Fatty acid oxidation peroxisomal system

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... 

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). 

Recent studies have indicated that in addition to mitochondria, peroxisomes are capable of removing acetyl-CoA moieties from long-chain fatty acids. The peroxisomal P-oxidative pathway is different in two major respects from the mitochondrial system. First, the hydrogen atoms removed are oxidized to water via H2O2. This process does not generate energy in the form of ATP. Second, peroxisomal P-oxidation stops when octanoyl-CoA (C8-C0A) is produced. 

The concept of a peroxisome being a closed compartiment also requires transport systems for fatty acids which undergo oxidation in the peroxisome. Since oxidation of fatty acids in peroxisomes is incomplete, the peroxisome must also have systems to allow export of chain-shortened fatty acids. Recent evidence notably in yeast suggests that... 

Direct measurement of peroxisomal fatty acid oxidation has shown that particularly hydrogenated fish oil and hydrogenated rapeseed oil increased the activity of the peroxisomal P-oxidation enzyme system [7]. 

The most important substrates handled by the peroxisomal fatty acid oxidation system from the perspective of peroxisomal disorders are (1) very-long-chain fatty acids (VLCFA), notably hexacosanoic acid (C26 0), (2) pris-tanic acid (2,6,10,14-tetramethylpentadecanoic acid), as derived from dietary sources either directly or indirectly from phytanic acid and (3) di- and trihydroxycholestanoic acid (DHCA and THCA). The latter two compounds are intermediates in the formation of the primary bile acids cholate and chenodeoxycholate from cholesterol in the liver. 

Both EPA and C14-S-acetic acid are converted to their respective CoA esters in mitochondria. Furthermore, in contrast to DHA-CoA, EPA-CoA and C14-S-acetyl-CoA are easily transferred into the mitochondria by the CAT system. EPA is more difficult to oxidize than saturated and monounsaturated fatty acids, due to the double bonds and C14-S-acetic acid is non-oxidizable by P-oxidation,due to the sulfur atom in 3-position. Thus, accumulation of their respective CoA esters in the mitochondria might give an fatty acid overload signal leading to inaeased mitochondrial fatty acid oxidation. C14-S-acetic acid mimics the effects of peroxisome proliferators such as the fibrates and it was recently shown that it may be a ligand for the peroxisome proliferating activated receptor (PPAR) a. As administration of the 3-thia fatty acids seem to force EPA to the mitochondria, an additional fish oil effect might be seen. 

A modified form of P-oxidation is found in peroxisomes and leads to the formation of acetyl-CoA and H2O2 (from the flavoprotein-linked dehydrogenase step), which is broken down by catalase. Thus, this dehydrogenation in peroxisomes is not linked directly to phosphorylation and the generation of ATP. The system facilitates the oxidation of very long chain fatty acids (eg, Cjq, C22). These enzymes are induced by... 

A second important difference between mitochondrial and peroxisomal fi oxidation in mammals is in the specificity for fatty acyl-CoAs the peroxisomal system is much more active on very-long-chain fatty acids such as hexacosanoic acid (26 0) and on branched-chain fatty acids such as phytanic acid and pristanic acid (see Fig. 17-17). These less-common fatty acids are obtained in the diet from dairy products, the fat of ruminant animals, meat, and fish. Their catabolism in the peroxisome involves several auxiliary enzymes unique to this organelle. The inability to oxidize these compounds is responsible for several serious human diseases. Individuals with Zellweger syndrome are unable to make peroxisomes and therefore lack all the metabolism unique to that organelle. In X-linked adrenoleukodystrophy (XALD), peroxisomes fail to... 

Wanders, R.J.A., van Grunsven, E.G., Jansen, G.A. (2000) Lipid metabolism in peroxisomes enzymology, functions and dysfunctions of the fatty acid a- and /3-oxidation systems in humans. Biochem. Soc. 7fans. 28, 141-148. 

Under fasting, fatty acids and glycerols derived from triglyceride in WAT are used as fuel during mitochondrial / -oxidation, and the byproduct of this oxidation generates ketone bodies, which are a major fuel source for the brain under starvation [86]. Moreover, fasting activates the mitochondrial / -oxidation, peroxisomal / -oxidation, and microsomal a -oxidation system... 

Figure 2.7. The complex pathways and processes involved in fat catabolism in vertebrate tissues such as cardiac and skeletal muscles. FFAs arrive at the cell boundary either via VLDL or albumin-associated and enter the cell either by simple diffusion or through transporters. In the cytosol, FFAs are bound by FABPs, which increase the rate and amount of FFA that can be transferred to sites of utilization. Shorter chain FFAs are converted to acetylCoA in peroxisomes longer chain FFAs are directly transferred to mitochondria (via a complex system involving acylcarnitines) as long-chain acylCoA derivatives these enter the /6-oxidation spiral and are released as acetylCoA for entrance into the Krebs or citric acid cycle in the mitochondrial matrix. Fatty acid receptors (FARs) in the nucleus bind to fatty acid response elements (FAREs) and in turn regulate the production of enzymes in their own metabolism. (Modified from Veerkamp and Maatman, 1995.)...

In summary, substantial progress has been made over the past few years in understanding the cytoplasmic organelle peroxisome and factors that alter its normal functions. Peroxisome proliferator-in-duced increase in the liver peroxisomes is associated with an approximately two-fold increase in catalase activity and several-fold increases in the activity of the peroxisomal fatty acid jS-oxidation system. It is also evident from the available literature that hepatic peroxisomal proliferation appears to be a carcinogenic event in rodents, and this may depend on the potency of the inducer. However, there is no single mechanism that is attributed to the peroxisome proliferation or carcinogenesis induced by... 

A small proportion of our diet consists of very-long-chain fatty acids (20 or more carbons) or branched-chain fatty acids arising from degradative products of chlorophyll. Very-long-chain fatty acid synthesis also occurs within the body, especially in cells of the brain and nervous system, which incorporate them into the sphin-golipids of myelin. These fatty acids are oxidized by peroxisomal p- and a-oxidation pathways, which are essentially chain-shortening pathways. 

LCFA oxidation occurs mairily in mitochondria but rat liver microsomes and peroxisomes contain also both membrane-bound/malonyl-CoA-sensitive and soluble/ malonyl-CoA-insensitive (luminal) CPT-like enzymes. " Thus, a similar fatty acid transport system operates in mitochondria, peroxisomes and microsomes, but it seems that the components involved in these systems are all different. The physiological role of these fatty acid transport systems in microsomes and peroxisomes remains unclear. The microsomal CPTs may have a role in providing fatty acids for transport of proteins through the Golgi apparatus and for acylation of secreted proteins. Since oxidation of very long-chain fatty acids is confined to peroxisomes, a possible role for the peroxisomal CPTs may be to shuttle chain-shorted products out of peroxisomes for further oxidation in mitochondria. 

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