Abstract
Dietary lipid peroxides (LOOHs) have been linked to gut pathologies including inflammatory bowel disease and cancer. As poorly differentiated (PDiff) intestinal epithelial (Caco-2) cells represent tumor cells and could model intestinal crypt cells, we investigated the cellular response of PDiff Caco-2 cells to the most common dietary LOOH, 13-hydroperoxyoctadecadienoic acid (13-HPODE), using RNA sequencing (RNA-seq). Further, we compared the results with the transcriptomic profiles of PDiff cells exposed to linoleic acid (LA) or hydrogen peroxide (H2O2). The results showed that 13-HPODE treatment induces expression of genes related to detoxification and several metabolic pathways including glycogen and amino acid metabolism, which may create a tumorigenic environment despite the downregulation of some proliferation-related genes. 13-HPODE also enhanced peroxisome proliferator-activated receptor signaling involved in lipid metabolism, homeostasis, and inflammation. Additionally, results indicated that 13-HPODE impacts ribosome biogenesis, phagosome, and mitochondrial function through disrupted electron transport chain, which may contribute to disease development or progression. RNA-seq results were validated using qRT-PCR. This study provides an understanding of PDiff Caco-2 cell response to 13-HPODE and the mechanisms by which 13-HPODE modulates cellular processes that may contribute to disease development or progression.
Highlights
The human intestinal epithelium is exposed to different chemicals that we ingest with food
We demonstrate that 13-HPODE treatment of poorly differentiated (PDiff) Caco-2 cells caused upregulation of mechanisms that help cells in detoxification as PDiff cells are more sensitive to xenobiotics than Diff cells [29,32,68]
We 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
Summary
The human intestinal epithelium is exposed to different chemicals that we ingest with food. Caco-2 cells, which are derived from human colorectal adenocarcinoma [13], have been widely used to study intestinal metabolism of molecules and drugs [14,15]. These cells, under standard culture conditions, have the ability to become differentiated (Diff; 14-Day) and acquire mature enterocyte-like structural and functional characteristics which makes it a suitable model to study lipid peroxidation [16,17,18,19,20,21,22]. On the other hand, undifferentiated or poorly differentiated (PDiff; 4-Day) Caco-2 cells mimic in vivo intestinal cancer cells and could model intestinal crypt cells, as they share the proliferative phenotype and lack of microvilli cells [23,24], which might be exposed to dietary LOOHs and contribute to disease
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