Introduction
Omega-3 fatty acids (ω-3 FAs), primarily EPA (eicosapentaenoic acid) and DHA (docosahexaenoic acid) from marine sources, are known for their anti-inflammatory properties. Green tea extracts, rich in catechins, are also potent antioxidants. While some believe that combining green tea and ω-3 FAs might hinder absorption, emerging research suggests a synergistic effect. This article explores the potential benefits of combining green tea and fish oil, examining how these two natural compounds can work together to enhance each other's positive effects, particularly in areas like reducing inflammation and improving bioavailability.
Understanding Omega-3 Fatty Acids
Omega-3 fatty acids (ω-3 FA) are polyunsaturated fatty acids with a double bond on the third carbon in their backbone. They are found in various marine species, such as salmon, sardines, tuna, halibut, krill, and algae, as well as plant-based sources. While α-linolenic acid (ALA) is primarily found in plant sources, EPA and DHA are predominantly derived from marine sources like fatty fish. The health effects of ω-3 FAs are more influenced by EPA and DHA than by ALA.
EPA and DHA exhibit potent anti-inflammatory effects by reducing adhesion molecule expression, leukocyte chemotaxis, and pro-inflammatory eicosanoids from arachidonic acid. These actions collectively shift the inflammatory environment toward reduced cell responsiveness, such as neutrophils, monocytes, macrophages, T-cells, and endothelial cells, and promote the resolution of inflammation. EPA and DHA have also improved conditions such as meibomian gland dysfunction, where supplementation can reduce eyelid inflammation, stabilize the tear film, and enhance the quality of life in affected patients.
The Challenge of Omega-3 Bioavailability
ω-3 FAs are inherently unstable due to their chemical structure, particularly their multiple double bonds readily reacting with oxygen, making them highly susceptible to oxidation. They are unstable in the gastrointestinal phase and have low intestinal absorption when orally consumed. The acidic environment of the stomach also dissociates micelle structures that are essential for the absorption of ω-3 FA, which leads to a loss of stability before reaching the small intestine. Furthermore, the micelle formation becomes incomplete when concentrations of bile salt are insufficient, which makes the absorption of ω-3 FAs more difficult. ω-3 FAs are oxidized via lipid radical formation and subsequent peroxyl radical propagation, which leads to lipid hydroperoxide accumulation and accelerated degradation. Antioxidants donate hydrogen atoms to neutralize free radicals in order to inhibit this process, thereby breaking the oxidative chain reaction and preventing further lipid oxidation. The stability of micelle structures plays a crucial role in maintaining the digestive stability of ω-3 FAs, which significantly influences their overall bioavailability. ω-3 FAs are incorporated into micelle structures in the small intestine, which facilitate their transport across the intestinal lining and absorption into the body.
The Power of Green Tea Extracts
Green tea extracts are a concentrated source of bioactive compounds, primarily rich in antioxidants like catechins. These extracts offer various health benefits, including anti-inflammatory and antioxidant effects. The antioxidant properties of catechins inhibit the oxidation of ω-3 FAs, stabilize micelle structures, and contribute to improved nutrient absorption. The catechins of green tea extracts strengthen the selective barrier against potentially harmful substances while allowing beneficial nutrients to pass through. They also alter the structure of the phospholipid bilayer, which leads to the downregulation of efflux proteins such as P-glycoprotein (P-gp) when ω-3 FA are absorbed into the small intestine. This inhibition of P-gp reduces the efflux of beneficial compounds, such as catechins, thereby enhancing their overall absorption.
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Challenging the Inhibitory Interaction Belief
It is widely believed that the co-intake of green tea and ω-3 FAs may reduce the digestive stability and absorption of ω-3 FAs due to potential inhibitory interactions. However, contrary to this popular belief, previous studies have suggested that green tea extracts, which are rich in catechins, possess potent antioxidant properties that may prevent lipid oxidation, a major factor contributing to ω-3 FAs instability during digestion. Studies also implied that green tea extracts improved absorption in the small intestine by stabilizing micelle structures in animal models.
Synergistic Effects on Cholesterol and Glucose Levels
Studies on mice fed high-fat diets have revealed that single or combined intakes of fish oil and green tea extract (GTE) significantly lowered plasma and liver total cholesterol (T-chol) and triacylglycerol (TG) concentrations. However, a positive effect of GTE alone was not observed in the plasma T-chol and TG concentrations of mice on low-fat diets. Plasma glucose (Glu) concentrations were significantly lowered by dietary fish oil in mice on the low- and high-fat diets. A tendency of GTE intake to decrease plasma Glu in mice on both the low- and high-fat diets was not significant.
Impact on Insulin and Adiponectin
Intake of GTE only minimally influenced plasma insulin, C-peptide, and adiponectin concentrations, but fish oil supplementation increased the adiponectin concentration in mice on the low- and high-fat diets.
