## 4 Discussion
Additionally, several unsaturated FAs including LA have been previously reported as COX-2 inhibitors [95]. Our results implicate that dietary peroxididized LA may promote a strong antioxidant response in the proliferative intestinal tumor or crypt cells to battle the stress derived from the exposure to LOOHs. Of note, the ability of PDiff Caco-2 cells, which are considered cancerous, to induce antioxidant response upon 13-HPODE treatment might lead to progression of disease as it enables cancer cells to survive under stress, which has been implicated in anti-cancer drug resistance [96]. In normal crypt cells, antioxidant response might help in preventing cellular damage that can be caused by oxidative stress and lead to disease. However, Wistar rats treated with repeatedly heated cooking oil, which contains high levels of LOOHs, have shown abnormal colonic epithelium (polyp formation) with aberrant crypts despite the increased antioxidant enzyme activity [97]. Taken together, these observations warrant further studies to determine the role of LOOH-induced antioxidant response in protecting cells or induction of mutagenic changes. We showed that 13-HPODE enhanced PPAR signaling in PDiff cells consisting with the studies reported oxidized LA as a PPAR ligand [34; 67; 98]. This might suggest the ability of PDiff cells to uptake 13-HPODE and induce PPAR signaling despite the lack of brush borders. Induction of PPAR signaling leads to activation of downstream genes involved in glucose and lipid metabolism including beta-oxidation. We observed upregulation of _PPARA_ gene and some of its downstream genes including _HMGCS2_, _FABP1_, and _CPTIA_ genes involved in ketogenesis, uptake of FA, and mitochondrial beta-oxidation, respectively, as well as _PLIN2_ that coats lipid droplets. We also observed upregulation of _FGF21_, which is required for activation of FA oxidation and ketogenic pathways and expression of _PPARA_ target genes [99]. _PCKI_ and _AQP7_ were also upregulated suggesting that gluconeogenesis might be enhanced by 13-HPODE. Activation of PPAR could also be a protective anti-inflammatory response against 13-HPODE [100] as we also observed downregulation of proinflammatory genes including _IL18_, _CCL20_, and _CXCL1/L3/L8_. Previous studies have shown reduced expression of chemokines _CXCL1/L8_ when expression level of PPAR\(\alpha\) was increased indicating anti-inflammatory effect [101; 102]. Another study has shown reduced expression of _IL18_ in mice treated with PPAR\(\alpha\) agonist, Wy14643 [103]. Moreover, it has been reported that fenofibrate, another PPAR\(\alpha\) agonist, also reduced expression of chemokines, including _CCL20_, in HT-29 cells [104]. On the other hand, previous reports suggested that PPAR activation in the intestinal stem cells may have pro-tumorigenic effect, which indicates that exposure of intestinal crypt cells or tumor cells to 13-HPODE might contribute to the development or progression of cancer [105]. It is worth to note that 13-HPODE caused upregulation of _SRC_ proto-oncogene, which has shown to be upregulated in CRC [106]. Additionally, increased expression of _PLIN2_ might indicate increased lipid droplets, which have shown to play a role in colon cancer progression [107]. Other reports suggested that PPAR signaling induces cell differentiation or apoptosis [108] and reduces proliferation through downregulation of _MYC_ proto-oncogene [109; 110], which we observed, in our study, in 13-HPODE-treated cells. These conflicting studies and our results might indicate dual effects of 13-HPODE-derived PPAR signaling on PDiff cells although the role of PPARs in tumor development requires further investigations. As seen in this study, starch and sucrose metabolic pathway was enhanced by 13-HPODE treatment of PDiff Caco-2 cells. _GYS2_ and _GBE1_ genes, involved in glycogen synthesis and solubility, _AGL_ and _PYGM_, involved in glycogen degradation, appeared to be upregulated suggesting alteration of cellular glycogen contents.