**3. Lipid peroxidation products contribute to the development of the metabolic syndrome**

Lipid oxidation products influence the pathogenesis of metabolic syndrome components such as obesity, hypertension, impaired fasting glucose/diabetes, and dyslipidemia, in various ways [12].

### **3.1 Obesity**

Obesity occurs when adipocytes increase in number and/or size, coupled with increased fat storage and reduced fat oxidation. Adipose tissue (AT) is functionally classified as brown or white (BAT and WAT, respectively). BAT consists of adipocytes specialized for thermogenesis, and hence contribute to reduction of obesity; while WAT, the major type of adipose tissue in humans, has less capacity for fat oxidation, and may contribute to obesity [13]. White adipocytes can exist in or acquire a brown-like (beige or brite) phenotype with higher fat oxidation than ordinary white adipocytes, and a higher number of beige adipocytes reduces an individual's susceptibility to obesity [13]. Expansion of WAT by differentiation of preadipocytes (hyperplasia) into mature adipocytes with adequate lipid filling and fat oxidation

capacity is beneficial for safe storage of fat; but mere expansion of mature adipocytes because of excessive lipid filling and reduced fat oxidation (hypertrophy) is associated with adverse health outcomes.

A certain amount of ROS is required for proper preadipocyte and mature adipocyte physiology. However, oxidative stress and excessive autophagy may inhibit preadipocyte differentiation and promote hypertrophy of mature adipocytes (**Figure 6**) [14]. Likewise, brown or beige adipocytes have many mitochondria for the enhanced fat oxidation, but mitochondrial oxidative stress causes loss of the mitochondria through mitophagy, thus leading to whitening, increased lipid storage and hypertrophy (**Figure 6**) [15]. Adenosine 5-monophosphate kinase (AMPK), sirtuins 1 and 3, protein kinase B (akt), peroxisome proliferator activated receptor gamma and alpha (PPARγ and PPARα, respectively), and PPARγ coactivator-1α (PGC-1α) are among the proteins that reduce oxidative stress and/or promote mitochondrial biogenesis in adipocytes [16, 17]. Both protein kinase A (PKA) and akt are required for PPARγ expression [18], which is required for differentiation of both brown and white adipocytes [19]. PPARγ promotes thermogenesis in mature brown adipocytes through activation of uncoupled protein 1 (UCP-1), and by upregulating glycerol kinase which catalyses glycerol-3-phosphate synthesis, which is required for TG synthesis [20]. While this looks paradoxical, TG synthesis may help reduce the lipotoxicity and oxidative stress induction by free fatty acids (discussed in Section 4), and allow targeted, β-adrenergic signaling-associated release of fatty acids for mitochondrial oxidation. AMPK activates autophagy and induces the transcription factor nrf2; and the latter upregulates antioxidant enzymes such as catalase, glutathione peroxidase, superoxide dismutase and heme oxygenase 1 [21]. Sirt1, which is mainly localized in the nucleus, increases the expression catalase and SOD as reviewed by Iside et al. [22]. In addition, it upregulates autophagy genes, and autophagy defect associated with its inhibition promotes release of exosomes which induce toll-like receptor 4 (TLR4) signaling, downstream activation of nuclear factor kappa B (NF-kB), and NF-kB-mediated upregulation of oxidative stress and inflammation-promoting genes [23].

**Figure 6.**

*Role of oxidative stress and lipid oxidation-induced carbonyl stress in the pathogenesis of hypertrophic obesity.*

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

Conditions that promote adipose tissue oxidative stress, including inappropriate diets (Section 4), induce lipid oxidation, and the latter generates carbonyl stress due to formation of various aldehydes as explained in Section 2. These aldehydes, including HNE and acrolein modify and inhibit AMPK and sirt1, thus amplifying oxidative stress and their own formation (**Figure 6**) [24–26]. HNE also carbonylates insulin receptor substrate1/2 (IRS1), leading to degradation and inhibition of the latter, thus inducing insulin resistance and downstream akt inhibition [27]. Thus, insulin resistant obese individuals have lower akt, AMPK ad sirt1 activity, but higher reactive carbonyls and carbonylated proteins [28]. Acrolein and HNE additionally aggravate oxidative stress through readily reacting with, and depleting the antioxidant glutathione [29, 30]. They modify the endoplasmic reticulum calcium pump SERCA, leading to its inhibition and ER stress [3], which aggravates oxidative stress, insulin resistance, sirt1 inhibition, expression of the pro-inflammatory cytokines, TNFα and IL6, and adipocyte whitening [31, 32]. Glutathionylated HNE and other aldehydes released from adipocytes under conditions of oxidative stress promote macrophage infiltration into WAT, and their acquisition of a proinflammatory M1 phenotype [33]. Malondialdehyde reacts with albumin, and the MDA-albumin conjugates promote a proinflammatory phenotype in macrophages and T cells [34]. Cytokines such as interleukin1-β, released from inflammatory macrophages, in turn promote adipocyte oxidative stress and whitening [35].

