Upstream eventFatty Acid Beta Oxidation, Decreased
Decreased, Ketogenesis (production of ketone bodies)
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||Moderate||Low|
Life Stage Applicability
|Adult, reproductively mature||Moderate|
Key Event Relationship Description
Peroxisomes participate in a variety of lipid metabolic pathways including the beta-oxidation of very long-straight chain (<20 C in length) or branched –chain acyl-CoAs (Lazarow 1978, Kersten 2014). The peroxisomal beta-oxidation pathway is not directly coupled to the electron transport chain and oxidative phosporylation, therefore the first oxidation reaction loses energy to heat (H2O2 production) while in the second step, energy is captured in the metabolically accessible form of high-energy electrons in NADH (Mannaerts and Van Veldhoven 1993, Desvergne and Wahli 1999). The peroxisomal beta-oxidation pathway provides fatty acid chain shortening where two carbons are removed in each round of oxidation in the form of acetyl-CoA (Desvergne and Wahli 1999). The shortened chain fatty acids (<20C) can then be transported to the mitochondria to undergo mitochondrial beta-oxidation for complete metabolism of the carbon substrate for cellular energy production (Desvergne and Wahli 1999). Mitochondrial fatty acid beta oxidation catabolizes short, medium and long chain fatty acids (<C20) into acetyl-CoA and ATP. The production of acetyl-CoA monomers is important as they serve as fundamental units for metabolic energy production (ATP) via the citric acid cycle followed by electron-transport chain mediated oxidative phosphorylation (Nelson and Cox, 2000A). Acetyl-CoA is also a fundamental units of energy storage via gluconeogenesis (Nelson and Cox, 2000B) and lipogenesis (Nelson and Cox, 2000C). The liver plays a key role in processing the fundamental energy substrate, acetyl-CoA, into metabolic currencies that contribute to the systemic cellular energy needs of the whole organism. The liver represents a key organ involved in systemic energy distribution given its ability to synthesize glucose (an ability shared only with the kidney, Gerich et al 2001) as well as its exclusive role in the generation of ketone bodies (Cahill 2006, Sengupta et al 2010, Kersten 2014). This is especially important for the metabolic energy needs of the brain which can only use glucose and the ketone body, β-hydroxybutyrate for cellular energy production (Cahill 2006, Owen 2005, Kersten 2014). Therefore, the KE, “ketogenesis (production of ketone bodies)” is critical to supporting general systemic energy homeostasis in fasting events (Cahill 2006, Evans et al 2004, Sengupta et al 2010).
Evidence Supporting this KER
The KER scores for weight of evidence for the KE, “fatty acid beta oxidation” -> the KE, “ketogenesis (production of ketone bodies)” was considered “strong” given that the former serves as a primary source of substrate for the latter (Badman et al. 2007, Potthoff et al. 2009). Interference with ketogenesis, for example by PPARα inhibition, has been demonstrated to inhibit β-hydroxybutyrate production (measured in serum) during fasting events in mice (Badman et al 2007, Potthoff 2009, Sengupta et al 2010). The quantitative understanding score for this KER was considered “moderate” given that weight of evidence for the individual KEs was robust and the results in a study by Badman et al (2007) indicating that metabolism of fatty acid substrates (measured as liver triglycerides) that would otherwise contribute to β-hydroxybutyrate production was additionally inhibited under PPARα knockout. Further, 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.
Biological plausibility of this KER is strong given the supporting relationships cited in the literature described in the previous bullets above.
As described in the previous sections, there is a fundamental linkage between KEs given that the KE, “fatty acid beta oxidation” produces raw materials that are used in the KE, “ketogenesis (production of ketone bodies)”. It is less clear how essential the former is to a sustainable throughput of the latter especially given that the latter can utilize substrates that can be produced by various other cellular energy processing pathways in addition to mitochondrial fatty acid beta oxidation.
Uncertainties and Inconsistencies
Additional investigations tracing substrate processing, specifically from sources resulting from the KE, “fatty acid beta oxidation” under control as well as starvation conditions would supplement current understanding of the connections between the KE, “fatty acid beta oxidation” and the KE, “ketogenesis (production of ketone bodies)”.
Quantitative Understanding of the Linkage
As discussed in the previous sections, the degree to which the, KE “fatty acid beta oxidation” affects the KE, “ketogenesis (production of ketone bodies)” is not well described, neither are modulators of the response-response relationships. Certainly, the pathways are interrelated and connected by PPARα as the master regulator of each process, so additional modulators related to resource availability and cellular signaling require exploration. We are not currently aware of any models available to extrapolate results among KEs.
Known modulating factors
Availability of alternative energy substrates may chance the dynamics of this KER.
Known Feedforward/Feedback loops influencing this KER
Ketogenesis diminishes after transition from a fasted state to a fed state.
Domain of Applicability
The relationships described herein have been primarily established in human and rodent models. Comparative investigations of ketone body formation comparing human and mouse is not well established relative to fatty-acid oxidation comparisons.
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)
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.
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.
Muoio, D.M., MacLean, P.S., Lang, D.B., Li, S., Houmard, J.A., Way, J.M., Winegar, D.A., Corton, J.C., Dohm, G.L., Kraus, W.E., 2002. Fatty acid homeostasis and induction of lipid regulatory genes in skeletal muscles of peroxisome proliferator-activated receptor (PPAR) alpha knock-out mice. Evidence for compensatory regulation by PPAR delta. J. Biol. Chem. 277, 26089-26097.
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.