**4. Role of dietary constituents in inducing tissue oxidative stress, lipid peroxidation and the metabolic syndrome**

Diets high in saturated fatty acids, cholesterol, sugar, salt, and red meat, contribute to higher lipid oxidation in the tissues and organs that have a central role in the metabolic syndrome, such as adipose tissue, endothelial tissue, muscle, liver and pancreas.

Although saturated fatty acids do not undergo peroxidation, they contribute to the induction of oxidative stress in cells, which then leads to peroxidation of unsaturated fatty acids. For example, the most abundant saturated fatty acid in the diet, palmitic acid, is a key substrate for the first reaction in ceramide biosynthesis [89]. Ceramides induce oxidative stress, for example by inhibiting components of the electron transport chain [90].

Palmitate also induces oxidative stress and ER stress independently of ceramide. For example, it increases diacylglycerol levels, which is associated with activation of protein kinase C (PKC), which inhibits the Kreb's cycle enzymes aconitase and isocitrate dehydrogenase [91]. Thus, the acetyl COA generated from peroxisomal and mitochondrial fatty acid beta oxidation accumulates in the cell, promoting

acetylation of mammalian target of rapamycin complex (MTORC-1) and high mobility group box-1 (HMGB-1), as has been demonstrated in hepatocytes [92]. Acetylation activates MTORC-1, which inhibits akt and further promotes oxidative stress by upregulating the expression of TLR4, thus upregulating the NF-kB-NADPH oxidase/iNOS axis [92]. Acetylation of HMGB-1 causes its translocation out of the cell, enabling it to induce oxidative stress by interacting with the receptor for advanced glycation end products (RAGE) as well as TLR4, which both induce NF-kB activation [93]. Obesity is associated with increased circulating HMGB-1, which accelerates the pathogenesis of obesity, hypertension and diabetes [72, 73, 94, 95]. TLR2/4 signaling also activates RAS components including angiotensin 2, whose signaling via its receptor AT1R induces NFkB and oxidative stress [3, 96].

PUFAS undergo peroxidation during cooking as well as in the digestive tract [97]. This is more pronounced when they are part of a meal containing meat, especially red meat, which has higher myoglobin content; since iron from the latter promotes lipid oxidation [98]. This leads to a postprandial increase in circulating carbonyls such as malondialdehyde and HNE, which promote oxidative stress, HDL modification and postprandial inflammation [98, 99]. On the other hand, absorbed, unoxidized unsaturated fatty acids including MUFAs and PUFAs reduce palmitateinduced oxidative stress and lipotoxicity in many cell types by promoting the incorporation of palmitate into TGs for safe storage [100–102]. Nevertheless, high concentrations of arachidonic acid also induce deleterious effects. Thus, supplementation of arachidonic acid to a high fat diet led to enhanced obesity in mice [103], which is attributable to the fact that this n-6 fatty acid promotes adipogenesis from preadipocytes, but its cyclooxygenase-mediated oxidation products, prostaglandins E2 and F2a (PGE2 and PGF2a) inhibit browning via ERK activation and associated decrease in UCP-1 expression [104, 105]. These prostaglandins activate NF-kB, diminish adiponectin production, upregulate pro-inflammatory mediators such as TNFα and MCP-1, and thus promote macrophage activation [106]. They promote oxidative stress and lipid oxidation, and the lipid oxidation product HNE in turn induces cyclooxygenase 2 [107]. Adipose inflammation has systemic effects, hence adipose tissue arachidonic acid was found to be independently associated with abdominal obesity, dyslipidemia, hypertension and fasting glucose [108]. Its myeloperoxidase products, 20-HETE is associated with insulin resistance and hyperglycemia [109]. Since humans synthesize arachidonic acid from linoleic acid, the arachidonic acid content in human adipose tissues does not necessarily reflect its dietary intake [110].

