Human Metabolism. Keith N. Frayn
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Plasma fatty acids themselves, not esterified to glycerol, are known as NEFAs, sometimes called free fatty acids (FFAs). In plasma they are mainly bound loosely and non-specifically to the plasma protein albumin. They dissociate from albumin to enter cells. Triacylglycerol is also transported in plasma, usually along with cholesterol. This is achieved by formation of sub-microscopic lipid droplets in which a core of triacylglycerol is stabilised in the aqueous environment of the plasma by a surface monolayer of phospholipids, like intracellular lipid droplets. These droplets, or particles as they are often known, are associated with specific proteins to guide them round the circulation. The whole particle is then known as a lipoprotein. Lipoprotein metabolism will be discussed extensively in Chapter 10. Here we will briefly mention two relevant classes of lipoprotein particles: the chylomicrons and the very-low-density lipoproteins (VLDLs) – the reasons for these names will be explained in Chapter 10.
The reactions involved in interconversion of fatty acids and triacylglycerol are central to lipid metabolism. As shown in Figure 1.4, triacylglycerols consist of three fatty acid molecules esterified to one of glycerol (a trihydric alcohol, CH2OH-CHOH-CH2OH). These ester bonds are hydrolysed by lipase enzymes. There are several families of lipases, which will be mentioned where relevant in the text. The reaction is identical to that used in the manufacture of soap, known as saponification. In soap manufacture, a triacylglycerol (usually of vegetable oil origin) is treated with caustic soda (NaOH), resulting in the hydrolysis of ester bonds and the liberation of glycerol and fatty acids (in the form of their sodium salts). In metabolism, however, the hydrolysis is achieved by lipase enzymes (Figure 1.18).
Figure 1.18 Parallel between soap manufacture (saponification) and fat mobilisation. In saponification, an alkali (usually NaOH) is used to hydrolyse a source of triacylglycerol – animal fat or a vegetable oil. The resultant sodium salts of fatty acids (together with glycerol) constitute soap. The hydrolysis of triacylglycerol stored in adipocytes is similar, but brought about by enzymes (more details in Chapter 5, Figure 5.10), and releases non-esterified fatty acids (NEFA) that may be used as a fuel in other tissues. However, in metabolism, unlike in soap manufacture, the process is reversible: fatty acids can also be re-esterified with glycerol to make new triacylglycerols (pathways are given in Chapter 4, Figure 4.8). This is the basis of the pathway by which triacylglycerol is laid down in adipocytes.
Unlike the relationship between vegetable oils and soap, however, in metabolism the process can be reversed: fatty acids can be re-esterified with glycerol to make new triacylglycerol. (The reaction usually uses glycerol 3-phosphate and will be described further in Chapter 5.) The fatty acids are added in the form of their coenzyme A esters, known as fatty acyl-CoA (i.e. fatty acid-CoA). (Note that fatty acyl-CoA is different from acetyl-CoA, although acetyl-CoA could be considered the simplest of the family of acyl-CoAs.)
1.3.3.2 Fat deposition and mobilisation
Most dietary fat is in the form of triacylglycerol (Table 4.1). Within the small intestine, dietary triacylglycerol molecules are hydrolysed by intestinal lipases and the products are absorbed into the cells lining the intestines (mucosal or epithelial cells, collectively known as enterocytes). The products of lipolysis are recombined with the enterocytes to form new triacylglycerol. These triacylglycerols, composed of dietary fat, are liberated into the circulation as lipoprotein particles: in fact, the largest and most fat-enriched of the lipoprotein particles, known as chylomicrons (more detail in Chapters 4 and 10). At target tissues, the triacylglycerol in the lipoprotein particles is hydrolysed by a lipase bound to the endothelial cells lining the capillaries, known as lipoprotein lipase. The resulting fatty acids are taken up by cells, and have two potential fates: (i) re-esterification with glycerol 3-phosphate to make new triacylglycerol (and other lipids) – the pathway of fat deposition; or (ii) oxidation. The former is the major route by which dietary fat is laid down for storage in adipose tissue (Figure 1.17; Section 5.2.2.1).
When the stored fat is required as a source of energy, for instance during physical activity when muscles will oxidise fatty acids, or during periods between meals, then the stored triacylglycerol is hydrolysed by a series of intracellular lipases to liberate fatty acids and glycerol, which can be released into the plasma. This is the process known as fat mobilisation. As noted earlier, these non-esterified (‘free’) fatty acids are transported bound to albumin. Glycerol, which is freely soluble, will travel mainly to the liver where it is a substrate for gluconeogenesis as described above (Section 1.3.2.1.5). On average, in a mature adult who is weight-stable, the amount of fat stored in a typical day will equal the amount mobilised. Most tissues can utilise NEFAs, but importantly fatty acids cannot cross the blood-brain barrier and therefore cannot be used as an energy source by the central nervous system. Also, their oxidation requires mitochondria, meaning that red blood cells (erythrocytes), which lack mitochondria, are unable to use them. However, fatty acids are a major fuel source for muscle and kidney, and for the heart and liver under certain conditions.
1.3.3.3 Fatty acid oxidation
Following uptake into cells, fatty acids are rapidly ‘activated’ by esterification to CoA, forming fatty acyl-CoA; this esterification (known as thio- esterification because of the –SH thio group of the CoA molecule) also removes the amphipathic, detergent-like character of the fatty acid, making it less toxic in the membrane-rich cytosol. This reaction requires ATP and releases inorganic pyrophosphate, PPi. PPi is rapidly broken down to Pi, meaning that this step is essentially irreversible. It therefore achieves the same end as glucose phosphorylation to glucose 6-phosphate on entering a cell: it both traps the fatty acid within the cell, and creates a concentration gradient to draw more fatty acids into the cell. The enzymes concerned are known as acyl-CoA synthases (ACSs): again there is a family of these, suited for fatty acids of different carbon chain lengths. The action of the ACSs may be intimately linked to the process of fatty acid transport into the cell, discussed further in Chapter 2.
The fatty acyl moiety may then undergo β-oxidation to yield acetyl-CoA (together with NADH and FADH2) for further oxidation and ATP formation (Figure 1.16 and Box 1.7). This process occurs in mitochondria (hence cells lacking this organelle, such as