Effecs Of Irr On Wound Healing

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FIGURE 3.3 Phospholipids are amphipathic molecules with two fatty acid side chains (R) and a phosphorylated alcohol head group. Linked to the phosphate group is an additional polar group (X) that may consist of choline, ethanolamine, serine, or inositol.

ATP, but they are also readily stored in adipocyte TAGs. One reason for this is that LC-SFAs require carnitine acyltransferase for transport into the mitochondria for oxidation,25 so they are, therefore, more readily incorporated into TAGs. Some saturated fatty acids, like stearic acid (18:0), will be stored in TAGs or will be desaturated and converted to monounsaturated fatty acids (MuFAs), such as oleic acid (18:1; ra-9), before storage or P-oxidation.26 Medium-chain fatty acids (8 to 14 carbon) are preferentially P-oxidized in liver mitochondria, because they do not require enzyme transport into the mitochondria. The MuFA are readily utilized for energy by P-oxidation in mitochondria but may also be stored in adipocyte TAGs.27 The long-chain rn-3 and m-6 PuFAs (> 18 carbon) (Figure 3.4) are a significant component of cellular phospholipids but may also occur, to some degree, in TAGs. This lipid class is considered essential, because mammals do not have the enzymatic ability to insert a cis double bond at the rn-3 or rn-6 position of a fatty acid chain, and therefore, these must be acquired from the diet. The types, amounts, and ratios of these nutrients in the diet have been the subject of extensive research due to the fact that they are the source of eicosanoids, which participate in control of the inflammatory response. The parent compounds for each of these fatty acid classes (linoleic acid, 18:2, rn-6 and a-linolenic acid, 18:3, rn-3) compete for 8-6-desaturase and elongase enzymes, and the 20-carbon rn-3 and rn-6 PuFA, eicosapentaenoic acid (EPA, 20:5; rn-3) and arachidonic acid (AA, 20:4; rn-6) compete for cyclooxygen-ase/lipoxygenase enzymes, which influences the amounts and types of eicosanoids formed from these nutrients. Arachidonic acid is a major component of mammalian membranes. Arachidonic acid is readily formed via elongation and desaturation of linoleic acid or by retroconversion of adrenic acid by removal of a two-carbon unit.

a-linolenic acid (18:3,m3) cis-linoleic acid (18:2, m6)

jj | A5-desaturase | jj eicosapentaenoic acid (20:5, m3) arachidonic acid (20:4, m6)

H | cyclooxygenase / lipoxygenase | Jj,

3-series prostanoids 2-series prostanoids

5-series leukotrienes 4-series leukotrienes

FIGURE 3.4 The parent compounds for the essential ro-3 and ro-6 fatty acids are18 carbon fatty acids that may be desaturated and elongated to form the longer-chain polyunsaturated fatty acids. Arachidonic acid (20:4, ro-6) and eicosapentaenoic acid (20:5, ro-3) are substrates for cyclooxygenase and lipoxygenase enzymes that result in the formation of eicosanoids from these fatty acids.

Likewise, EPA is readily formed from a-linolenic acid, but retroconversion from the highly unsaturated docosahexaenoic acid (DHA, 22:6; rn-3) requires removal of both a double bond and a two-carbon unit. The P-oxidation pathway in the peroxisomes is utilized for catalyzing the oxidation of very-long-chain fatty acids, and the highly unsaturated m-3 fatty acids stimulate peroxisomal P-oxidation.28,29 In the liver, the acetyl-CoA generated by P-oxidation is used to produce acetoacetate and P-hydroxybutyrate (ketone bodies), which the brain may use as an alternative energy source. There have been conflicting reports about the ability to store these fatty acids in adipocyte TAGs, especially the longer-chain rn-3 PuFA. One study found differences in postprandial storage of fatty acids in adipose tissue, with the amount of MuFA being > rn-6 PuFA > saturated > m-3 PuFA.30 Some reports indicate minimal storage ability for EPA,31,32 whereas others provide evidence for long-chain rn-3 PuFA (EPA and DHA) in adipose tissue.33 34 The possibility of rn-3 and rn-6 PuFA being released from adipocyte TAGs during wound healing could be significant if the nutritional status was such that there was mobilization of TAG fatty acid stores for energy metabolism (e.g., hypermetabolic state).

In nature, trans-fatty acids occur in small amounts in dairy products and in some plant oils. Currently, there are attempts to reduce the amount of these fats in prepared foods, but they are still a significant energy source in the Western diet due to the consumption of hydrogenated vegetable oils,35 and therefore should be mentioned in this section. Trans fatty acids behave very much like saturated fats, and they are transported in a manner similar to other fatty acids and can be found within the cholesterol ester, triacylglycerol, and phospholipid fractions of lipoproteins.36 There is evidence that the content of adipose tissue trans fatty acid is a reflection of diet content.37,38 These fats are associated with a greater risk of ischemic heart disease than even saturated fat.39,40 The effects on wound healing by this class of fatty acids are currently unknown.

