Peroxisomal Fatty Acid Oxidation

Fatty acid oxidation occurs in mitochondria and peroxisomes in most tissues but quantitatively muscle is a major consumer of fat. Although carbohydrates and fatty acids may both be used as fuels for muscle contraction, fatty acids are more calorific... 

Fatty acid utilized by muscle may arise from storage triglycerides from either adipose tissue depot or from lipid stores within the muscle itself. Lipolysis of adipose triglyceride in response to hormonal stimulation liberates free fatty acids (see Section 9.6.2) which are transported through the bloodstream to the muscle bound to albumin. Because the enzymes of fatty acid oxidation are located within subcellular organelles (peroxisomes and mitochondria), there is also need for transport of the fatty acid within the muscle cell this is achieved by fatty acid binding proteins (FABPs). Finally, the fatty acid molecules must be translocated across the mitochondrial membranes into the matrix where their catabolism occurs. To achieve this transfer, the fatty acids must first be activated by formation of a coenzyme A derivative, fatty acyl CoA, in a reaction catalysed by acyl CoA synthetase. 

Cheng, L., Ding, G., Qin, Q., et al. (2004) Cardiomyocyte-restricted peroxisome proUferator-activated receptor-delta deletion perturbs myocardial fatty acid oxidation and leads to cardiomyopathy. Nat. Med. 10,1245-1250. 

Fatty acid oxidation. Seeds, administered orally to rats at a dose of 200 g/kg, increased hepatic mitochondrial and the peroxisomal fatty acid oxidation rate " . Glucosidase inhibition. Ethyl acetate and water soluble fractions of the seed were inactive on the intestine " ... 

Mannaerts G.P. et al., (1979). Mitochondrial and peroxisomal fatty acid oxidation in hver homogenates and isolated hepatocytes from control and clofibrate-treated rats. Journal of Biological Chemistry 254 4585-4595. 

In contrast to the general peroxisome biogenesis defects, patients with X-linked adrenoleucodystrophy, whose very-long-chain fatty acid oxidation is impaired as a result of an uptake defect, show minimal abnormalities of their DHA levels. 

The mitochondrial matrix is the major site of fatty acid oxidation in animal cells, but in certain cells other compartments also contain enzymes capable of oxidizing fatty acids to acetyl-CoA, by a pathway similar to, but not identical with, that in mitochondria In plant cells, the major site of /3 oxidation is not mitochondria but peroxisomes. 

One of the most frequent defects of fatty acid oxidation is deficiency of a mitochondrial acyl-CoA dehydrogenase.50 If the long-chain-specific enzyme is lacking, the rate of P oxidation of such substrates as octanoate is much less than normal and afflicted individuals excrete in their urine hexanedioic (adipic), octanedioic, and decanedioic acids, all products of co oxidation.54 Much more common is the lack of the mitochondrial medium-chain acyl-CoA dehydrogenase. Again, dicarboxylic acids, which are presumably generated by 0) oxidation in the peroxisomes, are present in blood and urine. Patients must avoid fasting and may benefit from extra carnitine. 

A deficiency of very long-chain fatty acid oxidation in peroxisomes is apparently caused by a defective transporter of the ABC type (Chapter 8).55 The disease, X-linked adrenoleukodystrophy (ALD), has received considerable publicity because of attempts to treat it with "Lorenzo s oil," a mixture of triglycerides of oleic and the C22 monoenoic erucic acid. The hope has... 

Hashimoto T, Cook WS, Qi C, Yeldandi AV, Reddy JK, Rao MS. Defect in peroxisome proliferator-activated receptor alpha-inducible fatty acid oxidation determines the severity of hepatic steatosis in response to fasting. J Biol Chem 2000 275 28918-28928. 

Ganning AE, Olsson MJ, Peterson E, et al. 1989. Fatty acid oxidation in hepatic peroxisomes and mitochondria after treatment of rats with di(2-ethylhexyl)phthalate. Pharmacol Toxicol 65 265-268. 

Sharma R, Lake BG, Gibson GG. 1988. Co-induction of microsomal cytochrome P-452 and the peroxisomal fatty acid -oxidation pathway in therat by clofibrate and di-(2-ethylhexyl)phthalate. 

Vega R, Fluss J, Kelly D. the coactivator PGC-1 cooperates with peroxisome proliferator-activated receptor a in transcriptional of nuclear genes encoding mitochondrial fatty acid oxidation enzymes. Mol Cell Biol 2000 20 1868-1876. 

Process of oxidation of very-long-chain fatty acids in peroxisomes... 

A peroxisome proliferator is a chemical that induces peroxisome proliferation in rodent liver and other tissues and includes a wide range of chemicals such as certain herbicides, plasticizers, drugs, and natural products [38,39], The peroxisomes contain hydrogen peroxide and fatty acid oxidation systems important in lipid metabolism and activation of the peroxisome proliferator-activated receptor alpha (PPARa), is considered a key event in peroxisome proliferation in rodent hepatocytes [39], A number of studies have identified... 

Peroxisome proliferator-activated receptors (PPARs) comprise another subfamily of nuclear receptors whose members regulate the transcription of genes controlling fatty acid oxidation, including CYP4A (lauric acid hydroxylases). PPAR a, /3 (also known... 

This hepatomegaly is correlated to PPARa activation of acyl-CoA oxidase (AOX), the first enzyme of peroxisomal /3-oxidation of fatty acids and a gene with a PPRE in its promoter region14. In addition, hepatic mitochondrial /3-oxidation and microsomal w-oxidation of fatty acids are increased, as a direct result of PPARa activation of mRNA of specific enzymes associated with these pathways (carnitine palmitoyl transferase I and cytochrome P4504A, respectively). Activation of fatty acid oxidation by these three pathways would lead to enhanced fatty acid oxidation, given the appropriate substrate. PPARa has also been shown to enhance delivery of fatty acids to the oxidizing systems (Fig. 3). 

---