Polyunsaturated long-chain fatty acids oxidation

Christensen, E., Woldseth, B., Hagve, T.A., Poll-The, B.T., Wanders, R.J., Sprecher, H., Stokke, O. and Christophersen, B.O. (1993) Peroxisomal beta-oxidation of polyunsaturated long chain fatty acids in human fibroblasts. The polyunsaturated and the saturated long chain fatty acids are retroconverted by the same acyl-CoA oxidase. Scand. J. Clin. Lab. Invest. 215 S61-S74. 

The major bioactive products of fatty acid metabolism relevant to atherosclerosis are those that result from enzymatic or non-enzymatic oxidation of polyunsaturated long-chain fatty acids. In most cases, these fatty acids are derived from phospholipase A2-mediated hydrolysis of phospholipids (Chapter 11) in cellular membranes or lipoproteins, or from lysosomal hydrolysis of lipoproteins after internalization by lesional cells. In particular, arachidonic acid is released from cellular membrane phospholipids by arachidonic acid-selective cytosolic phospholipase Aj. In addition, there is evidence that group II secretory phospholipase Aj (Chapter 11) hydrolyzes extracellular lesional lipoproteins, and lysosomal phospholipases and cholesterol esterase release fatty acids from the phospholipids and CE of internalized lipoproteins. Indeed, Goldstein and Brown surmised that at least one aspect of the atherogenicity of LDL may lie in its ability to deliver unsaturated fatty acids, in the form of phospholipids and CE, to lesions (J.L. Goldstein and M.S. Brown, 2001). 

FIGURE 3-7 Pathways for the interconversion of brain fatty acids. Palmitic acid (16 0) is the main end product of brain fatty acid synthesis. It may then be elongated, desaturated, and/or P-oxidized to form different long chain fatty acids. The monoenes (18 1 A7, 18 1 A9, 24 1 A15) are the main unsaturated fatty acids formed de novo by A9 desaturation and chain elongation. As shown, the very long chain fatty acids are a-oxidized to form a-hydroxy and odd numbered fatty acids. The polyunsaturated fatty acids are formed mainly from exogenous dietary fatty acids, such as linoleic (18 2, n-6) and a-linoleic (18 2, n-3) acids by chain elongation and desaturation at A5 and A6, as shown. A A4 desaturase has also been proposed, but its existence has been questioned. Instead, it has been shown that unsaturation at the A4 position is effected by retroconversion i.e. A6 unsaturation in the endoplasmic reticulum, followed by one cycle of P-oxidation (-C2) in peroxisomes [11], This is illustrated in the biosynthesis of DHA (22 6, n-3) above. In severe essential fatty acid deficiency, the abnormal polyenes, such as 20 3, n-9 are also synthesized de novo to substitute for the normal polyunsaturated acids. 

The capacity of P-oxidation in about 10% of that in the mitochondria but it plays an important role in oxidising unusual fatty acids for example, very long-chain fatty acids, polyunsaturated fatty acids, dicarbox-ylic fatty acids. 

Up to one-third of the fatty acids in milk fat have a chain-length of 14 carbons or less. Because these acids are oxidized rapidly in the liver, have a lower energy value and are oxidized more readily than long-chain fatty acids, it follows that milk fat should contribute less to overweight than an equivalent amount of other dietary fats (Parodi, 2004). A study by Schnee-man et al, (2003) showed that milk fat is a more potent stimulator of cholecystokinin than a blend of non-milk fat with a similar ratio of polyunsaturated to saturated fatty acids. Cholecystokinin is a satiety hormone released into the blood stream by the intestine during feeding and acts to suppress further eating. 

Structurally, vitamin A and many synthetic retinoids consist of a (3-ionone ring, a polyunsaturated polyene chain, and a polar end group. The polar end group can exist in several oxidation states, as retinol, retinal, or retinoic acid. Retinol and retinyl esters are the most abundant vitamin A forms found in the body (Blaner and Olson, 1994). Retinol can be esterified with long-chain fatty acids (mainly palmitate, oleate, and stearate) to form retinyl esters, which are the body s storage form of vitamin A. Retinol also can undergo oxidation to retinal, which can be oxidized further to retinoic acid. The active... 

