Abstract
A balanced omega-6/omega-3 polyunsaturated fatty acid (PUFA) ratio has been linked to health benefits and the prevention of many chronic diseases. Current dietary intervention studies with different sources of omega-3 fatty acids (omega-3) lack appropriate control diets and carry many other confounding factors derived from genetic and environmental variability. In our study, we used the fat-1 transgenic mouse model as a proxy for long-term omega-3 supplementation to determine, in a well-controlled manner, the molecular phenotype associated with a balanced omega-6/omega-3 ratio. The fat-1 mouse can convert omega-6 to omega-3 PUFAs, which protect against a wide variety of diseases including chronic inflammatory diseases and cancer. Both wild-type (WT) and fat-1 mice were subjected to an identical diet containing 10% corn oil, which has a high omega-6 content similar to that of the Western diet, for a six-month duration. We used a multi-platform lipidomic approach to compare the plasma lipidome between fat-1 and WT mice. In fat-1 mice, an unbiased profiling showed a significant increase in the levels of unesterified eicosapentaenoic acid (EPA), EPA-containing cholesteryl ester, and omega-3 lysophosphospholipids. The increase in omega-3 lipids is accompanied by a significant reduction in omega-6 unesterified docosapentaenoic acid (omega-6 DPA) and DPA-containing cholesteryl ester as well as omega-6 phospholipids and triacylglycerides. Targeted lipidomics profiling highlighted a remarkable increase in EPA-derived diols and epoxides formed via the cytochrome P450 (CYP450) pathway in the plasma of fat-1 mice compared with WT mice. Integration of the results of untargeted and targeted analyses has identified a lipidomic biosignature that may underlie the healthful phenotype associated with a balanced omega-6/omega-3 ratio, and can potentially be used as a circulating biomarker for monitoring the health status and the efficacy of omega-3 intervention in humans.
Highlights
Most Western diets are deficient in omega-3 polyunsaturated fatty acids (PUFAs) and abundant in omega-6 PUFAs [1]
The imbalance between omega-6s and omega-3s is largely the result of the traditional reliance of Western diets on vegetables oils such as corn, soybean, safflower, and sunflower. These oils are enriched in omega-6 PUFAs, such as linoleic acid (LA), which can be metabolized in animals and humans to form longer chain fatty acids such as di-homo-gammalinolenic acid (DGLA), docosapentaenoic acid, and arachidonic acid (AA) are (Figure 1)
Western diets are lacking in leafy green vegetables, which are enriched in the omega-3 fatty acid, alpha-linolenic acid (ALA), and in oily fish, which contain the longer-chain omega-3 PUFAs such as eicosapentaenoic acid (EPA), omega-3 DPA, and docosahexaenoic acid (DHA) (Figure 1)
Summary
Most Western diets are deficient in omega-3 polyunsaturated fatty acids (PUFAs) and abundant in omega-6 PUFAs [1]. The imbalance between omega-6s and omega-3s is largely the result of the traditional reliance of Western diets on vegetables oils such as corn, soybean, safflower, and sunflower. These oils are enriched in omega-6 PUFAs, such as linoleic acid (LA), which can be metabolized in animals and humans to form longer chain fatty acids such as di-homo-gammalinolenic acid (DGLA), docosapentaenoic acid (omega-6 DPA), and arachidonic acid (AA) are (Figure 1). The human body cannot synthesize PUFAs de novo and must rely entirely on dietary intake for these essential nutrients It cannot interconvert between omega-6 and omega-3 fatty acids. It is the overall balance between omega-3s and omega-6s that seems to modulate many biological processes including the relaxation and contraction of smooth muscle tissue, blood coagulation, and – significantly – inflammation [11,12,13]
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