Key Event Title
|Level of Biological Organization|
Key Event Components
|fatty acid beta-oxidation||fatty acid||decreased|
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP|
|GR activation leading to hepatic steatosis||KeyEvent|
|Homo sapiens||Homo sapiens||High||NCBI|
|Mus musculus||Mus musculus||High||NCBI|
|Not Otherwise Specified||Not Specified|
Key Event Description
PPARα acts as a positive transcriptional regulator for many of the genes involved in mitochondrial 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). Thus, decreased PPARα nuclear signaling results in decreased transcriptional expression of genes that are regulated by PPARα, and subsequently, decreased expression of the coded proteins and enzymes that ultimately decrease fatty acid metabolism within the mitochondria.
Genes Involved: 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).
Metabolism Affected: Mitochondrial processing of fatty acids involves: (1) Import of short, medium and long chain fatty acids (<C20) acyl-CoAs into the mitochondria by carnitine palmitoyl-transferases 1a, 1b, and 1 (Cpt1a, Cpt1b, Cpt2) and acyl-carnitine translocase (Slc25a20, Brandt et al 1998; Mascaro et al 1998, Kersten et al 2014). (2) The first step of beta-oxidation catalyzed by the length-specific acyl-CoA hydrogenases (Acadvl, Acadl, Acadm, Acads; Aoyama et al 1998, Gulick et al 1994, Kersten et al 2014). (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, Kersten et al 2014). These enzymes are replaced upon progressive chain shortening by Hadh and Acaa2 (Kersten et al 2014). (4) The conversion of unsaturated and 2-methylated acetyl-CoAs into intermediates of beta-oxidation are catalyzed by Eci1, Eci2, Decr1, and Hsd17b10 (Sanderson et al 2008, Aoyama et al 1998, Kersten et al 2014).
How It Is Measured or Detected
Beta oxidation of fatty acids in mitochondria has been measured using mouse liver homogenates where a radio-labeled fatty acid substrate was reacted for 30 minutes and then centrifuged to separate reaction products for fractional radioactivity measurements (Aoyama et al 1998). Comparative measures of reaction products were also measured where potassium cyanide was added to the reaction mixture to inhibit mitochondrial beta oxidation activity to normalize the contribution of mitochondrial enzymatic reactions to the overall reaction product (Aoyama et al 1998).
Various methods were used for gene expression investigations. Brandt et al (1998) investigated concentration response effects of Oleate, Decanoate and Hexanoate fatty acid chains on mitochondrial carnitine palmitoyl-transferases I (M-CPT I) expression using promoter-reporter plasmid MCPT.Luc.1025 reporter transfected into rat neonate cardiac myocytes. Human M-CPT I was investigate using an analogous method (Brandt et al 1998). Expression of human medium chain acyl-CoA dehydrogenase (MCAD) was investigated using a MCAD.luc.1054 reporter transfected into HepG2 cells in response to fatty acids with various chain lengths (Gulick et al 1994). Investigation of various enzymes involved in hepatic fatty acid metabolism described in Aoyama et al (1998) were investigated using Western immunoblot quantitiation.
Domain of Applicability
Human (as reviewed in Brandt et al 1998, Evans et al 2004, Gulick et al 1994, Kersten 2014 and Desvergne and Wahli 1999). Mouse (as measured in Aoyama et al 1998, and as reviewed in Kersten 2014 and Desvergne and Wahli 1999).
Evidence for Perturbation by Stressor
Aoyama, T., Peters, J.M., Iritani, N., Nakajima, T., Furihata, K., Hashimoto, T., et al., 1998. Altered constitutive expression of fatty acid-metabolizing enzymes in mice lacking the peroxisome proliferator-activated receptor alpha (PPARalpha). Journal of Biological Chemistry 273:5678e5684.
Brandt, J.M., Djouadi, F., Kelly, D.P., 1998. Fatty acids activate transcription of the muscle carnitine palmitoyltransferase I gene in cardiac myocytes via the peroxisome proliferator-activated receptor alpha. Journal of Biological Chemistry 273:23786e23792.
Desvergne B, Wahli W (1999) Peroxisome proliferator-activated receptors: nuclear control of metabolism. Endocrine Reviews 20(5): 649-688.
Gulick, T., Cresci, S., Caira, T., Moore, D.D., Kelly, D.P., 1994. The peroxisome proliferator-activated receptor regulates mitochondrial fatty acid oxidative enzyme gene expression. Proceedings of the National Academy of Sciences of the United States of America 91:11012e11016.
Kersten S. 2014. Integrated physiology and systems biology of PPARalpha. Molecular Metabolism 2014, 3(4):354-371.
Mascaro, C., Acosta, E., Ortiz, J.A., Marrero, P.F., Hegardt, F.G., Haro, D., 1998. Control of human muscle-type carnitine palmitoyltransferase I gene transcription by peroxisome proliferator-activated receptor. Journal of Biological Chemistry 273:8560e8563.
Sanderson, L.M., de Groot, P.J., Hooiveld, G.J., Koppen, A., Kalkhoven, E., Muller, M., et al., 2008. Effect of synthetic dietary triglycerides: a novel research paradigm for nutrigenomics. PLoS One 3:e1681.