The Metabolism of Fatty Acids and Triglycerides

Chapter 23 The Metabolism of Fatty Acids and Triglycerides


Triglycerides (fat) supply 35% to 40% of the total calories in typical Western diets. Ninety-five percent of this energy is contributed by the fatty acids and only 5% by the glycerol. The human body uses triglycerides as the principal storage form of energy, and most people carry between 5 and 20 kg of fat in their adipose tissue. With a basal metabolic rate of 1800 kcal/day, a 10-kg store of fat (93,000 kcal) can keep a human alive for 52 days without food. Fat metabolism includes the following processes:







Fatty acids differ in their chain length and number of double bonds


A “standard” fatty acid is an unbranched hydrocarbon chain with a carboxyl group at one end. Most naturally occurring fatty acids have an even number of carbons. Chain lengths of 16 and 18 are the most common.


In saturated fatty acids, the carbons are linked exclusively by single bonds. Of the fatty acids listed in Table 23.1, acetic acid does not occur in natural fats and oils, but vinegar contains about 5% of free (unesterified) acetic acid. Butyric acid is also rare in natural fats except milk fat. It is notorious for its smell, which resembles that of malodorous feet. In the production of some types of cheese, butyric acid is released from milk fat by the action of microbial lipases and contributes to the flavor of the product. Myristic acid is abundant in nutmeg, coconut, and palm kernel oil. Palmitic acid and stearic acid are the most common saturated fatty acids in animal fat, accounting for 30% to 40% of the fatty acids in human adipose tissue.



The carbons of the fatty acids are numbered, starting with the carboxyl carbon. Alternatively, they are designated by Greek letters. As in the amino acids, the α-carbon is the one next to the carboxyl carbon, the β-carbon is carbon 3, and so forth. The last carbon in the chain is the ω-carbon, as in the example of stearic acid:



Monounsaturated fatty acids have one carbon-carbon double bond, and polyunsaturated fatty acids have more than one. The double bonds of the polyunsaturated fatty acids are always three carbons apart, with a single methylene (—CH2—) group in between. The positions of the double bonds are specified by their distance from the carboxyl end. A Δ9 double bond, for example, is between carbons 9 and 10. Alternatively, the distance from the ω carbon can be specified.


The latter designation is useful because fatty acids can be elongated and shortened only at the carboxyl end. For example, if oleic acid (Table 23.2) is elongated by two carbons at the carboxyl end, the product is no longer a Δ9 fatty acid but Δ11, but it is still an ω9 fatty acid. Humans cannot introduce new double bonds beyond Δ9. Therefore some of the polyunsaturated fatty acids, notably linoleic acid and possibly α-linolenic acid, are nutritionally essential. The structures of unsaturated fatty acids can be described by a formula indicating chain length, number of double bonds, and locations of the double bonds (see Table 23.2).



There is no free rotation around the carbon-carbon double bond, and the substituents are fixed in cis or trans configuration:



Whereas the trans configuration favors an extended shape of the hydrocarbon chain, a cis double bond forms an angle of 120 degrees:



Only fatty acids with cis double bonds are common in nature. The properties of the fatty acids can be predicted from their structures:






Chylomicrons transport triglycerides from the intestine to other tissues


The main products of fat digestion are 2-monoacylglycerol and free fatty acids (see Chapter 19). After their absorption, the fatty acids are activated to acylcoenzyme A (acyl-CoA) in the endoplasmic reticulum (ER) of the intestinal mucosal cell:



This is always the first reaction of intracellular fatty acid metabolism, much as phosphorylation by hexokinase is always the first reaction of intracellular glucose metabolism. Like the phosphorylated sugars, the CoA-activated fatty acids are strictly intracellular metabolites. They do not cross the plasma membrane and are not transported in the blood.


The synthesis of acyl-CoA is made irreversible by hydrolysis of the inorganic pyrophosphate that is formed in the reaction. The acyl-CoA then reacts with 2-monoacylglycerol to form triglyceride (Fig. 23.1).



Why are triglycerides hydrolyzed in the intestinal lumen only to be resynthesized in the mucosal cell? The reason is that triglycerides are too insoluble. Only free fatty acids and monoglycerides are sufficiently water soluble to diffuse to the cell surface for absorption.


In the ER of the intestinal mucosal cell, the triglycerides are assembled into small fat droplets (diameter 1 μm). These droplets, known as chylomicrons, also contain other dietary lipids and a small amount of ER-synthesized proteins. After processing through the secretory pathway, the chylomicrons are released into the extracellular space. Because the endothelium of intestinal capillaries has no fenestrations, chylomicrons are collected by the lymph rather than by the blood. They are carried to the left brachiocephalic vein by the thoracic duct.


The triglycerides in chylomicrons are utilized by adipose tissue, heart, skeletal muscle, lactating mammary glands, and, to a lesser extent, by spleen, lungs, kidneys, endocrine glands, and aorta. These tissues (but not the liver and brain) possess lipoprotein lipase (LPL), an enzyme that is attached to heparan sulfate proteoglycans on the surface of the capillary endothelium. As the chylomicrons pass through the capillaries, they bind to LPL. Their triglycerides are hydrolyzed to free fatty acids and 2-monoacylglycerol, and these products are taken up by the cells.


LPL expression is regulated. Feeding raises LPL activity in adipose tissue but reduces it in skeletal muscle and myocardium. This ensures that dietary fat is directed mainly to adipose tissue in the well-fed state but to the muscles during fasting. During lactation, LPL activity declines in adipose tissue but rises massively in the mammary gland. These effects are orchestrated by hormones, including insulin, epinephrine, glucocorticoids, and prolactin.


