## 4 Discussion  
Linoleic acid, the most common dietary PUFA, can be ingested in the peroxid oxidized form when vegetable oil is overheated such as in fried food. Studies have reported both harmful and possibly beneficial effects of LOOHs. DNA damage has been observed upon treating Caco-2 cells with subcytotoxic levels of LOOHs [60]. Peroxidized LA has also shown to exert pro-inflammatory effects and cause cell death in both Diff and PDiff Caco-2 cells [6]. Moreover, LOOHs have been strongly linked to atherogenesis [61; 62], inflammatory disease [63], aging [64], and cancer [65]. On the other hand, a protective effect of LOOHs that promotes apolipoprotein A1 (ApoA1) production, in Diff and PDiff Caco-2 cells, which reduces atherosclerosis has been reported [34; 66]. Of note, oxidized metabolites of LA are known to be ligands of PPARs, which are important for intestinal cell differentiation and play a role in lipid metabolism [67]. In this study, we demonstrate, using RNA-seq, that treating PDiff Caco-2 cells with peroxid oxidized linoleic acid, 13-HPODE, can alter their transcriptomic profile significantly, which may reflect the effects of dietary LOOHs on in vivo intestinal crypt or tumor cells. We also compare the effects of 13-HPODE on PDiff cells with the effects of unoxidized LA as well as H2O2, which is another source of oxidative stress. We demonstrate that 13-HPODE treatment of PDiff Caco-2 cells caused upregulation of mechanisms that help cells in detoxification as PDiff cells are more sensitive to xenobiotics than Diff cells [29; 68; 32]. Among the upregulated pathways were retinol metabolism, peroxisome, and cytochrome P450. Upregulation of these pathway suggests that there is a need for induction of antioxidant defense response against 13-HPODE-derived oxidative stress to prevent cellular damage. Upregulational retinol metabolism might be a protective mechanism as retinol is considered as a non-enzymatic antioxidant [69]. Products of peroxid oxidized lipids have significantly shown to affect retinoid metabolism [70]. We observed upregulation of beta-carotene oxygenase, _BCO1_, and retinol dehydrogenase, _RDH10_, in 13-HPODE-treated cells. The expression levels of these two genes have shown to be low in cirrhotic rat intestine, which indicates retinol's link to disrupted intestinal epithelial homeostasis [71]. In addition to its role in triglyceride and cholesterol metabolism [72], retinol is important for cellular growth, proliferation, and differentiation of intestinal epithelium and presents in higher amounts in intestinal crypts than villus cells [73]; therefore, enhancement of retinol could be a benefit of 13-HPODE. PDiff cells showed upregulation of peroxisomal pathway in 13-HPODE-treated cells, which metabolizes lipids, detoxifies radicals, and maintains redox homeostasis. _PEX6_ gene involved in peroxisome biosynthesis and protein import to peroxisomes was upregulated as well as the detoxifying _CAT_ in 13-HPODE-treated cells. Increased peroxisome proliferation and activity has been reported when PPAR ligands such as fatty acids were used [74]. _CROT_, _IDH1_, and _ABCD1_ genes were also upregulated enhancing peroxisomal lipid metabolism, a mechanism that some cancer cell types use to maintain tumorigenicity and survival through fatty acid oxidation [75]. We observed marginal induction of peroxisomal pathway as well as upregulation of _PEX6_, _ACOX2_, and _CROT_ genes in LA-treated cells. This supports studies reported induction of PPAR by LA [76] and induction of peroxisomal acyl-CoA oxidase, which is associated with increase peroxisome number, in LA-treated cultured rat hepatocytes [77]. We also showed that 13-HPODE upregulated the metabolism by cytochrome P450 in PDiff cells, which allows the cells to oxidize and metabolize lipids, and clear xenobiotic compounds including dietary LOOHs and their metabolites such as 4-HNE [78]. Among upregulated genes were _UGT2B4_, _CYP2B6_, _MAOB_, and _SULT2A1_.