Event:860

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Event Title

Mitochondrial Fatty Acid Beta Oxidation, Decreased

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

Taxonomic Applicability

Name Scientific Name Evidence Links
Homo sapiens Homo sapiens Strong NCBI
Mus musculus Mus musculus Strong NCBI

Level of Biological Organization

Biological Organization
Molecular

How this Key Event works

Mitochondrial 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).

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

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?

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.

Evidence Supporting Taxonomic 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).

References


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.

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.

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.