Investigating the Combined Effects of Fish Oil and EGCG
Extracellular plaques of β-amyloid (Aβ) peptides are implicated in Alzheimer's Disease (AD) pathogenesis. Aβ formation is precluded by α-secretase, which cleaves within the Aβ domain of APP generating soluble APP-α(sAPP-α). Thus, α-secretase upregulation may be a target AD therapy. Studies have shown that green tea derived EGCG increased sAPP-α in AD mouse models. Epidemiological studies suggested fish oil consumption is associated with reduced dementia risk. Research investigated whether oral co-treatment with fish oil (8 mg/kg/day) and EGCG (62.5 mg/kg/day, or 12.5 mg/kg/day) would reduce AD-like pathology in Tg2657 mice. In vitro co-treatment of N2a cells with fish oil and EGCG enhanced sAPP-α production compared to either compound alone. Fish oil enhanced bioavailability of EGCG versus EGCG treatment alone. Amyloid precursor protein (APP) “amyloidogenic” proteolysis by β and γ-secretases yields β-amyloid (Aβ) peptides implicated in Alzheimer's Disease (AD). In the “nonamyloidogenic” pathway, APP is cleaved at the α-secretase site, yielding soluble APP-α (sAPP-α); and precluding Aβ generation. Studies found Tg2576 mice intraperitoneally (i.p) treated with EGCG show decreased memory deficits and Aβ plaques, and elevated sAPP-α, at an oral dose of 50 mg/kg/day. Epidemiologic studies suggest consumption of fish oils (ω-3 polyunsaturated fatty acids) confers reduced AD risk by ~40%. Fish oil is known to induce hippocampal transthyretin (TTR) expression in the aged-rat hippocampus.
Synergistic Amyloid Reduction
Based on previous studies, it was hypothesized that fish oil may synergize the effectiveness of EGCG in terms of amyloid reduction in Tg2576 mice and found it enhances α-secretase activity promoted by EGCG in APP-overexpressing N2a cells. Studies involved treating Tg2576 mice (n=6 female) at 8 months of age for 6 months with water only. Age-matched non-transgenic mice (n = 6) also received water alone. Transgene expression was confirmed by genotyping. Mice were sacrificed at 14 months of age for analyses of Aβ levels and Aβ load in the brain according to previous methods. Mice were anesthetized with isofluorane and transcardinally perfused with ice-cold physiological saline containing heparin (10 U/mL). Brains were isolated and quartered using a mouse brain slicer (Muromachi Kikai Co., Japan). The 1st and 2nd anterior quarters were homogenized for ELISA and Western blot analysis, and the 3rd and 4th posterior quarters used for microtome or cryostat sectioning. Brains were fixed in 4% paraformaldehyde in PBS at 4 °C overnight and processed in paraffin in a core facility at the Department of Pathology (USF). Five, 5-μm thick coronal sections/brain were cut (150-μm intervals). Sections were deparaffinized and hydrated in a graded series of ethanols then pre-blocked for 30 min at ambient temperature with serum-free protein (Dakocytomation, Denmark). 4G8-positive Aβ deposits were examined under bright-field via Olympus BX-51 microscope. Quantitative image analysis for “Aβ burden” was performed for 4G8 immunohistochemistry for brains from all mice. Briefly, images of five 5-μm sections (150 μm apart) through each region of interest were captured and threshold optical density was obtained, discriminating staining form background. Manual editing of fields was used to eliminate artifacts. Data are reported as percentage of immunolabeled area captured (positive pixels)/the full area captured (total pixels).
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Elevated Plasma EGCG Levels
At sacrifice, blood and brains were collected from Tg2576 treated with EGCG alone (high and low doses) and low dose EGCG with fish oil for measurement of plasma free EGCG. Significantly elevated plasma free EGCG was found in the mice co-treated with fish oil + EGCG versus EGCG treatment alone at the same dose. Analysis of free EGCG in mice treated with EGCG alone (including the high and low doses), and also from Tg2576 mice treated with EGCG (low dose) and fish oil was performed. Percent differences of blood and brain EGCG were quantified via HPLC. T- test for independent samples revealed a significant difference in plasma levels of free EGCG in the mice co-treated with fish oil compared to mice treated with EGCG alone.
Enhanced sAPP-α Production
SweAPP N2a cells were co-treated with fish oil and EGCG overnight. Following, sAPP-α ELISA in cultured media was performed and indicated fish oil markedly enhances sAPP-α production induced by EGCG (5μM) versus EGCG or fish oil alone. Additionally Western blot (WB) on these samples showed increased sAPP-α in cultured media from co-treated condition versus EGCG at 5 μM or fish oil alone. Densitometry analysis shows significantly increased western blot band density in Fish oil + EGCG group. Data presented as mean ± SD of WB band density.
Bioavailability and α-Secretase Activation
Previous studies found that i.p. EGCG administration significantly reduced Aβ deposits. This translates into a human oral dose over six times this concentration in part due to first pass metabolism. Research found significantly elevated plasma and brain levels of free EGCG in mice cotreated with fish oil, suggesting a mechanism of increased bioavailability conferred by addition of fish oil to EGCG. Importantly, fish oil enhanced production of s-APPα, indicating increased non-amyloidenic processing. This may be due to the increased bioavailability of EGCG, as no previous reports indicated α-secretase enhancing ability for fish oil. Results are in accord with others showing activation of α-secretase reduces Aα-associated pathology in animal models of AD. Recent reports demonstrated sAPP-α is reduced in the CSF of AD patients; indirectly suggesting α-secretase processing is impaired in AD. Since α-secretase cleaves within the Aβ peptide domain, its activation may even have the added advantage of, not only generating the putatively neuroprotective sAPP-α, but also precluding neurotoxic Aβ peptide formation.
Potential Adverse Effects and Interactions
Cases of recurrent atrial fibrillation (AF) or flutter have been reported with the use of omega-3 fatty acids in patients with a symptomatic paroxysmal AF or persistent AF. This condition is more apparent within the first 2 to 3 months after the initiation of therapy. Increases in alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) levels have been observed in patients receiving omega-3 fatty acids. Therapy with omega-3 fatty acid preparations should be administered cautiously in patients with hepatic impairment.