Although linoleic acid is a precursor of arachidonic acid, studies of its effects on the metabolic syndrome have given mixed results, with both harmful and protective roles reported [111–113]. The differences are partly due to genetic factors. For example, there are individual and ethnic differences in the expression of fatty acid desaturase 1 and 2 (FADS 1/2); with genotypes favouring greater FADS1/2 activity and arachidonic acid synthesis being associated with greater susceptibility to metabolic dysregulation [114, 115]. Black people and Indians significantly generate arachidonic acid from dietary linoleic acid, unlike people of European origin [114, 116]. A high adipose tissue linoleic: arachidonic acid is inversely associated with cardiovascular mortality and hypertension [112]. Likewise, a low linoleic: arachidonic acid ratio in plasma phospholipids is associated with hypertension [117]. Polymorphisms in the receptor for oxLDL, Lox-1, might also determine differences in the response to increased dietary linoleic acid; since this PUFA increases Lox-1 expression in aortic endothelial cells [118]. The effects of linoleic acid may also be dependent on the overall diet. If the diet is high in other factors that induce oxidative stress such as dietary sugar and salt, the pro-oxidative environment thus created may abrogate potential linoleic acid benefits through its increased

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

oxidation. This is in analogy to the fact that high glycemic index foods abrogate the anti-obesity effects of fish oil [119]. A high linoleic acid diet may also be unfavourable for people who have already developed some component of the metabolic syndrome and thus have a more pro-inflammatory status.

Oleic acid is the major dietary fatty acid in the Mediterranean diet, which is generally associated with health benefits. This fatty acid is relatively resistant to peroxidation. Besides promoting the safe storage of palmitate in TGs, it induces thermogenesis by upregulating adipose triglyceride lipase and hormone sensitive lipase, which induce lipolysis coupled with fatty acid oxidation [120]. It promotes M2 macrophage phenotype in visceral adipose [121].

The dietary n-3 fatty acids are generally highly susceptible to oxidation because they all contain at least 3 double bonds. Although they are not 4-HNE precursors, decomposition of their hydroperoxides very readily produces acrolein, MDA, glyoxal and methylglyoxal. Despite this, they are largely beneficial, suppressing development of the metabolic syndrome [122]. In adipocytes, their binding to the GPR120/Ffar4 receptor inhibits TLR2 and TLR4 signaling and associated NFkB activation, oxidative stress and inflammation [123]. This receptor also upregulates miR-30b and 378, and induces FGF21 secretion, whose signaling activates AMPK, promotes browning and induces adiponectin [123–126]. The n-3 PUFAs are metabolized by cyclooxygenase to resolvins, protectins, maresins and isoprostanes which help in resolving inflammation [127].

A high dietary n-3: n-6 PUFA ratio has been found to be protective against the metabolic syndrome in some studies but not others [128, 129]. This might be partly due to inter-individual differences in the metabolism of n-6 fatty acids.

High carbohydrate diets promote obesity because excess sugars are stored as lipids. High sucrose or high fructose diets are particularly obesogenic [130]. Fructose metabolism robustly increases palmitate synthesis in adipocytes [131]. Moreover, fructose metabolism is associated with decreased cellular ATP, purine degradation and activation of xanthine oxidase which generates reactive oxygen species and associated lipid peroxidation [132], which is involved in adipocyte whitening and less thermogenesis. Uric acid, a product of purine degradation also induces oxidative stress through increased NADPH oxidase activity and RAS activation [131–134].

High salt (sodium chloride) diets promote obesity, by salt-induced activation of adipocyte Na/K+ ATPase, which is coupled to activation of src, which generates ROS, and transactivates PI3-K-Akt–MTOR and EGFR-ERK/MAPK pathways [135, 136]. This is associated with increased expression of proinflammatory mediators such as TNFα, MCP-1, COX-2, IL-17A, IL-6, leptin, and leptin [136, 137]. Sodium chloride also activates Na+/K+ ATPase and induces oxidative stress in endothelial cells and renal tubular epithelial cells, thereby promoting hypertension [132], and this is also subject to genetic susceptibility [138].

High dietary cholesterol is associated with a high risk of dyslipidemia [139]. Cholesterol-rich chylomicron remnants mainly deliver their cholesterol to the liver, and cholesterol accumulation in hepatocytes strongly induces oxidative stress, by modification of the mitochondrial membrane and limiting import of glutathione into the mitochondria, as well by inducing ER stress and proinflammatory cytokines [140].

The lipopolysaccharide (LPS) component of the walls of gram-negative bacteria is a pro-inflammatory molecule that contributes to metabolic low-grade inflammation (endotoxemia), by signaling through TLR2 and 4 in various cell types, leading to NFkB activation and release of pro-inflammatory cytokines. High sucrose and high saturated fat diets promote the growth of gram-negative bacteria, and thus increase the entry of LPS into the circulation [141].
