Fatty Acid Oxidation
In an individual of stable weight, the amount of fat consumed equals the quantity partitioned to meet energy needs. FA are a more efficient energy source than other macronutrients because of their high content in bonds between carbon and hydrogen. Such bonds are stronger and therefore contain more oxidizable energy than bonds between carbon and other atoms, as found in carbohydrates, protein, and alcohol. FA used for energy proceed through stages, including transport to oxidative tissues, transcellular uptake, mitochondrial transfer, and subsequent b-oxidation.
FA partitioned for oxidation are activated to fatty acyl-CoA, which are then transported into mitochondria to be oxidized. However, LCFA and their CoA derivatives cannot cross the mitochondrial membrane without carnitine, synthesized in humans from lysine and methionine. Transferase enzymes bind activated FA covalently to carnitine. After intramitochondrial transmission, FA are reactivated with CoA while carnitine recycles to the cytoplasmic surface.
Mitochondrial b-oxidation of FA entails the consecutive release of two-carbon acetyl-CoA units from the carboxyl terminus of the acyl chain. Prior to release of each unit, the b-carbon atoms of the acyl chain undergo cyclical degradation in four stages: dehydrogenation (removal of hydrogen), hydration (addition of water), dehydrogenation, and cleavage. Completion of these four reactions represents one cycle of b-oxidation. For unsaturated bonds within FA, the initial dehydrogenation reaction is omitted. The entire cycle is repeated until the fatty acyl chain is completely degraded. Absence of chain-shortened n-6 or n-3 FA in cellular or subcellular compartments indicates that once an FA begins cyclic degradation by b-oxidation, the process continues until the acyl chain is completely broken down.
Peroxisomal FA b-oxidation is similar to mitochondrial oxidation; yet there are several differences between these two organelles. First, very long acyl-CoA synthetase, the enzyme responsible for the activation of VLCFA, is present in peroxisomes and endoplasmic reticulum but not mitochondria, likely explaining why VLCFA are oxidized predominantly in peroxisomes. Second, the initial reaction in peroxisomal b-oxidation (desaturation of acyl-CoA) is catalyzed by an FAD-containing fatty acyl-CoA oxidase that is presumed to be the rate-limiting enzyme, whereas an acyl-CoA dehydrogenase is the first enzyme in the mitochondrial pathway. Third, peroxisomal b-oxidation is not directly coupled to the electron transfer chain that conserves energy via oxidative phosphorylation. In peroxisomes, electrons generated in the first oxidation step are transferred directly to molecular oxygen, yielding hydrogen peroxide that is disposed of by catalase, while energy produced in the second oxidation step (NAD+ reduction) is conserved in the form of high-energy electrons of nicotinamide adenine dinucleotide (NADH). Fourth, the second (hydration) and third (NAD+-dependent dehydrogenation) steps are catalyzed by a multifunctional protein that also displays d 3,d2-enoyl-CoA isomerase activity required for oxidation of unsaturated FA.
Recently, considerable interest has surrounded structure-dependent induction of FA oxidation. Thus, food selection may influence the partitioning of dietary fat for oxidation or retention for storage and structural use in humans. This issue is of health interest for at least two reasons. First, consumption of fats associated with greater retention may result in an increased tendency toward obesity. Second, the greater accumulation of less preferentially oxidized FA in cells may confer structural/functional changes because of shifts in membrane PL FA patterns or in prostaglandin (PG):thromboxane (TXA) ratios. The influence of tissue FA composition on functional ability, such as insulin sensitivity, is well recognized ( 53).
Discriminative oxidation of certain FA is well defined; for others it has been suggested. Short- and medium-chain triglyceride (MCT) consumption is associated with increased energy production in humans, perhaps because of direct portal transfer of SCFA and MCFA from gut to liver. The lack of requirement for carnitine in mitochondrial membrane transit by SCFA may also be responsible for their more rapid oxidation. For LCFA, increasing evidence suggests that n-6 and n-3 PUFA are more rapidly oxidized for energy than are SaFa. In animals, labeled PUFA are more readily converted to carbon dioxide than are SAFA ( 54), while PUFA consumption exhibits greater thermogenic effect (55), oxygen consumption (56), and sympathetic nervous system stimulation (57). Whole-body FA balance data also support the concept that C18:2n-6 is more readily used for energy than are SAFA (58). Although these findings have yet to be confirmed in humans, consumption of fats containing PUFA appears to enhance the contribution of dietary fat to total energy production in healthy individuals ( 59) and influences the use of other FA for energy (60); however, mechanisms remain to be defined. Portal venous transfer rates, release rates of FA from adipose tissue, hepatic FA oxidation enzyme activities, and mitochondrial entry rates of FA generally increase with the degree of acyl chain unsaturation.