Glucose and fatty acids are the main oxidative fuels in the body and account for a majority of oxidative metabolism. There are still many questions that need to be answered about the interaction of glucose and fatty acid metabolism, especially the differences that may exist between the resting and exercise states. However, an understanding of energy metabolism in the body requires an examination of how these two pathways interact. Lipolysis and lipogenesis in adipose tissue and fatty acid oxidation in liver and skeletal muscle may be influenced by the type of fat, as indicated above, but they are also under the control of several hormones and transcription factors that regulate fatty acid metabolism Adipose tissue contains a hormone-sensitive lipase that is suppressed by insulin. An elevation in blood glucose stimulates insulin secretion, which suppresses the release of NEFA from adipose tissue TAGs. However, when insulin levels fall, the hormone-sensitive lipase activates so that NEFA may be released. Beyond this simple explanation of what has come to be known as the glucose-fatty acid cycle,41-43 it is evident from many studies that the interaction between glucose and fatty acid metabolism involves additional levels of regulatory control and cross talk that influence utilization of these energy sources. If carbohydrate/glucose is the primary energy source, then glucose oxidation is promoted along with storage of energy as glycogen and TAGs, and fatty acid oxidation is inhibited. However, in the presence of adequate insulin, free fatty acids compete with glucose for uptake by peripheral tissues, so that the presence of free fatty acids promotes fatty acid oxidation and inhibition of glucose oxidation. Low insulin levels elevate lipolysis rates, and the free fatty acids actually enhance endogenous glucose output.42 This effect of fatty acids on glucose metabolism is likely due to a direct action of fatty acids upon the pancreatic P-cell, by influencing glucose-stimulated insulin secretion. Initially, fatty acids may potentiate the effects of glucose on the P-cell, but prolonged exposure (> 12 h) to high fatty acid concentrations can then result in inhibition.26

In addition to insulin, the adipocyte-derived hormones leptin and adiponectin are involved in fatty acid metabolism, as well as the recently identified acylation-stimulating protein (ASP). Leptin directly inhibits fatty acid synthesis4445 and increases the release and oxidation of fatty acids by activating hormone-sensitive lipase.46 Leptin also has multiple additional metabolic and endocrine functions. Leptin functions in immunoregulation, inflammation, and hematopoiesis,47 and regulates food intake by communicating with the hypothalamus about the degree of fat stores and changing eating behavior accordingly to maintain a level of homeostasis.48 It may also regulate TAG homeostasis by restricting TAG storage primarily to adipocytes and sparing nonadipocytes.49 Leptin deficiency may lead to hyperglycemia, hyperinsulinemia, and insulin resistance.50 A review of the role of leptin in lipid metabolism provides more information on this topic.51 A possible role for leptin in wound healing will be discussed in the section on fat metabolism in the healing wound. Adiponectin stimulates fatty acid oxidation and affects glucose metabolism by increasing insulin sensitivity. This hormone also may suppress inflammation.14,52 Additional research is needed to understand the role of ASP in fat metabolism, but the data indicate it may augment fat storage by increasing TAG synthesis and by decreasing intracellular lipolysis.13

In addition to hormonal effects on glucose and fatty acid metabolism, there are several transcription factors that regulate metabolism. Polyunsaturated rn-3 and rn-6 fatty acids are known to inhibit hepatic lipogenesis by inhibiting transcription of a number of genes necessary for lipid synthesis (fatty acid synthase, acetyl-CoA carboxylase, and stearoyl-CoA desaturase).53 This effect is currently known to be mediated, in part, by a family of membrane-bound transcription factors called sterol regulatory element-binding proteins (SREBPs) that occur as three iso-forms.54-57 Fatty acid homeostasis in cellular phospholipids is mediated by SREBPs. The cholesterol content of cell membranes serves as a feedback mechanism on the activity of SREBPs. When cholesterol content is adequate, the SREBPs are inactive and remain bound to endoplasmic reticulum (ER) membranes. Sterol depletion in the membrane is a signal for SREBPs to move to the Golgi in ER transport vesicles, and this process is initiated by an SREBP cleavage activating protein that functions both as a sterol sensor and an escort protein. In the Golgi, the release of the active amino-terminal portion of the SREBPs from the membrane is mediated initially by a serine protease and then a zinc metalloprotease before translocation to the nucleus. In addition to regulating sterol content of membrane phos-pholipids, SREBPs modulate the action of insulin on adipocyte gene expression by activating genes for cholesterol, fatty acid, and TAG synthesis58 and suppressing genes for fatty acid oxidation.59 Peroxisome proliferator-activated receptors (PPARs) are members of the superfamily of ligand-activated nuclear transcription factors. This family of receptors was first recognized as regulators for the synthesis, adipocyte storage, and oxidation of fatty acids. A secondary effect of their action on lipid metabolism is modulation of glucose homeostasis. A detailed analysis of PPARs activity may be found in several reviews on the subject.60,61 The three PPAR subtypes are: PPARa, PPARp/8, and PPARy.6263 PPARa is expressed primarily in liver and skeletal muscle; PPARy is found in adipose tissues64; and PPARp/8 is ubiquitous in most cell types.65 PPARs are activated by many LC-SFA, PuFA, and eicosanoids.11 When activated, PPARs affect gene transcription by binding to response elements of target genes. Many of the response elements are associated with genes encoding proteins of fatty acid metabolism, such as fatty acid synthase, acyl-CoA oxidase, lipoprotein lipase, and phosphoenolpyruvate carboxykinase.66,67 Activation of PPARy helps regulate glucose homeostasis by directing fatty acids derived from TAGs toward adipose tissue rather than muscle, which has the result of increasing muscle glucose metabolism. Activation of PPAR8 in adipose tissue induces genes needed for fatty acid oxidation.68,69 Beyond these effects of energy metabolism, this class of receptors is now recognized to have an additional role in inflammation and immune regulation.70,71

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Turbo Metabolism

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