Abstract
Lipid peroxides (LOOHs) abound in processed food and have been implicated in the pathology of diverse diseases including gut, cardiovascular, and cancer diseases. Recently, RNA Sequencing (RNA-seq) has been widely used to profile gene expression. To characterize gene expression and pathway dysregulation upon exposure to peroxidized linoleic acid, we incubated intestinal epithelial cells (Caco-2) with 100 µM of 13-hydroperoxyoctadecadienoic acid (13-HPODE) or linoleic acid (LA) for 24 h. Total RNA was extracted for library preparation and Illumina HiSeq sequencing. We identified 3094 differentially expressed genes (DEGs) in 13-HPODE-treated cells and 2862 DEGs in LA-treated cells relative to untreated cells. We show that 13-HPODE enhanced lipid metabolic pathways, including steroid hormone biosynthesis, PPAR signaling, and bile secretion, which alter lipid uptake and transport. 13-HPODE and LA treatments promoted detoxification mechanisms including cytochrome-P450. Conversely, both treatments suppressed oxidative phosphorylation. We also show that both treatments may promote absorptive cell differentiation and reduce proliferation by suppressing pathways involved in the cell cycle, DNA synthesis/repair and ribosomes, and enhancing focal adhesion. A qRT-PCR analysis of representative DEGs validated the RNA-seq analysis. This study provides insights into mechanisms by which 13-HPODE alters cellular processes and its possible involvement in mitochondrial dysfunction-related disorders and proposes potential therapeutic strategies to treat LOOH-related pathologies.
Highlights
Dietary lipids, including vegetable oils, contain different quantities of the most common dietary polyunsaturated fatty acid (PUFA), linoleic acid (LA), in the form of triglycerides, which are hydrolyzed by bile and lipases
The log ratio vs. mean average (MA) plots (Figure S3) show that differentially expressed genes (DEGs; red dots) with a large mean expression across untreated and treated cell groups call for significance
Our results indicate that 13-hydroperoxyoctadecadienoic acid (HPODE) may enhance detoxification by cytochrome P450 enzymes, which play a role in the metabolism of ingested drugs and toxins, and in the synthesis of steroid hormones, bile acids, and some other fats [68,69]
Summary
Dietary lipids, including vegetable oils, contain different quantities of the most common dietary polyunsaturated fatty acid (PUFA), linoleic acid (LA), in the form of triglycerides, which are hydrolyzed by bile and lipases. This process releases large amounts of free fatty acids (FFAs), often in millimolar quantities, that are absorbed by intestinal cells [1]. It has been demonstrated that dietary LOOHs from overheated oils contribute to the presence of peroxidized FAs in the lipoproteins [4], which indicates that even though dietary LOOHs undergo a set of enzymatic digestion, peroxidized FAs reach the intestine and get absorbed. The presence of peroxidized fat in the chylomicrons has been shown to increase the atherogenicity of dietary cholesterol [14] and promote the absorption of cholesterol [15]
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