Key Event Overview
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AOPs Including This Key Event
|AOP Name||Event Type||Essentiality|
|Antagonist binding to PPARalpha leading to starvation-like body-weight loss||KE||Strong|
|Homo sapiens||Homo sapiens||Strong||NCBI|
|Mus musculus||Mus musculus||Strong||NCBI|
Level of Biological Organization
How this Key Event works
PPARα is a nuclear transcription factor that controls the transcription of a variety of genes involved in lipid catabolism and energy production pathways (Desvergne and Wahli 1999, Kersten 2014). Fatty acids serve as the ligands that stimulate PPARα nuclear signaling where the fatty acids (likely in association with fatty acid binding proteins) bind to the ligand binding domain or PPARα along with co-activators to the PPARα regulatory complex initiating the transcription of genes that metabolize the fatty acids (Wolfrum et al. 2001, Desvergne and Wahli 1999, Kersten 2014, Xu et al 2001). PPARα regulates expression of genes encoding nearly every enzymatic step of fatty acid catabolism including fatty acid uptake into cells, fatty acid activation to acyl-CoAs, and the release of cellular energy from fatty acids through the oxidative breakdown of acyl-CoAs to acetyl-CoA , and in starvation conditions, the repackaging of Acetyl-CoA substrates into ketone bodies via ketogenesis pathways (Kersten 2014, Desvergne and Wahli 1999, Evans et al 2004). A pathway-level schematic for PPARα transactivation is illustrated in KEGG Pathway map03320 providing the specific gene targets and associated functional responses that are transcriptionally regulated by PPARα.
Detailed description of important pathways regulated by PPARα transactivation:
Peroxisomal fatty acid beta oxidation: 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). The first gene target identified for PPARα was Acyl-CoA oxidase (Acox1, Dreyer et al 1992) which represents the first enzyme in peroxisomal long-chain fatty acid oxidation (Kersten 2014) and is also the rate-limiting enzyme in this pathway (Desvergne and Wahili 1999). In addition to Acox1, a variety of additional enzymes involved in peroxisomal fatty acid metabolism are under transcriptional control of PPARα transactivation including enzymes that facilitate fatty acid uptake into the peroxisome (Abcd1, Abcd2 and Abcd 3), conversion of acyl-CoA/acetyl-CoA to acyl-carnitine/acetyl-carnitine (Crot/Crat), and conversion of acyl-CoAs back to fatty acids via thioesterases (Acots, as reviewed in Kersten 2014). PPARalpha also has transcriptional control over enzymes downstream of Acox1 in the peroxisomal beta-oxidation of acyl-CoA pathway including L-bifunctional enzyme (Ehhadh), D-bifunctional enzyme (Hsd17b4), and peroxisomal 3-ketoacyl-CoA thiolase activity (Acaa1a, Acaa1b, as reviewed in Kersten 2014).
Mitochondrial fatty acid beta oxidation: As reviewed in Kersten (2014), the genes (and associated functions) regulated by PPARα in the mitochondrial processing of fatty acids include the following: (1) Import of acyl-CoAs into the mitochondria is facilitated by PPARalpha-induced increases in expression of carnitine palmitoyl-transferases 1a, 1b, and 1 (Cpt1a, Cpt1b, Cpt2) and acyl-carnitine translocase (Slc25a20, Brandt et al 1998; Mascaro et al 1998). (2) The first step of mitochondrial beta-oxidation is catalyzed by length-specific acyl-CoA hydrogenases (Acadvl, Acadl, Acadm, Acads; Aoyama et al 1998, Gulick et al 1994). (3) The three subsequent steps in mitochondrial beta-oxidation that successively release acetyl-CoAs from the hydrocarbon chain are catalyzed by the mitochondrial trifunctional enzyme (Hadha and Hadhb). These enzymes are replaced upon progressive chain shortening by Hadh and Acaa2. (4) the final PPARalpha targets include Eci1, Eci2, Decr1, and Hsd17b10 which convert unsaturated and 2-methlylated aclyl-CoAs into intermediates of beta-oxidation (Sanderson et al 2008, Aoyama et al 1998).