Fig. 8. P-Oxidation of fatty acids in E. coli. Long-chain fatty acids are transported into the cell by FadL and converted to their CoA thioesters by FadD (not shown). The acyl-CoAs are substrates for the (1) acyl-CoA dehydrogenase (YafH) to form a trans-2-enoyl-CoA. The double bond is reduced by (2) rrans-2-enoyl-hydratase (crotonase) activity of FadB. The P-hydroxyacyl-CoA is then a substrate for the NADP -dependent dehydrogenase activity of FadB (3). A thiolase, FadA (4), releases acetyl-CoA from the P-ketoacyl-CoA to form an acyl-CoA for subsequent cycles. (5) Polyunsaturated fatty acyl-CoAs are reduced by the 2,4-dienoyl-CoA reductase (FadH). (6) FadB also catalyzes the isomerization of c/s-unsaturated fatty acids to trans. (7) The epimerase activity of FadB converts O-P-hydroxy thioesters to their L-enantiomers via the /rans-2-enoyl-CoA.

Very-long-chain fatty acids as erucic acid (A -docosenoic acid, C22 l), polyunsaturated fatty acids, methyl-branched fatty acids, dicarboxylic fatty acids, prostaglandins, and the cholesterol side chain in bile acid synthesis are preferentially or exclusively oxidised in peroxisomes. Peroxisomal P-oxidation starts with introduction of a A2,3-double bond catalysed by acyl-CoA oxidase, which consumes O2 and produces H2O2 (Foerster et al. 1981). 

To study the oxidation of these long-chain fatty acids we prepared their carnitine esters and tested them as substrates for isolated mitochondria from heart and other tissues. These experiments showed that the C22 fatty adds, both mono- and polyunsaturated indeed are poorly oxidized by mitochondria compared with ordinary fatty acids. Also, the presence of these very long-chain fatty acids interferes with the oxidation of the shorter-chain acids, e.g., palmitate [3,4]. 

In fractions of butteroil containing alpha-tocopherol and copper. These workers reported that l,5-octadlen-3-one from the oxidation of long-chain polyunsaturated n-3 fatty acids was responsible for metallic notes, but the fishiness appeared to be contributed by the 2,A,7-decatrlenals or a combination of these compounds. This relationship has been explored further In our laboratory through mechanistic studies employing alpha-tocopherol and Trolox C which Is a synthetic tocopherol-type antioxidant (Figure 2). 

The large number of precursors of volatile decomposition products affecting the flavor of oils has been discussed in Chapter 4. Only qualitative information is available on the relative oxidative stability of hydroperoxides, aldehydes and secondary oxidation products. As observed with the unsaturated fatty ester precursors, the stability of hydroperoxides and unsaturated aldehydes decreases with higher unsaturation. Different hydroperoxides of unsaturated lipids, acting as precursors of volatile flavor compounds, decompose at different temperatures. Hydroperoxides of linolenate and long-chain n-3 PUFA decompose more readily and at lower temperatures than hydroperoxides of linoleate and oleate. Similarly, the alkadienals are less stable than alkenals, which in turn are less stable than alkanals. The short-chain fatty acids produced by oxidation of unsaturated aldehydes will further decrease the oxidative stability of polyunsaturated oils. For secondary products, dimers are less stable than dihydroperoxides, which are less stable than cyclic peroxides. 

Normally, the method of choice for the analysis of complex mixtures of polyenoic fatty acids such as those derived from fish oils is capillary gas chromatography with prechromato-graphic derivatization and mass spectrometric detection. However, GC is impractical for the purification of the large amounts of polyenoic fatty acids required for biological and clinical studies. Moreover, the temperatures required in GC may cause degradation of oxidized long-chain polyunsaturated fatty acids that are present as minor components of the mixture. 

Frankel, E.N., Satue-Gracia, T., Meyer, A.S., and German, J.B. (2002). Oxidative stability of fish and algae oils containing long-chain polyunsaturated fatty acids in bulk and in oil-inwater emulsions. J. Agric. Food Chem. 50,2094 099. 

The development of both desirable and undesirable fishy flavors has long-been a concern to the seafood and fishery Industry (1-6). Oxidative processes occurring through enzymic and nonenzymlc mechanisms Initiate hydroperoxide formation In fish lipid systems that are responsible for the formation of the short chain carbonyls and alcohols which exhibit distinct flsh-llke flavors and aromas. Because the generation of fresh fish aroma compounds Involves some of the same polyunsaturated fatty acid precursors and oxidative pathways as autoxldatlon. It has been a tedious task to differentiate the mechanisms and aroma compounds... 

Das UN. Long-chain polyunsaturated fatty acids interact with nitric oxide.superoxide anion, and transforming growth factor-fl to prevent human essential hypertension. Eur. J. Clin. Nutr. 2004 58 195-203. 

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