The two n-3 LC-PUFAs found in fish oil, (eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) are widely recognised as having anti-inflammatory properties. Dietary studies have identified benefits in numerous diseases where inflammation is thought to be part of the development process. These include cancer, coronary artery disease, rheumatoid arthritis, depression and lupus.
Nutrigenomics research involves identifying and understanding the interaction of nutrients with the genome through molecular level mechanisms.
Understanding the mechanisms between n-3 LC-PUFAs, their metabolites and genes involved with controlling metabolic processes within cells and tissues, will help identify how these fatty acids exert their beneficial effects.
Omega-3 nutrigenomics was therefore the subject of a review by scientists from the Nutrition Research Unit at the Paediatric Hospital, 21st Century Medical Centre, Mexico City.
N-3 LC-PUFAs have a number of functions, which vary from “their structural function in cell membranes to their role as regulators of gene expression, mainly in lipid metabolism,” wrote lead author Dr. Maricela Rodríguez-Cruz.
A brief outline of the regulatory functions n-3 LC-PUFAs and the associated health implications is outlined below.
Cellular membrane regulators
The physicochemical properties, particularly the fluidity, of cell membranes are influenced by their fatty acid content and composition. Human DHA supplementation studies have shown that fatty acids are preferentially incorporated into phospholipids, and that fatty acid composition influences fluidity.
“Several studies carried out in human and animal models have shown that DHA-rich membranes have a different physicochemical behaviour compared with lipid bilayers that contain another type of PUFAs such as arachidonic acid (n-6),” wrote Rodríguez -Cruz.
“This supports the fact that DHA is the primary FA of the central nervous system. For instance, DHA is an integral component of phospholipids from neural membrane and is localized in synaptosomes,” she continued.
“High concentration of DHA regulates different neuronal processes such as neurogenesis, neuroplasticity, neurite growth, synaptogenesis, and membrane fluidity, resulting in improved velocity of signal transduction and neurotransmission and better cognitive function.”
Further understanding of the underlying mechanisms may strengthen the rationale for using DHA in the treatment of chronic inflammation.
Gene transcription regulators
N-3 LC-PUFAs control the expression of a large number of genes through four main transcription factors: sterol regulatory element-binding protein (SREBP), peroxisome proliferator-activated receptors (PPARs), carbohydrate response element-binding protein (ChREBP) and nuclear factor-kappa B (NF-κB).
These four GTRs are involved with coding proteins that are involved in a number of functions the metabolism of fats and carbohydrates, heat production within the body and inflammatory processes.
DHA and EPA have been shown in animal studies to reduce new fat deposition in the liver, mammary gland and other fatty tissues. Additionally, fish oil has been shown to improve fatty liver disease in mice.
High doses (2-4 grams/day) of n-3 LC-PUFAs have also been approved by the US Food and Drug Administration (FDA) as an adjunct therapy to lower blood triglyceride levels.
The effect is thought to arise from decreased SREBP-1 production induced by diets rich in EPA and (especially) DHA.
PPARs are involved with regulation of fatty acid oxidation, lipid and glucose metabolism, transport through cell membranes, mitochondrial metabolism and cell proliferation and apoptosis. Compounds such as DHA and EPA which modulate PPARs have therefore been identified as possible therapies for prevention and /or treatment of metabolic diseases or controlling cell proliferation in cancer.
“N-3 LC-PUFAs are being targeted as future drugs against metabolic diseases and possibly for cell proliferation control. As a result, a diet rich in n-3 LC-PUFAs with 20 to 22 carbons may be beneficial for human health,” wrote the researchers.
ChREBP is involved with regulating glucose and lipid metabolism in the liver. N-3 LC-PUFAs have been shown to inhibit ChREBP, but the molecular mechanisms need further investigation to determine possible targets and benefits of DHA and EPA on lipogenic and glycolytic gene expression.
Activation of NF-kappa-B is recognised to be part of the inflammatory process, and can be induced by pro-inflammatory cytokines, oxidants and lipopolysaccharides. Phosphorylation of the IkappaB protein, ubiquitin conjugation and proteolysis are steps leading to accumulation of free NF-kappaB, which subsequently binds to DNA and activates gene transcription.
The involvement of the transcription factor in the initiation of cancer has precipitated much research regarding its regulation.
“Therefore, there is intense interest in understanding the regulation of this transcription factor,” suggest the authors.
Previous studies suggest that EPA and (in particular) DHA can inhibit the activation of NF-kappaB by avoiding IkappaB phosphorylation and therefore might play a role in cancer prevention.
Wide-ranging anti-inflammatory benefits
Animal studies have demonstrated the anti-inflammatory action of N-3 LC-PUFAs via formation of metabolites including resolvins and protectins. Studies have frequently demonstrated the downregulation of a wide range of pro-inflammatory cytokines.
In humans, perioperative enteral administration has shown benefits in infants and adults reducing inflammatory response to surgery. These benefits include the reduced use of painkillers, shorter hospital and intensive care unit stays, and improved clinical outcomes.
Further studies needed
Despite the achievements of research to date, further in-depth clarification of the nutrigenomic interactions is needed.
“Further comprehensive studies [are required] on the same model regarding nutritional, biochemical, genetic, and immune aspects are necessary to identify specific molecular mechanisms involved in the beneficial effects of n-3 LC-PUFAs,” concluded the researchers.
Volume 41, page 90-96 DOI: 10.1016/j.nut.2017.04.012
“Nutrigenomics of ω-3 fatty acids: Regulators of the master transcription factors”
Authors: Maricela Rodríguez-Cruz, Donovan Solís Serna