Glycerol 3-phosphate synthesis: Glycerol 3-phosphate is the initial acceptor of fatty acids during TAG synthesis. There are two major pathways for its production (Fig. 16.13). [Note: A third process (glyceroneogenesis) is described on p. 190.] In both liver (the primary site of TAG synthesis) and adipose tissue, glycerol 3-phosphate can be produced from glucose, first using the reactions of the glycolytic pathway to produce dihydroxyacetone phosphate ([DHAP], see p. 101). DHAP is reduced by glycerol 3-phosphate dehydrogenase to glycerol 3phosphate. A second pathway found in the liver, but not in adipose tissue, uses glycerol kinase to convert free glycerol to glycerol 3phosphate (see Fig. 16.13). [Note: The glucose transporter in adipocytes (GLUT-4) is insulin dependent (see p. 312). Thus, when plasma glucose levels are low, adipocytes have only a limited ability to synthesize glycerol phosphate and cannot produce TAG de novo.] 4.
Fatty acid activation: A free fatty acid must be converted to its activated form (bound to CoA through a thioester link) before it can participate in metabolic processes such as TAG synthesis. This reaction, illustrated in Figure 15.6 on p. 177, is catalyzed by a family of fatty acyl CoA synthetases (thiokinases).
5.
Triacylglycerol synthesis: This pathway from glycerol 3-phosphate involves four reactions, shown in Figure 16.14. These include the sequential addition of two fatty acids from fatty acyl CoA, the removal of phosphate, and the addition of the third fatty acid.
H. Triacylglycerol fate in liver and adipose tissue
In WAT, TAG is stored in a nearly anhydrous form as fat droplets in the cytosol of the cells. It serves as “depot fat,” ready for mobilization when the body requires it for fuel. Little TAG is stored in healthy liver. Instead, most is exported, packaged with other lipids and apolipoproteins to form lipoprotein particles called very-low-density lipoproteins (VLDL). Nascent VLDL are secreted directly into the blood where they mature and function to deliver the endogenously derived lipids to the peripheral tissues. [Note: Recall from Chapter 15 that chylomicrons carry dietary (exogenously derived) lipids. Plasma lipoproteins are discussed in Chapter 18.]
IV. FAT MOBILIZATION AND FATTY ACID OXIDATION
Fatty acids stored in WAT, in the form of neutral TAG, serve as the body’s major fuel storage reserve. TAG provide concentrated stores of metabolic energy because they are highly reduced and largely anhydrous. The yield from the complete oxidation of fatty acids to CO2 and H2O is 9 kcal/g fat (as compared to 4 kcal/g protein or carbohydrate, see Fig. 27.5 on p. 359).
A. Fatty acid release from fat
The mobilization of stored fat requires the hydrolytic release of FFA and glycerol from their TAG form. This process of lipolysis is achieved by lipases. It is initiated by adipose triglyceride lipase (ATGL), which generates a diacylglycerol that is the preferred substrate for hormone-sensitive lipase (HSL). The monoacylglycerol (MAG) product of HSL is acted upon by MAG lipase.