Omega-3 mechanism of action in inflammation and endoplasmic reticulum stress in mononuclear cells from overweight non-alcoholic fatty liver disease participants: study protocol for the “Brazilian Omega Study” (BROS)—a randomized controlled trial

Abstract

The low-grade inflammation is pivotal in obesity and its comorbidities; however, the inflammatory proteins are out of target for traditional drug therapy. Omega-3 (ω3) fatty acids can modulate the downstream signaling of Toll-like receptor (TLR) and tumor necrosis factor-α receptor (TNFα) through GPR120, a G-protein-coupled receptor, a mechanism not yet elucidated in humans. This work aims to investigate if the ω3 supplementation, at a feasible level below the previously recommended level in the literature, is enough to disrupt the inflammation and endoplasmic reticulum stress (ER-stress), and also if in acute treatment (3 h) ω3 can activate the GPR120 in peripheral blood mononuclear cells (PBMC) and leukocytes from overweight non-alcoholic fatty liver disease (NAFLD) participants. The R270H variant of the Ffar4 (GPR120 gene) will also be explored about molecular responses and blood lipid profiles. A triple-blind, prospective clinical trial will be conducted in overweight men and women, aged 19–75 years, randomized into placebo or supplemented (2.2 g of ω3 [EPA+DHA]) groups for 28 days. For sample calculation, it was considered the variation of TNFα protein and a 40% dropout rate, obtaining 22 individuals in each group. Volunteers will be recruited among patients with NAFLD diagnosis. Anthropometric parameters, food intake, physical activity, total serum lipids, complete fatty acid blood profile, and glycemia will be evaluated pre- and post-supplementation. In the PBMC and neutrophils, the protein content and gene expression of markers related to inflammation (TNFα, MCP1, IL1β, IL6, IL10, JNK, and TAK1), ER-stress (ATF1, ATF6, IRE1, XBP1, CHOP, eIF2α, eIF4, HSP), and ω3 pathway (GPR120, β-arrestin2, Tab1/2, and TAK1) will be evaluated using Western blot and RT-qPCR. Participants will be genotyped for the R270H (rs116454156) variant using the TaqMan assay. It is hypothesized that attenuation of inflammation and ER-stress signaling pathways in overweight and NAFLD participants will be achieved through ω3 supplementation through binding to the GPR120 receptor. Trial registration ClinicalTrials.gov #RBR-7x8tbx. Registered on May 10, 2018, with the Brazilian Registry of Clinical Trials.

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“…High intakes of chocolate and sweets [ 194 , 195 ], butter, and low-fiber bread and low intakes of fresh fruits and vegetables comprised the predominant dietary pattern and were positively associated with total CVD [ 193 ]. In contrast, current evidence demonstrates that healthy dietary patterns are characterized by a high intake of fiber, antioxidants, vitamins, minerals, polyphenols, and monounsaturated and polyunsaturated fatty acids and a low intake of salt, refined sugar, saturated and trans fats, and carbohydrates with a low glycemic load [ 99 , 196 ]. This corresponds to a high intake of fruits, vegetables, legumes, fish and seafood, nuts, seeds, whole grains, vegetable oils (primarily extra virgin olive oil), and dairy foods, and a low intake of sweets, soft drinks, and red and processed meat [ 197 , 198 ].…”

The Role of Adipokines in Health and Disease

“…The combination of lifestyle changes and supplementation with n-3 fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) reduces inflammatory and metabolic damage in obese women but does not affect leptin levels [274]. In contrast, lifestyle interventions with increased omega-3s reduce insulin resistance, leptin concentrations, and endothelial dysfunction in obese adolescents [275].…”