Saturated fatty acids activate TLR-mediated proinflammatory signaling pathways

Abstract

Toll‐like receptor 4 (TLR4) and TLR2 were shown to be activated by saturated fatty acids (SFAs) but inhibited by docosahexaenoic acid (DHA). However, one report (ATVB 11:1944, 2009) suggested that SFA‐induced TLR activation in cell culture systems is due to contaminants in BSA used for conjugating fatty acids. This report casted doubt about proinflammatory effects of SFAs. Our studies herein demonstrate that sodium palmitate (C16:0) or laurate (C12:0) without BSA conjugation induced phosphorylation of IκBα, JNK, ERK, and NFκB p65 and TLR target gene expression in THP1 monocytes or RAW264.7 macrophages, respectively when cultured in low FBS (0.25%) medium. C12:0 induced NFκB activation through TLR2 dimerized with TLR1 or TLR6, and through TLR4. Since BSA was not used in these experiments, contaminants in BSA have no relevance. Unlike suspension cells (THP‐1), BSA conjugation is required for C16:0 to induce TLR target gene expression in adherent cells (RAW264.7). BSA‐conjugated C16:0 transactivated TLR2 dimerized with TLR1 or TLR6, and through TLR4 as seen with C12:0. These results and additional studies with LPS sequester polymixin B and MyD88−/− macrophages indicated that SFA‐induced activation of TLR2 or TLR4 is a fatty acid‐specific effect, but not due to contaminants in BSA or fatty acid preparations. (USDA‐ARS‐WHNRC Program Funds and NIHDK 064007)

Is Palmitoleic Acid a Plausible Nonpharmacological Strategy to Prevent or Control Chronic Metabolic and Inflammatory Disorders?

“…[12,87,88] In particular, elevated plasma levels of NEFAs are frequently observed in patients with MetS and visceral obesity [52] ; NEFAs may promote endothelial dysfunction, the first step of atherosclerosis, by immune activation and upstream regulation of the nuclear transcription factor kappa B (NFκB). [87] By triggering NFκB, [89] saturated fatty acids such as palmitate (16:0) and stearate (18:0), promote crucial events in the initial steps of atherogenesis. [90] They enhance the adherence and transmigration of monocytes and lymphocytes by increasing the expression of cell adhesion molecules (ICAM-1, VCAM-1, and Eselectin), upregulating the expression of inflammatory cytokines (TNF-α, IL-6, and IL-8), and promoting apoptosis of endothelial cells.…”

Oleic acid stimulates system A amino acid transport in primary human trophoblast cells mediated by toll-like receptor 4

“…How fatty acid species other than oleic acid might affect amino acid transport remains to be established. However, in other tissues, it has been shown that different fatty acid species modulate TLR4 signaling differently, with saturated fatty acids activating and polyunsaturated fatty acids inhibiting TLR4 signaling ( 10,11 ). TLR4 was required for oleic acid to stimulate amino acid transport, and oleic acid activated JNK and STAT3.…”

Western lifestyle and immunopathology of multiple sclerosis

“…An increasing amount of literature shows that fat‐induced alterations in T cell lineages and the activation status of macrophages and microglia exacerbate neuroinflammation in MS and the EAE model 98, 99, 100, 101, 102, 103. Interestingly, excessive fat consumption is also a key factor inducing obesity, which increases the risk of developing MS 60, 61, 62.…”

“…Endotoxins can promote T H 1 and T H 17 polarization,106, 107 as well as the inflammatory activation of peripheral and CNS‐resident innate immune cells 108, 109. Of interest, SFAs, such as palmitate (C16:0) and laurate (C12:0), can also directly activate TLR‐mediated proinflammatory signaling pathways in innate immune cells 100. Finally, while feeding dietary monounsaturated fats reduces low‐density lipoprotein (LDL) levels, SFAs are reported to elevate circulating LDL 110.…”