A protective lipidomic biosignature associated with a balanced omega-6/omega-3 ratio in fat-1 transgenic mice.
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.
Health Sciences, Waters Corporation, Milford, Massachusetts, United States of America; Department of Biochemistry and Molecular & Cellular Biology, Georgetown University, Washington, DC, United States of America.
Giuseppe
G
Astarita
Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
Jennifer H
JH
McKenzie
Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
Bin
B
Wang
Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Netherlands Metabolomics Centre, Leiden University, Leiden, The Netherlands.
Katrin
K
Strassburg
Health Sciences, Waters Corporation, Milford, Massachusetts, United States of America.
Angela
A
Doneanu
Health Sciences, Waters Corporation, Milford, Massachusetts, United States of America.
Jay
J
Johnson
Health Sciences, Waters Corporation, Milford, Massachusetts, United States of America.
Andrew
A
Baker
Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Netherlands Metabolomics Centre, Leiden University, Leiden, The Netherlands.
Thomas
T
Hankemeier
Health Sciences, Waters Corporation, Milford, Massachusetts, United States of America.
James
J
Murphy
Analytical Biosciences, Leiden Academic Centre for Drug Research, Leiden University, Leiden, The Netherlands; Netherlands Metabolomics Centre, Leiden University, Leiden, The Netherlands.
Rob J
RJ
Vreeken
Health Sciences, Waters Corporation, Milford, Massachusetts, United States of America.
James
J
Langridge
Laboratory for Lipid Medicine and Technology, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts, United States of America.
Jing X
JX
Kang
D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000097:blood; D004041:Dietary Fats / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000097:blood*; D043371:Fatty Acids, Omega-6 / Q000097:blood / Q000494:pharmacology*; D005260:Female; D008055:Lipids / Q000097:blood*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction
D004041:Dietary Fats; D015525:Fatty Acids, Omega-3; D043371:Fatty Acids, Omega-6; D008055:Lipids; D003577:Cytochrome P-450 Enzyme System