Biosynthesis of Triacylglycerols:-Triacylglycerol Biosynthesis in Animals Is Regulated by Hormones
In humans, the amount of body fat stays relatively con stant over long periods, although there may be minor short-term changes as caloric intake fluctuates. Carbo hydrate, fat, or protein consumed in excess of energy needs is stored in the form of triacylglycerols that can be drawn upon for energy, enabling the body to with stand periods of fasting. Biosynthesis and degradation of triacylglycerols are regulated such that the favored path de pends on the metabolic resources and requirements of the moment. The rate of triacylglycerol biosynthesis is profoundly altered by the action of several hormones. Insulin, for example, promotes the conversion of carbohydrate to triacylglycerols (Fig. 21–19). People with severe diabetes mellitus, due to failure of insulin secretion or action, not only are unable to use glucose properly but also fail to synthesize fatty acids from carbohydrates or amino acids. If the diabetes is un treated, these individuals have increased rates of fat oxidation and ketone body formation (Chapter 17) and therefore lose weight.
An additional factor in the balance between biosyn thesis and degradation of triacylglycerols is that ap proximately 75% of all fatty acids released by lipolysis are reesterified to form triacylglycerols rather than used for fuel. This ratio persists even under starvation conditions, when energy metabolism is shunted from the use of carbohydrate to the oxidation of fatty acids. Some of this fatty acid recycling takes place in adipose tissue, with the reesterification occurring before release into the bloodstream; some takes place via a systemic cycle in which free fatty acids are transported to liver, recycled to triacylglycerol, exported again to the blood (transport of lipids in the blood is discussed in Section 21.4), and taken up again by adipose tissue after release from triacylglycerol by extracellular lipoprotein lipase (Fig. 21–20; see also Fig. 17–1). Flux through this tri acylglycerol cycle between adipose tissue and liver may be quite low when other fuels are available and the release of fatty acids from adipose tissue is limited, but as noted above, the proportion of released fatty acids that are reesterified remains roughly constant at 75% under all metabolic conditions. The level of free fatty acids in the blood thus reflects both the rate of release of fatty acids and the balance between the synthesis and breakdown of triacylglycerols in adipose tissue and liver. When the mobilization of fatty acids is required to meet energy needs, release from adipose tissue is stim ulated by the hormones glucagon and epinephrine (see Figs 17–3, 17–12). Simultaneously, these hormonal signals decrease the rate of glycolysis and increase the rate of gluconeogenesis in the liver (providing glucose for the brain, as further elaborated in Chapter 23). The released fatty acid is taken up by a number of tissues, in cluding muscle, where it is oxidized to provide energy. Much of the fatty acid taken up by liver is not oxidized but is recycled to triacylglycerol and returned to adipose tissue. The function of the apparently futile triacylglycerol cycle (futile cycles are discussed in Chapter 15) is not well understood. However, as we learn more about how the triacylglycerol cycle is sustained via metabolism in two separate organs and is coordinately regulated, some possibilities emerge. For example, the excess capacity in the triacylglycerol cycle (the fatty acid that is even tually reconverted to triacylglycerol rather than oxidized as fuel) could represent an energy reserve in the bloodstream during fasting, one that would be more rap idly mobilized in a “fight or flight” emergency than would stored triacylglycerol. The constant recycling of triacylglycerols in adipose tissue even during starvation raises a second question: what is the source of the glycerol 3-phosphate required for this process? As noted above, glycolysis is sup pressed in these conditions by the action of glucagon and epinephrine, so little DHAP is available, and glycerol released during lipolysis cannot be converted directly to glycerol 3-phosphate in adipose tissue, because these cells lack glycerol kinase (Fig. 21–17). So, how is sufficient glycerol 3-phosphate produced? The answer lies in a pathway discovered more than three decades ago and given little attention until recently, a pathway intimately linked to the triacylglycerol cycle and, in a larger sense, to the balance between fatty acid and carbohydrate metabolism.
FIGURE 21–18 Phosphatidic acid in lipid biosynthesis. Phosphatidic acid is the precursor of both triacylglycerols and glycerophospholipids. The mechanisms for head-group attachment in phospholipid synthesis are described later in this section.
FIGURE 21–19 Regulation of triacylglycerol synthesis by insulin. Insulin stimulates conversion of dietary carbohydrates and proteins to fat. Individuals with diabetes mellitus lack insulin; in uncontrolled disease, this results in diminished fatty acid synthesis, and the acetyl-CoA arising from catabolism of carbohydrates and proteins is shunted instead to ketone body production. People in severe ketosis smell of acetone, so the condition is sometimes mistaken for drunkenness.
FIGURE 21–20 The triacylglycerol cycle. In mammals, triacylglycerol molecules are broken down and resynthesized in a triacylglycerol cycle during starvation. Some of the fatty acids released by lipolysis of triacylglycerol in adipose tissue pass into the bloodstream, and the remainder are used for resynthesis of triacylglycerol. Some of the fatty acids released into the blood are used for energy (in muscle, for ex ample), and some are taken up by the liver and used in triacylglycerol synthesis. The triacylglycerol formed in the liver is transported in the blood back to adipose tissue, where the fatty acid is released by extracellular lipoprotein lipase, taken up by adipocytes, and reesterified into triacylglycerol.
