Upstream eventDecreased, PPARalpha transactivation of gene expression
Decreased, Ketogenesis (production of ketone bodies)
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||Moderate||Not Specified|
|Mus musculus||Mus musculus||Strong||NCBI|
|Homo sapiens||Homo sapiens||Strong||NCBI|
|Rattus rattus||Rattus rattus||Strong||NCBI|
Life Stage Applicability
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). The KE, “decreased PPARα transactivation of gene expression” results in the KE, “decreased transcriptional expression for genes that catalyze ketogenesis” (Cahil 2006, Kersten et al. 2014, Sengupta et al. 2010, Desvergne and Wahli 1999) by inhibiting expression of the enzymes involved in ketogenesis. Enzyme description (Kersten 2014, Sengupta et al. 2010) and metabolic flux examinations (Sengupta et al. 2010) additionally providing fairly robust characterization in support of the KER.
Weight of Evidence
Inhibition of PPARα signaling has been demonstrated to inhibit transcriptional expression of genes that catalyze ketogenesis as well as ketone body production (Badman et al 2007, Potthoff 2009, Sengupta 2010) affecting circulating levels of ketone bodies for systemic use. Kersten et al (1999) demonstrated that PPARα is induced in fasted mice mobilizing the oxidation of fatty acids for energy production. In that study, PPARα-null mice did not actively induce fatty acid oxidation or ketogenesis leaving the mice unable to meet energy demands during fasting and leading to hypoglycemia, hyperlipidemia, hypoketonemia and fatty liver. Upstream metabolic events, such as the KEs “peroxisomal fatty acid beta oxidation” and “mitochondrial fatty acid beta oxidation” play a key role in producing substrates for ketogenesis. Although the connection between the KE, “decreased PPARα transactivation of gene expression” -> the KE, “decreased ketogenesis” is well established given the literature cited above, the dependency on the KEs “peroxisomal fatty acid beta oxidation” and “mitochondrial fatty acid beta oxidation” for substrate availability can affect the KE, “decreased ketogenesis” in addition to the influence of the up-stream KE, “decreased PPARα transactivation of gene expression, therefore we scored the KER for the KE, “decreased PPARα transactivation of gene expression” -> the KE, “Ketogenesis (production of ketone bodies)” as “moderate”.
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
Given that inhibition of PPARα transactivation results in downstream inhibition of transcriptional expression for the genes that catalyze ketogenesis, as well as ketone body production (Badman et al 2007, Potthoff 2009, Sengupta 2010), that KE occurs prior to the KE of decreased ketogenesis.
Uncertainties or Inconsistencies
A critical data gap regarding this AOP is an absence of studies that have investigated the effects null mutants for ketogenesis on the physiology and individual performance during long term starvation relative to wild type individuals.
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?
Enzyme description (Kersten 2014, Sengupta et al. 2010) and metabolic flux examinations (Sengupta et al. 2010) additionally providing fairly robust characterization in support for the KE of decreased ketogenesis. Little dose-response information is available regarding decreased transcriptional expression of genes involved in ketogenesis and ketone body production.
Evidence Supporting Taxonomic Applicability
The relationships described herein have been primarily established in human and rodent models.
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.
Cahill Jr., G.F., 2006. Fuel metabolism in starvation. Annual Review of Nutrition 26:1e22.
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.
Kersten S. 2014. Integrated physiology and systems biology of PPARalpha. Molecular Metabolism 2014, 3(4):354-371.
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.
Sengupta S, Peterson TR, Laplante M, Oh S, Sabatini DM: mTORC1 controls fasting-induced ketogenesis and its modulation by ageing. Nature 2010, 468(7327):1100-1104.