**1. Introduction**

The metabolic syndrome (MS) refers to the occurrence in an individual of multiple physiological disorders related to obesity, hypertension, dysregulated blood glucose and dysregulated blood lipids, and is a risk factor for diabetes and cardiovascular disease [1]. It has been defined more specifically, and in slightly different ways by the National Cholesterol Education Program (NCEP) Adult Treatment Panel III, and by the World Health Organization (WHO). According to the former, MS is characterized by at least three of the following five clinical or biochemical abnormalities: abdominal obesity, arterial hypertension, elevated fasting blood glucose, high plasma triglycerides, and reduced high density lipoprotein cholesterol (HDL-c) [2]. On the other hand, WHO defined it as the occurrence of impaired glucose tolerance or impaired fasting glucose or diabetes and any two of the following: hypertension; elevated trigycerides or low HDL-c; abdominal obesity or obesity as determined by BMI; or microalbuminaria [1].

A proper understanding of the etiology of MS is necessary for its prevention and treatment. This chapter focuses on the role of lipid peroxidation in this pathophysiological process. It begins with a current understanding of the mechanisms of lipid oxidation, with emphasis on the formation of highly reactive lipid oxidation products such as 4-hydroxy-2-nonenal, malondialdehyde, acrolein and glyoxal. This is followed by a discussion of how these aldehydes and other lipid oxidation products contribute to the different MS components. The role of major dietary components in the initiation of oxidative stress and lipid oxidation, as well as mechanisms by which specific dietary components inhibit such undesirable events are also discussed.

### **2. Mechanisms of lipid peroxidation (LPO) and the formation of bioactive lipid oxidation products**

In cells, extensive lipid oxidation and the accumulation of lipid oxidation products occurs under conditions of oxidative stress, when the concentrations of reactive oxygen species (ROS) such as superoxide anions, hydrogen peroxide and singlet oxygen increase, and are not matched by an increase in the cellular antioxidant capacity [3]. Electron leakage from the mitochondrial electron transport chain, or the actions of enzymes such as NADPH oxidases and xanthine oxidase generate superoxide anions (·- O2), which are converted by superoxide dismutase to hydrogen peroxide (H2O2), which may be converted by ferrous ions (Fe 2+) to hydroxyl radicals (·OH) according to the Fenton reaction Eq. (1). Superoxide anion also reacts with nitric oxide (NO), formed by nitric oxide synthases, to form the highly reactive peroxynitrite anion (-OONO), which reacts with H2O2 to form singlet oxygen according to Eq. (2), and this is only one of many possible mechanisms of formation of singlet oxygen in biological systems [4–6].

$$\text{COOH} + \text{Fe}^{2+} \rightarrow \text{Fe}^{3+} + \text{^{\cdot}OH} + \text{HO}^{\cdot} \tag{1}$$

$$\rm{HONOO^{-}} + \rm{HOOH} \rightarrow \rm{^{1}O\_{2}} + \rm{ONO^{-}} + \rm{H\_{2}O} \tag{2}$$

Lipid peroxidation involves a reaction between unsaturated lipids and oxygen. This may be enzyme-catalysed or non-enzymatic. Non-enzymatic lipid oxidation is either mediated by singlet oxygen, or it may involve free radical oxidation [7]. Singlet oxygen reacts by electrophilic addition to any of the double bonds in an unsaturated fatty acid such as linoleic acid (LA) to form hydroperoxide isomers such as the 10-, 12- and 13-LA hydroperoxides (10-LA-OOH, 12-LA-OOH and 13-LAOOH) as shown in **Figure 1**.

On the other hand, free radical oxidation begins by the abstraction of a hydrogen atom from a fatty acid, for example by the hydroxyl radical, to form a carbon centred radical, which rearranges to form a relatively stable conjugated radical (**Figure 2**). The latter reacts with oxygen to form a peroxyl radical, which abstracts a hydrogen from another fatty acid molecule to form a hydroperoxide and a new carbon centred radical, hence establishing a free radical chain reaction (**Figure 2**).

