Functions of omega-3 fatty acids and FFA4 (GPR120) in macrophages
Section snippets
Omega-3 polyunsaturated fatty acids and FFA4
Omega-3 polyunsaturated fatty acids (n-3 PUFAs) are essential fatty acids with a double bond at the third carbon atom from the methyl end (the ω end) of the fatty acid carbon chain (Calder, 2014, Im, 2012). Intakes of n-3 PUFAs, such as, α-linolenic acid (ALA, C18:3), eicosapentaenoic acid (EPA, C20:5), and docosahexaenoic acid (DHA, C22:6) are important from a nutritional view point, because they cannot be synthesized by the human body. Since epidemiologic studies showed lower incidences of
Pharmacology of FFA4 for n-3 PUFA
Briscoe et al. (2006) observed FFA4-mediated Ca2+ increase by ALA, EPA, linoleic acid, and palmitoleic acid in HEK293 cells using a baculovirus overexpression system and a FLIPR instrument. Oh et al. (2010) overexpressed FFA4 with SRE-reporter gene in HEK293 cells and found n-3 PUFA activated FFA4, but that saturated fatty acids did not. Furthermore, ALA, DHA, EPA, and palmitoleic acid were agonistic, but oleic acid, γ-linolenic acid, arachidonic acid, palmitic acid, and myristic acid were not (
Macrophages in inflammation and M1/M2 polarization
Macrophages are highly plastic monocyte-derived cells that acquire different molecular and functional phenotypes after being exposed to different bioactive molecules and environments (Ariel and Serhan, 2012). Macrophages evolved in simple multicellular organisms to clear dying cells by phagocytosis during development and adult life, and to protect the host via innate immunity as resident tissue macrophages and monocyte-derived recruited cells under inflammatory conditions (Martinez and Gordon,
Anti-inflammatory function of n-3 PUFAs via FFA4 in macrophages
In general, saturated fatty acids are pro-inflammatory, unsaturated fatty acids are weakly pro-inflammatory or neutral, and n-3 PUFAs are anti-inflammatory (Calder, 2005, Lee et al., 2003). Several anti-inflammatory mechanisms have been suggested for n-3 PUFAs, such as, the competitive inhibition of COX-2-mediated prostaglandin E2 production by EPA (Calder, 2014, Im, 2012). The discovery that FFA4 is an n-3 PUFA receptor led to study of its anti-inflammatory roles in macrophages (Hirasawa et
Anti-inflammatory effects of n-3 PUFA in animal studies
In vivo phenotypes have also been analyzed in adipose tissue macrophages (ATMs) from WT and FFA4 KO mice (Oh et al., 2010). In adipose tissues, a high fat diet induced a large increase in F4/80 positive M1 macrophages, which form crown-like structures around adipocytes in both WT and KO mice. Adding n-3 PUFA to the diet resulted in a decrease in M1 macrophages and a marked increase in MGL1 positive M2 macrophages in WT mice, but not in FFA4 KO mice (Oh et al., 2010). FACS analysis showed high
Functions of FFA4 in obesity, metainflammation, and insulin resistance
Obesity induces an inflammatory state associated with many clinically important complications, such as, insulin resistance, diabetes, atherosclerosis, and non-alcoholic fatty liver disease (Ferrante, 2007). Obesity is associated with a state of chronic, low-grade inflammation that is also referred to as metabolic-triggered inflammation (metainflammation), which is a long-term inflammatory responses triggered by nutrients and metabolic surplus (Hotamisligil, 2006). White adipose tissue is an
Functions of FFA4 in other macrophages
Macrophages are named depending on where they reside, such as, the Kupffer cells of liver, osteoclasts in bone, and microglia in brain, and the effects of n-3 PUFAs on these cells may differ from those of isolated macrophages or ATMs.
In early 1988, Kupffer cells from rats fed fish oil for 6 weeks were found to produce less prostaglandin, thromboxane, IL-1, and TNF when stimulated with LPS than cells from rats fed corn oil (Billiar et al., 1988). Effects of FFA4 and n-3 PUFAs on nonalcoholic
Future perspective
The functions of macrophages in immune responses have expanded to metabolism, and their activations and polarizations are characteristic of conditions in vivo, and it now appears that the modulation of macrophage activation could provide therapeutic strategies in obesity related morbidity. It is interesting that the classical concept of fat as an energy storage medium has evolved to the level of intercellular signaling, and the identification of GPCRs for FFAs now provides therapeutic targets.
Acknowledgement
This research was supported by the Korean National Research Foundation funded by the Korean Government (MSIP) (Grant no. 2009-0083538).
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