Fatty acid p-oxidation

By the above steps of p-oxidation fatty acids are completely degraded to acetyl CoA units. The acetyl CoA formed from fatty acids can be oxidised to carbon dioxide and water via citric acid cycle. 

It has been shown previously that chain-shortened 3-thia fatty acids have less hypohpidemic effect than TTA (Table 2). Thus the less biologieal poteney by the P-oxidable fatty acids compared to TTA could be due to chain shortening of the administered thia fatty acids by mitochondrial P-oxidation. Another possibihty is the formation of an inhibitory metabolite during P-oxidation of these p-oxidable thia fatty acids as is the case for 4-thia fatty acids. 

Fatty acids are synthesized by the successive addition of two-carbon units from acetyl CoA, followed by reduction. Like P-oxidation, fatty acid synthesis is a spiral sequence of reactions, with different enzymes catalysing the reaction sequence for synthesis of short, medium- and long-chain fatty acids. 

Fatty-acid p-oxidation Fatty-acid synthesis... 

These short-chain fatty acids are acetic, butyric, lactic and propionic acids, also known as volatile fatty acids, VFA. They are produced from fermentation of carbohydrate by microorganisms in the colon and oxidised by colonocytes or hepatocytes (see above and Chapter 4). Butyric acid is activated to produce butyryl-CoA, which is then degraded to acetyl-CoA by P-oxidation acetic acid is converted to acetyl-CoA for complete oxidation. Propionic acid is activated to form propionyl-CoA, which is then converted to succinate (Chapter 8). The fate of the latter is either oxidation or, conversion to glucose, via glu-coneogenesis in the liver. 

Fate of free fatty acids The free fatty acids derived from hydrolysis of triacylglycerol may directly enter adjacent mus cells or adipocytes. Alternatively, the free fatty acids may be tra ported in the blood in association with serum albumin until tt are taken up by cells. [Note Serum albumin is a large prot secreted by the liver. It transports a number of primarily hydropl bic compounds in the circulation, including free fatty acids a some drugs.2] Most cells can oxidize fatty acids to produ energy (see p. f88). Adipocytes can also reesterify free fa acids to produce triacylglycerol molecules, which are stored ui the fatty acids are needed by the body (see p. 185). 

Mold, P. A., Oscal, L. B. and Holloszy, J, 0. (1971) Adaptation of muscle to exercise. Increase in levels of palmltyl CoA synthetase, carnitine palmltyl-transferase and palmltyl CoA dehydrogenase and In the capacity to oxidize fatty acids. J. Clin. Invest. 50 2323-30. 

M. N. Sack, T. A. Rader, S. Park, J. Bastin, S. A. McCune, and D. P. Kelly, Fatty acid oxidation enzyme gene expression is downregulated in the failing heart, Circulation 94,2837-2842 (1996). 

The myocardium preferentially oxidizes fatty acids to fulfill the energy requirements necessary for efficient pump function. However, during myocardial ischemia, decreased cellular oxygen content, in conjunction with reduction of the redox potential, result in the inhibition of fatty acid P-oxidation leading to the accumulation of fatty acyl metabolites, including acylCoA and acylcamitine (cf, Neely and Morgan, 1974). 

Electrons from succinate are transferred to FAD in complex n and several Fe-S centers and then to UQ. Electrons from cytoplasmic NADH are transferred to UQ via a pathway involving glycerol-3-phosphate and the flavoprotein glycerol-3-phosphate dehydrogenase (see p. 316). Fatty acids are oxidized as coenzyme A derivatives. Acyl-CoA dehydrogenase, one of several enzymes in fatty acid oxidation, transfers 2 electrons to FAD. They are then donated to UQ. 

Alpha oxidation and omega oxidation. Animal tissues degrade such straight-chain fatty acids as palmitic acid, stearic acid, and oleic acid almost entirely by p oxidation, but plant cells often oxidize fatty acids one carbon at a time. The initial attack may involve hydroxylation on the a-carbon atom (Eq. 17-3) to form either the d- or the L-2-hydroxy The... 

Fatty acids are used as fuels principally when they are released from adipose tissue triacylglycerols in response to hormones that signal fasting or increased demand. Many tissues, such as muscle and kidney, oxidize fatty acids completely to CO2 and H2O. In these tissues, the acetyl CoA produced by p-oxidation enters the TCA cycle. The FAD(2H) and the NADH from p-oxidation and the TCA cycle are... 

As Otto Shape runs, his skeletal muscles increase their use of ATP and their rate of fuel oxidation. Fatty acid oxidation is accelerated by the increased rate of the electron transport chain. As ATP is used and AMP increases, an AMP-dependent protein kinase acts to facilitate fuel utilization and maintain ATP homeostasis. Phosphorylation of acetyl CoA carboxylase results in a decreased level of malonyl CoA and increased activity of carnitine palmitoyl CoA transferase I. At the same time, AMP-dependent protein kinase facilitates the recruitment of glucose transporters into the plasma membrane of skeletal muscle, thereby increasing the rate of glucose uptake. AMP and hormonal signals also increase the supply of glucose 6-P from glycogenoly-sis. Thus, his muscles are supplied with more fuel, and all the oxidative pathways are accelerated. 

Thia fatty acids represent non-p-oxidizable fatty acid analogues in which a S atom substitutes for the P-methylene group in the chain. They are known to reduce serum tri-acylglycerol and cholesterol. The hypolipaemia is detectable within 3 hours of administration and is explained initially by an increase in mitochondrial P-oxidation and a decrease in triacylglycerol secretion, followed by an increase in activity of peroxisomal P-oxidation enzymes after 12 hours. ... 

When the synthesis of lipids is reduced due to the presence of fatty acid analogs, the NEFAs will be diverted from the esterification pathway. The level of NEFAs in the hepatocytes treated with 3-thia fatty acids tended to decrease. This indicates that the mitochondrial P-oxidation was increased, as the peroxisomal P-oxidation was unchanged in these hepatocytes. Thus, it is likely that the non-P-oxidizable fatty acid analogs reduced the availability of fatty acids for TG-synthesis due to increased mitochondrial fatty oxidation. The lack of effect on the peroxisomal P-oxidation confirms the in vivo data that the hypotriglyceridemic effect of the analogs can be dissociated from the proliferation of peroxisomes." ... 

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