Peroxisomal oxidation

Peroxisomes Oxidize Very Long Chain Fatty Acids... 

Mectianism of Action A combination of ethyl esters of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) that inhibits acyl coenzyme A l,2-diacylglycerol acyltransferase and increases peroxisomal oxidation in the liver. Therapeutic Effect Reduces the synthesis of triglycerides in the liver. 

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... 

Lazarow P (1981) Assay of peroxisomal -oxidation of fatty acids. Methods in Enzymology 72 315-319... 

Primary carnitine deficiency is caused by a deficiency in the plasma-membrane carnitine transporter. Intracellular carnitine deficiency impairs the entry of long-chain fatty acids into the mitochondrial matrix. Consequently, long-chain fatty acids are not available for p oxidation and energy production, and the production of ketone bodies (which are used by the brain) is also impaired. Regulation of intramitochondrial free CoA is also affected, with accumulation of acyl-CoA esters in the mitochondria. This in turn affects the pathways of intermediary metabolism that require CoA, for example the TCA cycle, pyruvate oxidation, amino acid metabolism, and mitochondrial and peroxisomal -oxidation. Cardiac muscle is affected by progressive cardiomyopathy (the most common form of presentation), the CNS is affected by encephalopathy caused by hypoketotic hypoglycaemia, and skeletal muscle is affected by myopathy. 

In pantothenic acid-deficient rats, tissue CoA is depleted, affecting mainly the peroxisomal oxidation of fatty acids, which is mainly concerned with detoxication mitochondrial /3 -oxidation, which is an essential energy-yielding pathway, is spared to a great extent (Youssef et al., 1997). However, relatively moderate deficiency in animals results in increased plasma triacylglycerol and nonesterifled fatty acids, suggesting some impairment of lipid metabolism (Wittwer et al., 1990). 

Fig. (4). Instead, the alternative A8-route begins with the elongation of Ci8 to C20, followed by two desaturations. Fig. (4). There also exists another unusual pathway to produce DHA which has been characterised in mammals and fish, called the Sprecher s pathway, this route is characterized by a lack of desaturation reaction at A4-position, but successive A5 and A6-desaturations of ALA (a-linolenic acid, 18 3 ) generating a C24 intermediate which is finally shortened by peroxisomal -oxidation forming DHA, Fig. (4).

Although the mitochondria are the primary site of oxidation for dietary and storage fats, the peroxisomal oxidation pathway is responsible for the oxidation of very long-chain fatty acids, jS-methyl branched fatty acids, and bile acid precursors. The peroxisomal pathway also plays a role in the oxidation of dicarboxylic acids. In addition, it plays a role in isoprenoid biosynthesis and amino acid metabolism. Peroxisomes are also involved in bile acid biosynthesis, a part of plasmalogen synthesis and glyoxylate transamination. Furthermore, the literature indicates that peroxisomes participate in cholesterol biosynthesis, hydrogen peroxide-based cellular respiration, purine, fatty acid, long-chain... 

In the human genetic disease X-linked adreno-leukodystrophy (ADL), peroxisomal oxidation of very long chain fatty acids is defective. The ADL gene encodes the peroxisomal membrane protein that trans-... 

See also / -Oxidation of Saturated Fatty Add Unsaturated Fatty Add Oxidation, Oxidation of Odd-Numbered Fatty Acids, Peroxisomal / -Oxidation, Fatty Acids... 

No ATPs are generated as a result of this electron transfer, but heat is generated. Peroxisomal oxidation also only proceeds as far as C4 and C6 acyl-CoAs. However, the C4 and C6 acyl groups can be transferred to carnitine for transport into mitochondria (Figure 18.15), where oxidation can be completed. The function of the peroxisomal pathway is not yet clear, but it probably involves the initial stages in oxidizing very long-chain fatty acids and other lipids. 

Medium Chain (Octanoylcarnitine transferase) 6-12 Substrate is medium-chain acyl CoA derivatives generated during peroxisomal oxidation. 

Dietary medium-chain-length fatty acids are more water soluble than long-chain fatty acids and are not stored in adipose triacylglyce. After a meal, they enter the blood and pass into the portal vein to the liver. In the liver, they enter the mitochondrial matrix by the monocarboxylate transporter and are activated to acyl CoA derivatives in the mitochondrial matrix (see Fig. 23.1). Medium-chain-length acyl CoAs, like long-chain acyl CoAs, are oxidized to acetyl CoA via the (3-oxidation spiral. Medium-chain acyl CoAs also can arise from the peroxisomal oxidation pathway. 

Very-long-chain fatty acids of 24 to 26 carbons are oxidized exclusively in peroxisomes by a sequence of reactions similar to mitochondrial p-oxidation in that they generate acetyl CoA and NADH. However, the peroxisomal oxidation of straight-chain fatty acids stops when the chain reaches 4 to 6 carbons in length. Some of the long-chain fatty acids also may be oxidized by this route. 

PEROXISOMAL OXIDATION OF VERY-LONG-CHAIN FATTY ACIDS... 

The octanoyl CoA that is the end-product of peroxisomal oxidation leaves the peroxisomes and the octanoyl group is transferred through the inner mitochondrial membrane by medium-chain-length acylcarnitine transferase. In the mitochondria, it enters the regular p-oxidation pathway, beginning with medium-chain-length acyl CoA dehydrogenase (MCAD). 

Zellweger s (cerebrohepatorenal) syndrome occurs in individuals with a rare inherited absence of peroxisomes in all tissues. Patients accumulate C26-C38 polyenoic acids in brain tissue owing to defective peroxisomal oxidation of the very-long-chain fatty acids synthesized in the brain for myelin formation. In liver, bile acid and ether lipid synthesis are affected, as is the oxidation of very-long-chain fatty acids. 

Peroxisomes oxidize fatty acids that have more than 18 carbons and reduce their lengths to C18. The shorter chains are better substrates for (3 oxidation in the mitochondria. Therefore, clofibrate probably aids the degradation of fatty acids generally and thereby will lower the level of triglycerides. 

Another inhalation study in mice and rats correlated light microscopic and ultrastructural liver effects with liver levels of cyanide-insensitive palmitoyl CoA oxidase, a marker for peroxisomal -oxidation (Odum et al. 1988). Animals were exposed to 200 ppm of tetrachloroethylene for 28 days or 400 ppm for 14,21, or 28 days. Centrilobular hepatocellular vacuolization was induced in mice by tetrachloroethylene exposure. Electron microscopy revealed that this effect corresponded to lipid accumulation. Centrilobular hepatocytes with cytoplasmic eosinophilia on light microscopy had marked proliferation of cytoplasmic peroxisomes at the ultrastructural level, and there was a significant increase in the marker enzyme. These changes occurred in mice at both doses and all exposures and were most pronounced in male mice. Exposed male rats in both dose groups and female rats exposed to 400 ppm developed centrilobular hepatocellular hypertrophy, which ultrastructurally consisted of proliferation of smooth endoplasmic reticulum. There was no increase in peroxisomes (Odum et al. 1988). 

---