Fatty beta-oxidation

Mortensen PB. C6-C10-dicarboxyUc aciduria in starved, fat-fed and diabetic rats receiving decanoic acid or medium-cbain triacylglycerol. An in vivo measure of the rate of beta-oxidation of fatty acids. Biochim BiophysActa, 1981, 664(2), 349-355. 

Wood PA Defects in mitochondrial beta-oxidation of fatty acids. CurrOpin Lipidol 1999 10 107. 

Fatty acid beta-oxidation Inhibition by valproate, tetracyclines, nonsteroidal antiinflammatory drugs, antianginal cationic amphiphilic drugs, female sex hormones, CoA depleters such as valproate and salicylate... 

Labbe, G. et al. (1991) Effects of various tetracycline derivatives on in vitro and in vivo beta-oxidation of fatty acids, egress of triglycerides from the liver, accumulation of hepatic triglycerides, and mortality in mice. Biochemical Pharmacology, 41 (4), 638-641. 

Interconversion between ACAC and is dependent upon the NADiNADH ratio. Hydroxybutyrate dehydrogenase (HBDH) is localised mainly in the mitochondria. During fasting, fatty acids are transported to the liver to undergo beta oxidation. 

Ensenauer R, He M, Willard JM, et al (2005) Human acyl-CoA dehydrogenase-9 plays a novel role in the mitochondrial beta-oxidation of unsaturated fatty acids. J Biol Chem 280 32309-32316... 

Giak Sim K, Carpenter K, Hammond J, Christodoulou J, Wilcken (2002) Quantitative fibroblast acylcarnitine profiles in mitochondrial fatty acid beta-oxidation defects phenotype/me-tabolite correlations. Mol Genet Metab 76 327-334... 

Jakobs BS, Wanders RJ (1995) Fatty acid beta-oxidation in peroxisomes and mitochondria the first, unequivocal evidence for the involvement of carnitine in shuttling propionyl-CoA from peroxisomes to mitochondria. Biochem Biophys Res Commun 213 1035-1041... 

To date there are no true inborn errors associated with essential fatty acid metabolism. However, we do know that the final step of DHA formation is the peroxisomal beta-oxidation of a homologous C24 fatty acid [7]. Consequently, patients with a generalised defect of peroxisomal function, such as Zellweger syndrome, are prone to develop deficiencies of essential fatty acids including DHA [9]. 

In order to carry out all of these different functions, peroxisomes are equipped with a unique set of enzyme proteins, catalysing the different reactions involved. In addition, the peroxisomal membrane contains specific transporters in order to take up substrates from the cytosol and release the end products of peroxisomal metabolism. Since peroxisomes lack a citric acid cycle as well as a respiratory chain, the end products of peroxisomal metabolism, such as acetyl-CoA, propionyl-CoA and a range of other acyl-Co A esters predominantly derived from fatty acid beta-oxidation, are exported from the peroxisomal interior and shuttled to mitochondria for full oxidation to C02 and H20. The same applies to the NADH produced during beta-oxidation, which is reoxidised via redox-shuttles so that the NADH generated in peroxisomes is ultimately reoxidised in the mitochondrial respiratory chain at the expense of molecular oxygen. 

Figure 17.4 Parallel beta oxidation pathways for a xenobiotic substituted benzene, 5-phenyl pen-tanoic acid, and a naturally occurring fatty acid, stearic acid (Nelson and Cox, 2000).

Side effects. The common dose-related side effects of valproate include nausea, vomiting and gastrointestinal distress weight gain is frequent (estimated as high as 30%) and may be associated with a drug-induced decrease in the beta oxidation of fatty acids. Sedation is also frequent. Alopecia is an unusual side effect of valproate, possibly caused by an abnormal metabolite. Valproate has a number of metabolically linked side... 

Fatty acids are cleaved from triglycerides and metabolized through beta oxidation. This process is shown in Figure 12.41. This process clips the fatty acids into two-carbon fragments. The two-carbon fragments emerge from beta oxidation as acetyl CoA. Each acetyl CoA molecule is accompanied by the production of an NADH and a QHr Of course, when the chain is finally cut down to just two carbons, they are as an acetyl CoA. Since there are no carbon-carbon bonds to oxidatively cleave, no NADH or QH2 are produced. 

In mammals, complex lipids are catabolised by lipases to yield fatty acids, glycerol and other components. The fatty acids are then broken down by beta-oxidation to give NADH, reduced flavoprotein and acetyl-CoA, which then enters the tricarboxylic acid cycle. Lipase activity has been detected in several cestodes (513, 772) but there is no evidence for an active beta-oxidation sequence in any species investigated to date. Somewhat surprisingly, however, some of the beta-oxidation enzymes have been... 

The authors suggested that this patient had a defect in lipid metabolism, based on the muscle biopsy. Muscle mitochondria are a principle site for beta-oxidation of fatty acids. Microvesicular steatosis can progress to liver failure with severe and prolonged impairment of beta-oxidation. This metabolic defect may have exacerbated the direct toxic effects of cocaine. 

Cleavage of the ether linkage of the 2,4-dichlorophenoxyalkanoic acids by a strain of Flavobacterium to yield the intact alkanoic acid and 2,4-dichlorophenol has also been observed (34,35). The intact alkanoic acid is further metabolized by beta oxidation. The bacterium produced the free fatty acid corresponding to the aliphatic moieties of six omega-linked dichlorophenoxyalkanoic acids in the series from 3-(2,4-dichloro-phenoxy) propionic acid to 8-(2,4-dichlorophenoxy)octanoic acid. 

Sohlenius, A. K., Eriksson, A. M., Hogstrom, C., Kimland, M., Depierre, J. W. Perfluorooctane sulfonic acid is a potent inducer of peroxisomal fatty-acid beta-oxidation and other activities known to be affected by peroxisome proliferators in mouse liver. Pharmacol Toxicol, 72 90-93... 

Yonssef JA, Song WO, and Badr MZ (1997) Mitochondrial, bnt not peroxisomal, beta-oxidation of fatty acids is conserved in coenzyme A-deflcient rat liver. Molecular and Cellular Biochemistry 175,37-42. 

Chemicals that damage mitochondrial structure, enzymes, or DNA synthesis can disrupt beta oxidation of hpids and oxidative energy production within hepatocytes. Prolonged interruption of beta oxidation leads to micro-vesicular steatosis which can progress to macrovesicular steatosis. This sequence of events has been noted with alcoholic and nonalcoholic steatohepatitis. The role of mitochondria has been extensively studied with nonalcoholic fatty hver disease, a major issue in human medicine. Alcoholic steatosis and other forms of hepatic steatosis have been linked to impairment of ATP homeostasis and mitochondrial abnormalities have been reported in a growing body of hterature. 

There are several drugs that inhibit beta oxidation of fatty acids in mitochondria leading to lipid accumulation, such as aspirin, valproic acid, and tetracyclines. 

R.J. Wanders, E G van Grunsven, and GA. Jansen. 2000. Lipid metabolism in peroxisomes Enzymology, functions and dysfunctions of the fatty acid alpha- and beta-oxidation systems in humans Biochem. Soc. Trans. 28 141-149. (PubMed)... 

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