ABSTRACT
Consumption of deep-fried products is very popular in Western countries due to their desirable avor, color, and crispy texture. In a Spanish cohort from the EPIC study the percentage of energy intake from fried food was estimated to be approximately 25% in the highest quintile of consumption (Guallar-Castillón et al. 2007). During deep frying a heterogeneous mixture of chemically distinct lipid oxidation products is generated in the frying fat (Choe and Min 2007), which is together with the lipid oxidation products absorbed into the fried food and thus ingested when the fried food is consumed. Thus, fried food is an important source for the consumption of oxidized lipids. Based on the fat content of typical fried foods, like potato crisps,
Introduction ............................................................................................................ 231 Lipid Oxidation Products as Regulators of Intracellular Signaling Pathways ....... 232
Lipid Oxidation Products and PPAR Signaling ................................................ 232 Lipid Oxidation Products and NF-κB Signaling ............................................... 235
Biological Effects of Dietary Oxidized Lipids Mediated by Activation of Intracellular Signaling Pathways ........................................................................... 236
Lowering of Plasma and Liver Lipids ............................................................... 236 Inhibition of Alcohol-Induced Fatty Liver Development .................................. 239 Elevation of Hepatic Carnitine Concentration ..................................................240 Inhibition of Atherosclerotic Plaque Development ...........................................242 Modulation of Stress and Inammatory Responses ..........................................244
Conclusions ............................................................................................................246 Abbreviations .........................................................................................................246 References .............................................................................................................. 247
doughnuts, and French fries (10-40%; Moreira et al. 1999), and their consumption frequency in Western countries, the amounts of oxidized lipids taken up from fried foods can easily reach more than 50 g/day. Apart from the fact that consumption of high amounts of fried foods leads to a high fat and energy intake and is therefore associated with obesity (Guallar-Castillón et al. 2007; Sayon-Orea et al. 2013), a great number of studies with rats, mice, and pigs showed that administration of oxidized lipids compared with fresh fats induces versatile biological effects (reviewed by Ringseis and Eder 2011), from which some, like blood lipid-lowering effects, are surprisingly benecial to health. Recent evidence from studies in vivo and in vitro suggests that these effects are mediated by specic lipid oxidation products contained in oxidized lipids through interfering with intracellular signaling pathways. Likely candidates of such lipid oxidation products are not only hydroxy and hydroperoxy fatty acids but also cyclic fatty acid monomers (CFAM). While hydroxy and hydroperoxy fatty acids are formed during heating of frying fats even at moderate temperatures of below 100°C (Choe and Min 2007; Toschi et al. 1997), the CFAM are only signicantly formed from unsaturated 18-carbon fatty acids at temperatures above 200°C (Sebedio and Grandgirard 1989). Both hydroxy and hydroperoxy fatty acids and CFAM come into question as modulators of intracellular signaling pathways in vivo because absorption of these lipid oxidation products from the intestine and delivery as part of lipoproteins via the blood to tissues has been demonstrated (Martin et al. 1997; Wilson et al. 2002). This chapter will focus on two signaling pathways, peroxisome proliferator-activated receptor (PPAR) signaling and nuclear factor-kappa B (NF-κB) signaling, which are regulated by lipid oxidation products and are likely targets to mediate specic biological effects of dietary oxidized lipids.
A number of lipid oxidation products have been shown to be activators of the PPAR signaling pathway. PPAR are ligand-activated transcription factors, which act as important regulators of lipid and energy metabolism and inammation (Desvergne and Wahli 1999). Upon binding of a ligand to the ligand-binding domain the PPAR forms a heterodimer with the retinoid X receptor (RXR), which causes binding of transcriptional coactivators and release of transcriptional corepressors. The activated PPAR/RXR heterodimer then binds to specic DNA sequences, called peroxisome proliferator response elements (PPREs), in the promoter, the intronic or the 5´-untranslated region of target genes, thereby stimulating transcription of these genes. Typical genes upregulated by PPARs, particularly PPARα, are genes involved in most aspects of lipid catabolism such as cellular fatty acid uptake, intracellular fatty acid transport, mitochondrial fatty acid uptake, fatty acid oxidation, carnitine uptake, and carnitine synthesis (Mandard et al. 2004; Ringseis and Eder 2012; Figure 12.1). This explains why activation of PPARα in the liver results in increased fatty acid catabolism, elevated liver carnitine concentrations and decreased triacylglycerol (TAG) concentrations in liver and plasma. However, PPARs can also negatively
regulate transcription of genes that are under the control of stress-sensitive transcription factors such as NF-κB and encode proteins involved in the stress and inammation response (Figure 12.1). This is the molecular basis for the well-documented anti-inammatory effects of PPARs. The PPARs exist in three isotypes, PPARα, PPARβ/δ, and PPARγ, all of which share a high degree of structural homology, particularly in the DNA-binding and ligand-and cofactor-binding domain. The relatively high structural homology in the ligand-binding domain explains that the different PPAR isotypes have at least some common ligands. Apart from synthetic ligands, such as the brate class of lipid-lowering drugs and the antidiabetic thiazolidinediones, fatty acids and their derivatives (e.g., eicosanoids) have been described as PPAR ligands (Forman et al. 1997; Göttlicher et al. 1992). In general, fatty acids bind best to PPARα, followed by PPARγ and PPARβ/δ (Krey et al. 1997). Polyunsaturated fatty acids such as linoleic acid, α-linolenic acid, arachidonic acid, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) were shown to be the strongest activators of PPARα (Forman et al. 1997; Krey et al. 1997), whereas saturated fatty