#### **3.2 Hypertension**

Arterial hypertension occurs because of (i) increased renal retention of sodium and water (ii) dysregulation of vasodilators and vasoconstrictors and (iii) arterial stiffness. Obesity is a major risk factor for hypertension [36]. For example, adiponectin inhibits adrenal production of aldosterone, a potent inducer of hypertension [37], but obesity reduces adiponectin secretion and increases circulating aldosterone [38]. Thus, by promoting obesity, lipid peroxidation products indirectly promote hypertension. However, they also induce hypertension independently of obesity. For example, the non-aldehydic linoleic acid oxidation product, 12,13-epoxy-9-keto-10-*Ε*-octadecenoic acid (Shown in **Figure 3**) also promotes adrenal production of aldosterone to induce hypertension [39].

Aldosterone binds to the renal tubular epithelial cell mineralocorticoid receptor, which, as a transcription factor, upregulates the expression of the epithelial sodium channel, which promotes sodium retention [40]. Independently of gene transcription, aldosterone activates the non-receptor tyrosine kinase cSrc in these cells, probably through the angiotensin receptor type 1 (AT1R), and cSrc activates epidermal growth factor receptor (EGFR) signaling, leading to activation of the mitogen activated protein kinase Erk1/2 [40]. Erk1/2 activates Na+ /K+ ATPase, which promotes sodium and water retention [41]. Aldosterone-cSrc signaling also induces oxidative stress [40], which induces formation of lipid oxidation products. 4-HNE, inhibits AMPK and sirt1, thus inhibiting eNOS, leading to reduced NO bioavailability, and this causes increased transactivation of EGFR and downstream Erk1/2 [42–44]. Thus, blood HNE levels are increased in hypertension [45], and the latter can be ameliorated by carbonyl quenching [46]. Oxidized low density lipoprotein, which contains oxidatively modified lipids such as HNE, induces oxidative stress in renal tubular endothelial cells, which activates the renal renin-angiotensin system (RAS); whose component, angiotensin 2, overstimulates sodium transporters and thus induces hypertension [47, 48]. Hypertension in turn promotes oxidative stress and LDL oxidation, thereby creating a vicious circle [49].

Inhibition of endothelial cell sirt1, sirt3 and AMPK, which can be mediated by LPO products, causes inhibition of endothelial nitric oxide synthase (eNOS) and

decreases production of NO, the main arterial vasodilator [50–52]. HNE induces endothelial cell insulin resistance, and the associated akt inhibition both inhibits eNOS and upregulates the vasoconstrictor, endothelin [3, 53]. The dysfunctional endothelial cells further produce pro-inflammatory factors such as TNFα, IL-1β, IL-8 and MCP-1 which recruit circulating neutrophils, platelets and monocytes, and the latter differentiate into macrophages [53, 54]. Neutrophils, monocytes and macrophages secrete myeloperoxidase [55]. Myeloperoxidase oxidizes LDL [56]. It also promotes the activation of endothelial cyp4a12a, which catalyzes the formation of 20-hydroxy-eicosatetraenoic acid (20-HETE) from arachidonic acid [57]. 20-HETE upregulates endothelial RAS components including angiotensin 2, a potent vasoconstrictor, which also induces aldosterone secretion [58]. Both angiotensin 2 and aldosterone aggravate endothelial oxidative stress and dysfunction. Androgens promote 20-HETE synthesis, and this may explain the higher occurrence of hypertension in men than women [58].

