Specified|
How Does This Key Event Relationship Work
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). Inhibition of PPARα transactivation (KE1) results in decreased transcriptional expression for genes that catalyze the peroxisomal fatty acid beta oxidation pathway (Desvergne and Wahili 1999, Kersten 2014, Dreyer et al. 1992, Lazarow 1978) by inhibiting expression of the enzymes involved in peroxisomal fatty acid metabolism. The processes of the KE, peroxisomal fatty acid beta-oxidation, are fairly 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.
Weight of Evidence
PPARα acts as a positive transcriptional regulator for many of the genes involved in peroxisomal 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), hence the KER for the KE, “decreased PPARα transactivation of gene expression” -> the KE “decreased peroxisomal 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).
Biological plausibility of this KER is strong given the supporting relationships cited in the literature described in the previous bullets above.
Empirical Support for Linkage
Include consideration of temporal concordance here
PPARα knock out nullifies downstream expression of transcripts for genes involved in peroxisomal beta-oxidation of fatty acids (Kersten et al 2014).
Uncertainties or Inconsistencies
The KER relationship between the KE, “decreased PPARα transactivation of gene expression” and the KE, “decreased peroxisomal 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 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 peroxisomal fatty acid beta oxidation”.
Evidence Supporting Taxonomic Applicability
The relationships described herein have been primarily established in human and rodent models.
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.
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.