Storage of Fatty Acids As Triacylglycerols

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ether­linked chains are fatty alcohols (Figure 9.13) rather than fatty acids. These alcohols are formed in higher animals by a two­step, NADPH­linked reduction of fatty acyl CoAs in the endoplasmic reticulum. In organs that produce relatively large amounts of ether­containing lipids, the concurrent production of fatty acids and fatty alcohols is probably closely coordinated.
Figure 9.13 Fatty alcohol.
9.4— Storage of Fatty Acids As Triacylglycerols
Most tissues in the body can convert fatty acids to triacylglycerols (Figure 9.14) by a common sequence of reactions, but liver and adipose tissue carry out this process to the greatest extent. Adipose tissue is a specialized connective tissue designed for synthesis, storage, and hydrolysis of triacylglycerols. This is the main system for long­term energy storage in humans. We are concerned here with white adipose tissue as opposed to brown adipose tissue, which occurs in much lesser amounts and has other specialized functions. Triacylglycerols are stored as liquid droplets in the cytoplasm, but this is not ''dead storage" since they turn over with an average half­life of only a few days. Thus, in a homeostatic situation, there is continuous synthesis and breakdown of triacylglycerols in adipose tissue. Some storage also occurs in skeletal and cardiac muscle, but only for local consumption.
Triacylglycerol synthesis in liver is used primarily for production of blood lipoproteins, although the products can serve as energy sources for other liver
Figure 9.14 Alternative pathways for biosynthesis of triacylglycerols from dihydroxyacetone phosphate.
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functions. Required fatty acids may come from the diet, from adipose tissue via blood transport, or from de novo biosynthesis. Acetyl CoA for biosynthesis is derived principally from glucose catabolism.
Triacylglycerols Are Synthesized from Fatty Acyl CoAs and Glycerol 3­Phosphate in Most Tissues
Triacylglycerols are synthesized in most tissues from activated fatty acids and a phosphorylated three­carbon product of glucose catabolism (see Figure 9.14), which can be either glycerol 3­phosphate or dihydroxyacetone phosphate. Glycerol 3­phosphate is formed either by reduction of dihydroxyacetone phosphate produced in glycolysis or by phosphorylation of glycerol. White adipose tissue contains little or no glycerol kinase, so it derives glycerol phosphate from glycolytic intermediates. Fatty acids are activated by conversion to their CoA esters in the following reaction:
This two­step reaction has an acyl adenylate as intermediate and is driven by hydrolysis of pyrophosphate to Pi.
Figure 9.15 Synthesis of phosphatidic acid from glycerol 3­phosphate.
Synthesis of triacylglycerols from phosphorylated three­carbon fragments involves formation of phosphatidic acid, which is a key intermediate in synthesis of other lipids as well (see Chapter 10). This may be formed by two sequential acylations of glycerol 3­phosphate, as shown in Figure 9.15. Alternatively, dihydroxyacetone phosphate may be acylated directly at C­1 followed by reduction at C­2. The resultant lysophosphatidic acid can then be further esterified, as illustrated in Figure 9.16. If phosphatidic acid from either of these routes is used for synthesis of triacylglycerol, the phosphate group is next hydrolyzed by phosphatidate phosphatase to yield diacylglycerol, which is then acylated to triacylglycerol (Figure 9.17).
There is at least one tissue, intestinal mucosa, in which the synthesis of triacylglycerols does not require formation of phosphatidic acid as described above. A major product of intestinal digestion of lipids is 2­monoacylglycerols, which are absorbed as such into mucosa cells. An enzyme in these cells catalyzes acylation of these monoacylglycerols with acyl CoA to form 1,2­diacylglycerols, which then can be further acylated as shown above.
The specificity of the acylation reactions in all these steps is still quite controversial. Analysis of fatty acid patterns in triacylglycerols from various human tissues shows that the distribution of different acids on the three positions of glycerol is neither random nor absolutely specific. The patterns in different tissues show some characteristic tendencies. Palmitic acid tends to be concentrated in position 1 and oleic acid in positions 2 and 3 of human adipose tissue triacylglycerols. Two main factors that determine localization of a particular fatty acid to a given position on glycerol are the specificity of acyltransferase involved and relative availability of different fatty acids in the fatty acyl CoA pool. Other factors are probably involved but their relative importance has not been determined.
Mobilization of Triacylglycerols Requires Hydrolysis
The first step in recovering stored fatty acids for energy production is hydrolysis of triacylglycerols. A variety of lipases catalyze this reaction, the sequence of hydrolysis from the three positions on glycerol depending on the specificities of the particular lipases involved.
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Lipases in adipose tissue are, of course, key enzymes for release of the major energy stores. The lipase that removes the first fatty acid is a controlled enzyme, which is sensitive to a variety of circulating hormones. This control of triacylglycerol hydrolysis must be balanced with the process of triacylglycerol synthesis to assure adequate energy stores and avoid obesity (see Clin. Corr. 9.1 and 9.2). Fatty acids and glycerol produced by adipose tissue lipases are released to circulating blood, where fatty acids are bound by serum albumin and transported to tissues for use. Glycerol returns to liver, where it is converted to dihydroxyacetone phosphate and enters glycolytic or gluconeogenic pathways.
Figure 9.16 Synthesis of phosphatidic acid from dihydroxyacetone phosphate.
Figure 9.17 Synthesis of triacylglycerol from phosphatidic acid.