Stiffness of the coronary artery and other major arteries inhibits their systolic dilatation, and thus promotes systolic hypertension [59]. Degradation of the elastic fiber, elastin, in the walls of the major arteries, and its replacement with collagen fibres is a hallmark of the pathogenesis of arterial stiffness [59]. The myeloperoxidase product, 20-HETE, activates matrix metalloproteinase 12 (MMP-12, macrophage elastase), which degrades elastin [60]. Myeloperoxidase additionally inhibits the elastase inhibitor, α1, and this is antagonized by sulfur compounds such as glutathione [61]. Acrolein and HNE, on the other hand, deplete glutathione [62]. 20-HETE additionally sensitizes vascular smooth muscle cells to stimuli that promote their dedifferentiation and proliferation [58], which contributes to arterial stiffening especially of the muscular arteries [63]. One of the most readily formed aldehydic linoleic acid oxidation products, 9-oxononanoic acid (**Figure 3**) activates phospholipase A2 (PLA2) leading to generation of eicosanoids and thromboxane A2 in blood [64]. Thromboxane A2 causes vasoconstriction and the proliferation of smooth muscle cells [65].

Malondialdehyde forms collagen crosslinks that prevent collagen degradation, thus promoting arterial stiffness [66]. Thus, MDA-modified LDL independently predicts arterial stiffness [67]. Glyoxal contributes to arterial stiffness by reacting with collagen to form advanced glycation end products such as GOLA, GOLD, GODIC and carboxymethyl lysine (CML) [68]. CML induces endothelial oxidative stress through the RAGE receptor, which activates components of NF-kB signaling that promote expression of collagen 1 and 2 [69, 70].

#### **3.3 Dyslipidemia**

Dyslipidemia in metabolic syndrome is defined by elevated circulating triglycerides (hypertriglyceridemia) or low levels of high-density lipoprotein cholesterol (low HDLc); and hepatic steatosis, a component of non-alcoholic fatty liver disease (NAFLD) is its main risk factor [71]. This is because, in hepatic steatosis, there occurs greater production and secretion of triglyceride-rich very low-density lipoproteins (VLDL), leading to hypertriglyceridemia; as well as higher hepatic lipase activity, which increases the hepatic uptake and degradation of HDL [71]. Hepatocyte oxidative stress, ER stress and associated lipid peroxidation are involved in the development of hepatic steatosis [72, 73], and this makes lipid peroxidation an important factor in the development of dyslipidemia [74].

Low HDLc also occurs in obesity independently of elevated triglycerides, indicating that it occurs even independently of NAFLD [75]. Hypoadiponectinemia, which depends on obesity rather than NAFLD [76], may cause reduced HDLc through increased hepatic lipase activity; reduced

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

hepatic expression of the HDL protein apo A; reduced expression of the cholesterol export protein ABCA1 which transfers cholesterol to HDL; and upregulated synthesis of LCAT which transfers cholesterol from HDLc to chylomicrons [77]. Obesity is also associated with increased plasma TNFα [78] which suppresses hepatocyte apo AI gene expression via ERK and JNK [79]. HNE contributes to JNK over-activation in hepatocytes [80].

### **3.4 Prediabetes and diabetes**

Diabetes is a state of elevated postprandial and/or fasting blood glucose that, if not controlled, leads to the damage of various organs; while prediabetes refers to an intermediate level of fasting and/or postprandial blood glucose, higher than normal but less than diabetic blood glucose levels [1]. It is an earlier stage toward the development of diabetes, but which can revert to normoglycemia. The major causes of (pre)diabetes are pancreatic alpha and beta cell dysfunctions leading to glucagon over-secretion and insulin under-secretion, respectively; coupled with skeletal muscle, adipose and/or hepatic insulin resistance [81].

Both obesity and hypertension contribute to the pathogenesis of prediabetes, hence the lipid oxidation products that induce obesity and hypertension indirectly promote diabetes thereby. Nevertheless, lipid oxidation products also directly promote (pre)diabetes. For example, malondialdehyde was found to dose-dependently reduce the insulin content in the pancreas and to contribute to beta cell death [82]. HDL prevents beta cell apoptosis and diabetes by promoting cholesterol efflux from these cells, but acrolein- or MDA-modified HDL loses this protective property [83–85]. oxLDL impairs insulin gene expression and causes death of pancreatic beta cells, through induction of oxidative stress and ER stress [86]. As already discussed, lipid oxidation products induce endothelial dysfunction. Pancreatic endothelial cell dysfunction contributes to diabetes, being associated with leukocyte recruitment and increased production of proinflammatory cytokines [87]. Cytokines such as IL-1β and TNFα induce alpha and beta cell oxidative stress [88] and associated lipid peroxidation. Insulin resistance, which can be induced by HNE and acrolein, is part of the alpha cell and beta cell dysfunctions leading to diabetes [81].