A fatty acid hydroperoxide can be converted to an alkoxyl radical by Fe2+ (**Figure 3**), in analogy to the conversion of H2O2 to the hydroxyl radical according to Eq. (1). The alkoxyl radical can be converted to a number of non-aldehydic products, including a hydroxy acid and a keto-acid, or it can cyclize to form an epoxy-allylic radical whose further oxygenation affords a hydroperoxy-epoxide

*Lipid Peroxidation as a Link between Unhealthy Diets and the Metabolic Syndrome DOI: http://dx.doi.org/10.5772/intechopen.98183*

#### **Figure 1.**

*Formation of different hydroperoxide isomers by the singlet oxygen-mediated oxidation of linoleic acid.*

**Figure 2.**

*Free radical peroxidation of linoleic acid showing the formation of one of the two most readily formed hydroperoxides, the 9-hydroperoxide. The other easily formed hydroperoxide is the 13-hydroperoxide (shown in Figure 1).*

(not shown) that can further be converted to various products including epoxyketo-acids, such as 12,13-epoxy-9-keto-10*E*-octadecenoic acid (**Figure 3**), which contributes to hypertension as discussed in Section 3.2.

An alkoxyl radical can also undergo beta scission (C-C cleavage) to form an aldehyde and a carbon centred radical, and this is only facile if the latter is a resonance stabilized allylic radical, such as would be formed from the 10-LA-OOH (**Figure 4**) or 12-LA-OOH but not 13-LA-OOH [8]. Beta scission is also facile if the carbon bearing the alkoxyl radical occurs next to another oxygen-bearing carbon [9]. Various pathways fulfilling these conditions have been proposed for the formation of the major bioactive lipid-derived aldehydes such as MDA, HNE, acrolein and glyoxal [9, 10].

Acrolein is mainly formed from PUFAS with more than two double bonds, such as arachidonic acid, eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA) and docosahexaenoic acid (DHA) [9]. **Figure 5** shows examples of how MDA, HNE and glyoxal can all be formed from linoleic acid, the most abundant PUFA in most human tissues [3–6]. It starts with the 13-LA-OOH, formed by singlet

#### **Figure 3.**

*Conversion of the 13-hydroperoxide of linoleic acid (13-LA-OOH) via the corresponding alkoxyl radical to different types of non-aldehydic products.*

#### **Figure 4.**

*b-Scission of an alkoxy radical to form an aldehyde (2-heptenal) and an allylic radical. Scission on the other side of the alkoxyl radical to form a vinyl radical and 12-oxo-9-dodecenoic acid is energetically unfavourable.*

oxygen -mediated or free radical oxidation, which further reacts with singlet oxygen to form a hydroperoxy-dioxetane (addition of singlet oxygen to a conjugated double bond system forms dioxetanes rather than hydroperoxides). The dioxetane is unstable, and decomposes to form two aldehydes, namely 9-oxononanoic acid and 4-hydroperoxy-2-nonenal (4-HPNE). The former is one of the predominant products of linoleic acid oxidation, and contributes to hypertension through activating phospholipase A2 (Section 3.2). A primary amine (RNH2) such as lysine or phosphatidylethanolamine may catalyse the conversion of 4-HPNE via a dioxetanyl anion to a dioxetane whose cleavage affords MDA and hexanal (**Figure 5**). While it has long been known that linoleic acid is a precursor of MDA, albeit not as readily as from more highly unsaturated PUFAS, its mechanism of formation from linoleic acid remained elusive [11]. 4-HPNE can alternatively react with another singlet oxygen molecule to form a hydroperoxy-dioxetanyl aldehyde whose decomposition affords glyoxal and 2-hydroperoxy-heptanal (not shown). 4-HPNE can also be converted to an alkoxyl radical, which can abstract a hydrogen to form 4-HNE, or to an epoxy-alkyl radical which can rearrange to an ether radical whose further

*Lipid Peroxidation as a Link between Unhealthy Diets and the Metabolic Syndrome DOI: http://dx.doi.org/10.5772/intechopen.98183*

**Figure 5.** *Mechanisms of the conversion of the 13-hydroperoxide of linoleic acid (LA-OOH) to 4-HNE, MDA, glyoxal, hexanal and 9-oxo-nonanoic acid. Other pathways to these products exist but are not shown.*

reaction with oxygen leads to formation of a per acetal that can decompose to MDA and hexane. The epoxy-alkyl radical can also directly react with oxygen to form a hydroperoxy-epoxide whose decomposition affords glyoxal. In the cell, glutathione peroxidase may contribute to the conversion of 4-HPNE to 4-HNE.
