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Decreased, PPARalpha transactivation of gene expression leads to Decreased, Ketogenesis (production of ketone bodies)
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding||Point of Contact||Author Status||OECD Status|
|Antagonist binding to PPARα leading to body-weight loss||adjacent||Moderate||Moderate||Agnes Aggy (send email)||Open for citation & comment||WPHA/WNT Endorsed|
Life Stage Applicability
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, “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. Ketogenesis is critical to supporting general systemic energy homeostasis in fasting events (Cahill 2006, Evans et al 2004, Sengupta et al 2010), thus KE4 becomes important after short term energy stores (glycogen) become limited (Muoio et al 2002). Le May, et al (2000) have shown decreased ketogenesis in livers of PPAR null mice linked to impaired mitochondrial hydroxymethylglutaryl-CoA synthase (Hmgcs) gene expression.
Evidence Collection Strategy
Evidence Supporting this KER
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 description above.
Uncertainties and 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.
Known modulating factors
Availability of alternative energy substrates may chance the dynamics of this KER.
Ketogenesis is more prevalent in fasted state.
A period of fasting such that available glucose is consumed is usually a pre-requisite for increased ketogenesis.
Known Feedforward/Feedback loops influencing this KER
Ketogenesis diminishes after transition from a fasted state to a fed state.
Domain of Applicability
Evidence provided for human in Cahill (2006), Owen et al (2005) and Williamson et al (1962). Evidence for mouse provided in Kersten et al (1999). Comparative investigations of ketone body formation comparing human and mouse is not well established relative to fatty-acid oxidation comparisons.
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 GF, Jr. Fuel metabolism in starvation. Annu Rev Nutr 2006, 26:1-22.
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.
Kersten S. 2014. Integrated physiology and systems biology of PPARalpha. Molecular Metabolism 2014, 3(4):354-371.
Lazarow, P.B., 1978. Rat liver peroxisomes catalyze the beta oxidation of fatty acids. J. Biol. Chem. 253, 1522-1528.
Le May et al., 2000. Reduced hepatic fatty acid oxidation in fasting PPARK null mice is due to impaired mitochondrial hydroxymethylglutaryl-CoA synthase gene expression. FEBS Lett. 475: 163-166.
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.
Owen OE: Ketone bodies as a fuel for the brain during starvation. Biochem Mol Biol Educ 2005, 33(4):246-251.
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.