Fatty acid breakdown regulation

In chapter 18, Metabolism of Fatty Acids, we discuss the synthesis and breakdown of fatty acids. The chapter starts with a discussion of fatty acid breakdown. A second section covers the pathway for fatty acid biosynthesis. Finally, we consider the regulatory mechanisms that determine the conditions under which each of these processes occurs. As in the case of glucose metabolism, it is convenient to discuss the synthesis and breakdown in the same chapter so that the closely related topic of regulation can be considered alongside. 

The major source of free fatty acids in the blood is from the breakdown of triacylglycerol stores in adipose tissue which is regulated by the action of hormone-sensitive triacylglycerol lipase (see Topic K4). Fatty acid breakdown and fatty acid synthesis are coordinately controlled so as to prevent a futile cycle (see Topic K3). 

Coenzyme availability can also often have a limiting effect (5). If the coenzyme is regenerated by a second, independent metabolic pathway, the speed of the second pathway can limit that of the first one. For example, glycolysis and the tricarboxylic acid cycle are mainly regulated by the availability of NAD" (see p. 146). Since NAD is regenerated by the respiratory chain, the latter indirectly controls the breakdown of glucose and fatty acids (respiratory control, see p. 144). 

As previously mentioned, the homogeneity of foamed materials and the proportion of open and closed cells can be influenced by additives such as emulsifiers and stabilizers. Emulsifiers (e.g., sodium, potassium, or zinc salts of long-chain fatty acids) cause a uniform distribution of water in the reaction mixture, ensuring homogeneous foaming, while stabilizers (certain silicone oils) prevent a breakdown of the cell structure at the beginning of the reaction and also act as pore regulators. 

Phosphofructokinase-1 is a regulatory enzyme (Chapter 6), one of the most complex known. It is the major point of regulation in glycolysis. The activity of PFK-1 is increased whenever the cell s ATP supply is depleted or when the ATP breakdown products, ADP and AMP (particularly the latter), are in excess. The enzyme is inhibited whenever the cell has ample ATP and is well supplied by other fuels such as fatty acids. In some organisms, fructose 2,6-bisphosphate (not to be confused with the PFK-1 reaction product, fructose 1,6-bisphosphate) is a potent allosteric activator of PFK-1. The regulation of this step in glycolysis is discussed in greater detail in Chapter 15. 

CM and VLDL secreted by intestinal cells and VLDL synthesized and secreted in the liver have similar metabolic fates. After secretion into the blood, newly formed CM and VLDL take up apoprotein (apo-C) from HDL and are subsequently removed from the blood (plasma half-life of less than 1 h in humans [137]) primarily by the action of lipoprotein lipase (LPL). Lipoprotein lipase is situated mainly in the vascular bed of the heart, skeletal muscle, and adipose tissue and catalyzes the breakdown of core TG to monoglycerides and free fatty acids, which are taken up into adjacent cells or recirculated in blood bound to albumin. The activity of LPL in the heart and skeletal muscle is inversely correlated with its activity in adipose tissue and is regulated by various hormones. Thus, in the fasted state, TG in CM and VLDL is preferentially delivered to the heart and skeletal muscle under the influence of adrenaline and glucagon, whereas in the fed state, insulin enhances LPL activity in adipose tissue, resulting in preferential uptake of TG into adipose tissue for storage as fat. 

The breakdown of fatty acids in (3-oxidation (see Topic K2) is controlled mainly by the concentration of free fatty acids in the blood, which is, in turn, controlled by the hydrolysis rate of triacylglycerols in adipose tissue by hormone-sensitive triacylglycerol lipase. This enzyme is regulated by phosphorylation and dephosphorylation (Fig. 5) in response to hormonally controlled levels of the intracellular second messenger cAMP (see Topic E5). The catabolic hormones glucagon, epinephrine and norepinephrine bind to receptor proteins on the cell surface and increase the levels of cAMP in adipose cells through activation of adenylate cyclase (see Topic E5). The cAMP allosterically activates... 

It is hardly surprising then that for many years now the study of the behaviour of such slices has continued to provide a goldmine of useful information. The detailed mechanisms of glucose breakdown, amino acid interconversions, and fatty acid synthesis have been resolved in slice preparations. And, more and more, it is becoming possible to use them to tackle much more general problems of the regulation and control of the whole pattern of cell... 

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