Ketogenesis: Not only does PPARalpha induce the upstream production of the raw materials for use in ketogenesis through fatty acid beta-oxidation (see peroxisomal and mitochondrial fatty acid beta oxidation above), but also directly induces key enzymes in the ketogenesis pathway including Hmgcs2, Hmgcl and Acat1 (Kersten et al 2014). PPARalpha is recognized as the master transcriptional activator of ketogenic genes (Sengupta et al 2010, Desvergne and Wahli 1999).
How it is Measured or Detected
Methods that have been previously reviewed and approved by a recognized authority should be included in the Overview section above. All other methods, including those well established in the published literature, should be described here. Consider the following criteria when describing each method: 1. Is the assay fit for purpose? 2. Is the assay directly or indirectly (i.e. a surrogate) related to a key event relevant to the final adverse effect in question? 3. Is the assay repeatable? 4. Is the assay reproducible?
A variety of transcript expression assays have been used to demonstrate the effect of PPARα signaling inhibition on downstream transcript expression (see literature cited above for specific methods within each investigation). A global screen for PPARα transcriptional targets (especially those involved in fatty acid metabolism) is provided in Rakhshandehroo et al (2007) which utilized microarray based expression screening followed by RT-qPCR and in silico screening of putative PPAR response elements.
Evidence Supporting Taxonomic Applicability
Mus musculus (Kersten 2014), Homo sapiens in clinical observations (Kersten 2014) and in in vitro assays (reviewed in Kersten 2014).
Aoyama T, Peters JM, Iritani N, Nakajima T, Furihata K, Hashimoto T, Gonzalez FJ: Altered Constitutive Expression of Fatty Acid-metabolizing Enzymes in Mice Lacking the Peroxisome Proliferator-activated Receptor α (PPARα). J Biol Chem 1998, 273(10):5678-5684.
Brandt JM, Djouadi F, Kelly DP: Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor alpha. J Biol Chem 1998, 273(37):23786-23792.
Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine Reviews 20(5): 649-688.
Dreyer C, Krey G, Keller H, Givel F, Helftenbein G, Wahli W: Control of the peroxisomal beta-oxidation pathway by a novel family of nuclear hormone receptors. Cell 1992, 68(5):879-887.
Gulick T, Cresci S, Caira T, Moore DD, Kelly DP: The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proc Natl Acad Sci U S A 1994, 91(23):11012-11016.
Kersten S. 2014. Integrated physiology and systems biology of PPARalpha. Molecular Metabolism 2014, 3(4):354-371.
Mascaró C, Acosta E, Ortiz JA, Marrero PF, Hegardt FG, Haro D: Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator-activated receptor. J Biol Chem 1998, 273(15):8560-8563.
Rakhshandehroo M, Sanderson LM, Matilainen M, Stienstra R, Carlberg C, de Groot PJ, Muller M, Kersten S: Comprehensive analysis of PPARalpha-dependent regulation of hepatic lipid metabolism by expression profiling. PPAR research 2007, 2007:26839.
Sanderson LM, Boekschoten MV, Desvergne B, Müller M, Kersten S: Transcriptional profiling reveals divergent roles of PPARα and PPARβ/δ in regulation of gene expression in mouse liver, vol. 41; 2010.
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.
Xu HE, Lambert MH, Montana VG, Plunket KD, Moore LB, Collins JL, Oplinger JA, Kliewer SA, Gampe RT, McKee DD et al: Structural determinants of ligand binding selectivity between the peroxisome proliferator-activated receptors. Proceedings of the National Academy of Sciences 2001, 98(24):13919-13924.
Xu HE, Stanley TB, Montana VG, Lambert MH, Shearer BG, Cobb JE, McKee DD, Galardi CM, Plunket KD, Nolte RT et al: Structural basis for antagonist-mediated recruitment of nuclear co-repressors by PPAR[alpha]. Nature 2002, 415(6873):813-817.