Lipids are oxidized by reactive oxygen species produced as byproducts of normal metabolism. Reactive oxygen species include superoxide ( O2-), hydroxyl radical (OH), hydrogen peroxide, singlet oxygen (1O2), and hypochlorous acid (HOCl-). In healthy individuals, generation of reactive oxygen species should be in balance with antioxidant defenses. Circumstances that enhance oxidant exposure, such as increased formation of reactive oxygen species caused by chemicals and drugs, or that compromise antioxidant capability, such as decreased antioxidant vitamin levels because of malnutrition, are referred to as oxidative stress. Possible free radical effects on cells include oxidative damage to proteins, carbohydrates, and DNA. Oxidative stress has also long been known to be capable of inducing lipid oxidation and, in the presence of oxygen, lipid peroxidation of cell membranes.
It is generally accepted that lipid oxidation proceeds via a free radical mechanism called autoxidation, which includes initiation, propagation, and termination stages and predominantly occurs with PUFA. Polyunsaturated acyl chains of membrane PL are particularly sensitive to lipid peroxidation. Lipid oxidation, both nonenzymatic and enzymatic, is self-propagating in cellular membranes. Peroxidation of PUFA is classically depicted as a series of three or four basic reactions; however, the process becomes more complex as both the degree of unsaturation and severity of peroxidative conditions increases. The following initiation, propagation, and termination reactions characterize the general scheme of autoxidation:
A peroxidation sequence in a membrane or PUFA is initiated by the attack of any free radical with sufficient reactivity to abstract a hydrogen atom from an allelic methylene group of an unsaturated FA; this includes the HO' and HO2 radicals. The initiating free radical (X) abstracts a hydrogen atom from the carbon chain, generating a lipid carbon-centered radical ( L, reaction 1). This carbon-centered lipid radical tends to be stabilized by a molecular rearrangement that produces a conjugated diene, which then readily reacts with molecular oxygen to yield a hydroperoxyl radical ( LOO', reaction 2). The peroxyl radical can propagate the oxidizing chain reaction by abstracting electrons from other susceptible PUFA, forming another lipid free radical and a molecule of lipid hydroperoxide ( LOOH) (reaction 3). The overall chain reaction has a pyramidal effect through which a relatively few initiating radicals break down PUFA. These reactions continue until the chain is terminated, either by the combination of two radicals to form a nonradical product (reactions 4-7) or by termination of the propagation reaction in the presence of a hydrogen or an electron donor. Termination may also result from hydrogen abstraction from vitamin E (a-tocopherol) or another lipid antioxidant to form hydroperoxides. Vitamin E is termed a chain-breaking antioxidant because it donates a hydrogen atom to lipid radicals, thereby terminating the propagative process and lipid peroxidation. Lipid peroxidation can also be inhibited by reduction of lipid hydroperoxides by selenoperoxidases, such as glutathione (GSH)-peroxidase, to their corresponding alcohols.
Lipid peroxides are rapidly decomposed in vivo by metal ions and their complexes. The alkoxyl or peroxyl radical byproducts of lipid hydroperoxide breakdown can propagate the chain reaction of lipid peroxidation (61). Although lipid peroxides are highly toxic, they are poorly absorbed in vivo. The toxicity of peroxides has in part been attributed to their ability to oxidize the thiol groups of proteins, glutathione, and other sulfhydryl compounds and form insoluble deposits called lipofuscin in the artery wall or neural tissue (61).
The end products of lipid peroxidation include aldehydes and hydrocarbon gases. Short-chain aldehydes can attack amino groups on protein molecules to form cross-links between different protein molecules. The most commonly measured product is malondialdehyde (MDA), known to react with proteins and amino acids ( Fig... 4.5). Several studies have shown a positive relationship between in vivo lipid peroxidation and urinary excretion of MDA. MDA adduct formation with proteins, PL, and nucleic acids may be a cause of pathology as MDA adducts with serine, lysine, ethanolamine, and guanidine have been detected in urine ( 62).
lT*Hr.3|i. '-. ||.. I H.I-H 4£hCh. pìTAmP 'Hli.'l I
Figure 4.5. Three oxidation products associated with toxicity.
lT*Hr.3|i. '-. ||.. I H.I-H 4£hCh. pìTAmP 'Hli.'l I
Figure 4.5. Three oxidation products associated with toxicity.
Lipid peroxidation has been implicated in the pathogenesis of diseases, including cancer and atherosclerosis. Although products of lipid peroxidation are readily measurable in blood, the significance and occurrence of lipid peroxidation is controversial. A major criticism has been that lipid peroxidation may not be initially involved in causing the underlying disease pathology, as excess production of lipid peroxidation byproducts could result from the primary disease process. Also, many analytic methods produce some disruption of cell structure. Such disruption could produce misleading findings, as lipid peroxidation may accompany tissue damage, although some recent studies have dissociated lipid peroxidation from in vitro cell death ( 63).
The PL components of cellular membranes are highly vulnerable to oxidative damage because of the susceptibility of their PUFA side chains to peroxidation. Membrane lipid peroxidation results in loss of PUFA, decreased membrane fluidity, and increased permeability of the membrane to substances such as Ca 2+ ions. Lipid peroxidation can lead to loss of enzyme and receptor activity and have deleterious effects on membrane secretory functions. Continued lipid peroxidation can lead to complete loss of membrane integrity, as can be observed from the hemolysis associated with lipid peroxidation of erythrocyte membranes.
