Abstract
High blood concentrations of n-6 fatty acids (FAs) relative to n-3 FAs may lead to a “physiological switch” towards permanent low-grade inflammation, potentially influencing the onset of cardiovascular and inflammatory diseases, as well as cancer. To explore the potential effects of FA ratios prior to disease onset, we measured blood gene expression profiles and plasma FA ratios (linoleic acid/alpha-linolenic acid, LA/ALA; arachidonic acid/eicosapentaenoic acid, AA/EPA; and total n-6/n-3) in a cross-section of middle-aged Norwegian women (n = 227). After arranging samples from the highest values to the lowest for all three FA ratios (LA/ALA, AA/EPA and total n-6/n-3), the highest and lowest deciles of samples were compared. Differences in gene expression profiles were assessed by single-gene and pathway-level analyses. The LA/ALA ratio had the largest impact on gene expression profiles, with 135 differentially expressed genes, followed by the total n-6/n-3 ratio (125 genes) and the AA/EPA ratio (72 genes). All FA ratios were associated with genes related to immune processes, with a tendency for increased pro-inflammatory signaling in the highest FA ratio deciles. Lipid metabolism related to peroxisome proliferator-activated receptor γ (PPARγ) signaling was modified, with possible implications for foam cell formation and development of cardiovascular diseases. We identified higher expression levels of several autophagy marker genes, mainly in the lowest LA/ALA decile. This finding may point to the regulation of autophagy as a novel aspect of FA biology which warrants further study. Lastly, all FA ratios were associated with gene sets that included targets of specific microRNAs, and gene sets containing common promoter motifs that did not match any known transcription factors. We conclude that plasma FA ratios are associated with differences in blood gene expression profiles in this free-living population, and that affected genes and pathways may influence the onset and progression of disease.
Highlights
The type and amount of fatty acids (FAs) in a person’s diet determine the relative amounts of FAs in the tissues of the body, and may influence the pathogenesis of cardiovascular and inflammatory diseases, as well as cancer [1,2,3]
The population mean of all FA ratios was dominated by n-6 FAs
There were no significant differences between any of the FA ratio deciles regarding technical variables
Summary
The type and amount of fatty acids (FAs) in a person’s diet determine the relative amounts of FAs in the tissues of the body, and may influence the pathogenesis of cardiovascular and inflammatory diseases, as well as cancer [1,2,3]. A multitude of mechanisms have been shown to influence disease pathogenesis, including lipid metabolism and inflammation. To study the complex molecular mechanisms involved in the association between nutritional factors and multifactorial diseases, highthroughput technologies like transcriptomics are increasingly being used. Membrane phospholipids can be modified into lipid mediators such as inositol triphosphate (IP3), and FAs residing in the cellular membranes can be mobilized through the action of phospholipases and undergo modifications to yield a variety of immunoactive eicosanoids. PPARs and their binding partners, retinoid X receptors (RXR), regulate cellular and physiological processes including FA metabolism, cellular stress, and inflammation
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