Review
Omega-3 fatty acids in anti-inflammation (pro-resolution) and GPCRs

https://doi.org/10.1016/j.plipres.2012.02.003Get rights and content

Abstract

Omega-3 fatty acids, such as, DHA and EPA, have well established beneficial effects on human health, but their action mechanisms remain unknown. Recent pharmacological studies have suggested several molecular targets for the anti-inflammatory effects of omega-3 fatty acids, namely, nuclear receptor PPARγ and the G protein-coupled receptor GPR120. Furthermore, the conversions of omega-3 fatty acids to anti-inflammatory and pro-resolving resolvins and protectins and the identifications of putative target GPCRs, ChemR23, BLT1, ALX/FPR2, and GPR32, have drawn great attention. In addition, the pharmacology of omega-3 fatty acids is now under scrutiny. However, questions remain to be answered regarding the in vivo effects of omega-3 fatty acids at the molecular level. In this review, anti-inflammatory effects of omega-3 fatty acids are discussed from the viewpoint of molecular pharmacology, particularly with respect to the above-mentioned GPCRs.

Introduction

Recently, two approaches have identified molecular targets of the anti-inflammatory effect of omega-3 fatty acids, such as, docosahexaenoic acid (DHA, C22:6) and eicosapentaenoic acid (EPA, C20:5). GPR120 is one of these targets and recognizes long-chain polyunsaturated fatty acids as ligands [1]. The physiological significance of GPR120 has been reported in macrophages, adipose tissue, and enteroendocrine L cells [1], [2]. The other targets are anti-inflammatory and pro-resolving lipid mediators, such as, resolvins and protectins, which are formed from EPA and DHA [3], [4]. In addition to the known ligands, chemerin and leukotriene B4 [5], [6], two G protein-coupled receptor (GPCR)s, namely, ChemR23 (also known as CMKLR1) and BLT1 (leukotriene B4 receptor 1) have been found to be receptors of resolvin E1, [7], [8]. On the other hand, orphan GPR32 and ALX/FPR2, which are closely related GPCRs have been shown to bind resolvin D1 and lipoxin A4 with high affinity and high potency (Fig. 1) [9]. ALX/FPR2 has also been reported to be a receptor of lipoxin A4, annexin I, and others [10], [11], [12], [13]. Although multiple molecular targets have been identified and many excellent review articles have been published on each target [3], [14], no objective comparative review article is available on known targets. In this article, known information on the anti-inflammatory effects of omega-3 fatty acids from the molecular pharmacologic viewpoints is reviewed and questions are raised for further study.

Section snippets

Epidemiologic and biochemical views on omega-3 fatty acids

Omega-3 fatty acids (popularly referred to as ω-3 fatty acids or n-3 fatty acids) are essential polyunsaturated fatty acids with a double bond between the third and forth carbon atoms from the methyl end (also known as the omega (ω) end or the n end) of the fatty acid carbon chain. Nutritionally important omega-3 fatty acids include α-linolenic acid (ALA, C18:3), EPA, and DHA. Although the health benefits of long-chain omega-3 fatty acids were discovered in the 1970s by researchers studying the

PPARγ as a molecular target of omega-3 fatty acids

Peroxisome proliferator-activated receptor gamma (PPARγ) is a type II nuclear receptor, which acts as a biosensor for fatty acids and plays key roles in fatty acid metabolism and homeostasis [25]. In addition, PPARγ activation inhibits inflammatory responses by blocking NF-κB activation [26]. High concentration of omega-3 fatty acids (EC50  10–100 μM) have been reported to activate PPARγ [27], [28], whereas DHA and EPA are weaker agonists of PPARγ than their metabolites, such as, protectin D1 [9]

Resolvins and their GPCRs as effectors of omega-3 fatty acids

Acute inflammation is an essential host response to danger signals elicited by pathogens or tissue injury. The duration and magnitude of inflammation depend on competing physiological processes, namely pro-phlogistic mechanism that amplifies inflammation and endogenous braking programs that control the resolution of inflammation [35]. Progression through the resolution phase of inflammation has now been established to be an active coordinated process that is spatiotemporally controlled [36].

GPR120 as a molecular target of omega-3 fatty acids

Recently, five GPCRs (FFAR1 (GPR40), FFAR2 (GPR43), FFAR3 (GPR41), GPR84, and GPR120) were reported to recognize free fatty acids (Fig. 1) [60], [61]. FFAR1, which recognizes medium-long chain fatty acids like palmitic acid and linoleic acid [62], [63], enhances glucose-induced insulin secretion in pancreatic β cells [63]. FFAR2 and FFAR3 recognize short-chain fatty acids like acetate and butyrate [64], whereas GPR84 recognizes medium-chain fatty acid like lauric acid [65]. GPR120 has attracted

Conclusions and perspective

Several molecular targets of omega-3 fatty acids and their metabolites have been suggested to explain their anti-inflammatory actions (Fig. 2). Strongest effects have been obtained for resolvin E1 and D1 (EC50  1 pM and Kd  10−12 M) and their effects on ChemR23, BLT1, GPR32, and ALX/FPR2 well explain their anti-inflammatory effects, especially pro-resolution in genetic and mouse models [53], [54]. However, the anti-inflammatory effects of other oxidized omega-3 fatty acids (except resolvin E1 and

Acknowledgement

This work was supported by MRC program No. 2009-0083538 of the National Research Foundation of Korea funded by the Korea government (MEST).

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