A wide range of dietary components has been reported to influence membrane susceptibility to oxidative damage. Cellular lipid peroxidation depends strongly on PUFA intake as well as intake of vitamin E and other lipid antioxidants. In isolated erythrocytes from human subjects, the production of lipid peroxidation products following hydrogen peroxide-induced oxidative stress has been measured as thiobarbituric acid-reactive substances (TBARS). Multivariate analysis showed that the unsaturation index was the best predictor of erythrocyte TBARS variability ( 64). A relatively stable C18:2n-6:vitamin E ratio in vegetable oils provides protection from risk of excessive lipid peroxidation and vitamin E deficiency at high PUFA intakes. Fish oils are an exception to the observation of a natural association between PUFA and vitamin E in edible fats and oils and the stability of PUFA to oxidation in the diet and body. The highly unsaturated n-3 pentanoic and hexanoic FA, found in abundance in fish and marine oils with relatively low vitamin E content, markedly increase the in vivo susceptibility of these oils to peroxidation ( 65). TBARS increased with higher concentrations of total n-3 PUFA in isolated human erythrocytes, whereas TBARS decreased with higher concentrations of total MUFA ( 64).
The effects of oxygen free radicals on membrane CH may be as important as the effects observed on membrane PL, since oxidized CH derivatives, the oxysterols or CH oxides, have been suggested to play a key role in development of atherosclerosis (66). This concept has been fostered by increasing evidence of the role of oxidatively modified lipoproteins in atherogenesis. CH readily undergoes oxidation ( 67), and the metabolites derived display a wide variety of actions on cellular metabolism, including angiotoxic, mutagenic, and carcinogenic effects (66). Common CH oxidation products include cholesterol-5a,6a-epoxide, cholesterol-5b,6b-epoxide, and cholestane-3b,5a,6b triol ( Fig.. .. 4...5). CH oxides disturb endothelial integrity by perturbing vascular permeability, whereas purified CH has no effect. CH oxidation products have been detected in human serum lipoproteins and human atheromatous plaques ( 68). Substantial amounts of oxidized CH are detected in a variety of foods of animal origin exposed to oxidizing conditions ( 67). These highly atherogenic oxysterols may also be ingested and absorbed from processed foods or generated by free radical oxidation of lipoproteins. To date, however, it is unclear whether CH oxides merely serve as markers for oxidatively modified lipoproteins or if they contribute to the toxicity of oxidized lipoproteins. In addition, analysis of oxysterols is beset by such difficulties as artifact generation and decomposition of oxysterols during sample manipulation (67).
LDL oxidation has been implicated as a causal factor in development of human atherosclerosis (69). Unsaturated lipids in LDL are subject to peroxidative degradation, and the susceptibility of LDL to oxidation has been correlated with the degree of coronary atherosclerosis ( 70). Autoantibodies exist in human serum, and oxidized LDL is present in atherosclerotic plaque, indicating that oxidized LDL exists in vivo ( 71). Possible sources of oxidation include endothelial cells, smooth muscle cells, monocytes, macrophages, and other inflammatory cells. In the presence of the promoter copper, peroxidation of LDL results in formation of hydroxyalkenals and MDA, which modify Apo-B by reacting with its lysine amino groups. This modification of Apo-B could, in turn, impair its uptake by the LDL receptor. Oxidatively modified LDL may exert atherogenic effects via their cytotoxic and chemotactic properties and the promotion of LDL uptake by the scavenger receptors on macrophages leading to the formation of lipid-enriched foam cells.
Nutritional and biochemical studies suggest that diet can modulate the susceptibility of plasma LDL to oxidative degradation by altering the concentration of PUFA and antioxidants in the lipoprotein particle. The first targets of peroxidation in the oxidation of LDL are PUFA of PL on the LDL surface. In studies of LDL isolated from healthy humans and animals, a diet rich in C18:2n-6 increased the susceptibility of plasma LDL to copper-induced oxidation and to in vitro macrophage uptake, compared with a diet high in C18:1n-9 (72). C18:1n-9 and other MUFA do not contain the easily oxidized conjugated double bonds found in PUFA. Also, C18:1n-9 has a high affinity for transition metals, making them unavailable for LDL peroxidation. Depending on the dose used, subjects treated with n-3 PUFA showed either an increase or no change in LDL oxidation (73). Other studies have shown that increasing the amount of vitamin E in the LDL particle via oral supplementation decreased LDL susceptibility to in vitro oxidative damage (74). A difficulty with in vitro assays of plasma lipoprotein oxidation is that these assays are subject to influences by a variety of plasma substrates and conditions, making their relevance to physiologic situations uncertain. However, recent clinical evidence of protection against cardiovascular disease by vitamin E supplementation and the inhibition of atherosclerotic lesions in animals by antioxidants supports the oxidative hypothesis of atherosclerosis and the likely effectiveness of dietary antioxidants ( 7,5, 76). The lower incidence of cardiovascular disease in populations consuming more olive oil may be partly due to an inhibition of LDL oxidation by the antioxidant action of olive oil as well as by those antioxidants found in fruits and vegetables associated with the Mediterranean diet.
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