Injected heparin detaches LPL from the capillary wall and increases its enzymatic activity. Therefore LPL activity can be determined in the laboratory by measuring serum lipase activities before and after heparin injection.



Adipose tissue is specialized for the storage of triglycerides


Triglyceride is the best storage form of energy because of its high energy density. It has a caloric value of 9.3, as opposed to 4.0 for glycogen, and whereas fat can be stored without accompanying water, each gram of glycogen binds 2 g of water. Therefore the energy value of 15 kg of fat is equivalent to 100 kg of hydrated glycogen.


After a mixed meal containing fat, carbohydrate, and protein, adipose tissue obtains most of its fatty acids from the action of LPL on chylomicron triglycerides. These fatty acids are transported into the cell and are activated to their CoA-thioesters before they can be used for triglyceride synthesis.


The glycerol of the triglycerides is derived from glycerol-3-phosphate. Adipose tissue has low levels of glycerol kinase. Therefore most glycerol phosphate is made not from free glycerol but from the glycolytic intermediate dihydroxyacetone phosphate. The NADH-dependent glycerol phosphate dehydrogenase that catalyzes this reaction is the same enzyme that participates in the glycerol phosphate shuttle (see Chapter 21) and in gluconeogenesis from glycerol (see Chapter 22). Dihydroxyacetone phosphate is derived from glucose after a carbohydrate meal or from lactate during fasting and after a high-fat, low-carbohydrate meal (Fig. 23.2).



Fat breakdown (lipolysis) in adipose tissue requires three lipases: adipose tissue triglyceride lipase, diglyceride lipase, and monoglyceride lipase. The diglyceride lipase traditionally has been described as the hormone-sensitive adipose tissue lipase, although the triglyceride lipase is responsive to hormones as well.


Unlike liver and intestine, adipose tissue releases lipid not in the form of lipoproteins but as “free” (unesterified) fatty acids. These fatty acids are transported to distant sites in reversible binding to serum albumin. The albumin-bound fatty acids have a plasma half-life of only 3 minutes. The other product of fat breakdown, glycerol, is used for gluconeogenesis by the liver.


A good deal of futile cycling occurs during fat metabolism. Approximately 40% of the fatty acids released by lipolysis during fasting does not leave the tissue but is resynthesized into storage triglyceride. This futile cycling consumes about 3% of the energy in the triglyceride, but it permits better regulation of lipolysis by controlling both the lipases that release the fatty acids and the enzymes needed for resynthesis of triglyceride from the released fatty acids.



Fat metabolism in adipose tissue is under hormonal control


Hormones control both the adipose tissue triglyceride lipase and the “hormone-sensitive” diglyceride lipase:


Norepinephrine (noradrenaline) from sympathetic nerve terminals and epinephrine (adrenaline) from the adrenal medulla are released during physical exercise and stress. They stimulate lipolysis through β-adrenergic receptors and cyclic AMP (cAMP). Figure 23.3 shows the mechanism for stimulation of the hormone-sensitive diglyceride lipase by the catecholamines and other cAMP-elevating hormones. The catecholamines also stimulate the adipose tissue triglyceride lipase by unknown mechanisms.



Synaptically released norepinephrine is more important than circulating epinephrine. In animal experiments, sympathetic denervation causes excessive fat accumulation in the denervated portions of adipose tissue. This is most obvious under conditions of food deprivation or cold exposure, when fat is degraded in the surrounding innervated tissue.


Insulin is released by glucose and amino acids after an opulent meal. A high insulin level signals the abundance of dietary nutrients that are eligible for storage. Conversely, a low insulin level signals a shortage of nutrients during fasting and a need for fat breakdown.


Insulin reduces lipolysis in adipose tissue. Part of this effect is mediated by activation of the cAMP-degrading phosphodiesterase PDE3B. Another effect is a reduction in the synthesis of the adipose tissue triglyceride lipase.


Insulin increases the uptake of glucose into the cell by the GLUT4 transporter. The metabolism of glucose stimulates fat synthesis by providing the precursor glycerol phosphate. In addition, insulin stimulates LPL in the capillaries of adipose tissue and induces glycerol phosphate-acyltransferase, the enzyme that adds the first fatty acid to glycerol phosphate in the biosynthetic pathway (see Fig. 23.2).


Tumor necrosis factor-α (TNF-α) stimulates lipolysis through multiple signaling cascades, leading to long-term stimulation of lipolysis that is mediated mainly by increased synthesis of the lipolytic enzymes. As a cytokine that is released during chronic infections and other severe diseases, TNF-α is in large part responsible for the mobilization of fat stores during severe chronic diseases.


Glucocorticoids, growth hormone, and thyroid hormones facilitate lipolysis by inducing the synthesis of lipolytic proteins. Glucocorticoids also reduce the reesterification of free fatty acids by repressing phosphoenolpyruvate (PEP) carboxykinase in adipose tissue, although they induce this gluconeogenic enzyme in the liver. This reduces futile cycling in times of stress and fasting, when the body needs all the energy it can get.


Not all kinds of adipose tissue respond equally to glucocorticoids. Patients with Cushing syndrome (excess glucocorticoids) lose fat in the extremities but develop truncal obesity and a “buffalo hump.”



Jun 18, 2016 | Posted by in BIOCHEMISTRY | Comments Off on The Metabolism of Fatty Acids and Triglycerides

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