5-Hydroxy-eicosapentaenoic acid is an endogenous GPR119 agonist and enhances glucose-dependent insulin secretion

Kogure, Ryouta; Toyama, Kazuya; Hiyamuta, Shuichi; Kojima, Itaru; Takeda, Shigeki

doi:10.1016/j.bbrc.2011.10.141

Cited by 57 publications

(39 citation statements)

References 26 publications

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“…Moreover, antagonist of GPR119 strongly blocked macrophage-dependent Treg induction by EPA. Considering that 5-HEPE is a specific ligand for GPR119 39 , we concluded that EPA induced Treg induction mainly through its metabolite, 5-HEPE via GPR119.…”

Section: Discussionmentioning

confidence: 88%

Eicosapentaenoic acid and 5-HEPE enhance macrophage-mediated Treg induction in mice

Onodera

Fukuhara

Shin

et al. 2017

Sci Rep

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Eicosapentaenoic acid (EPA) is an omega-3 fatty acid with immunomodulatory and anti-inflammatory effects. Beyond its direct effects, the metabolic products of EPA also regulate various immune responses. Animal experiments demonstrated that EPA reduces adipose inflammation in high fat diet-induced obese mouse. However, the effects of EPA on infiltrated immune cell populations in adipose tissue and underlying mechanisms remain to be elucidated. We performed flow cytometry of stromal vascular fraction of epididymal adipose tissues from C57BL/6J and ob/ob mice fed normal chow mixed with or without 5% EPA. The numbers of hematopoietic cells, including Tregs, were higher in both C57BL/6J and ob/ob mice fed EPA diet compared with control diet. EPA enhanced the induction of Tregs in co-cultures of adipose tissue macrophages (ATMs) and naïve T cells. Among EPA metabolites, 5-HEPE was the most potent inducer of Tregs. GPR119 and GPR120 are receptors for 5-HEPE and EPA, respectively, and antagonist of GPR119 blocked Treg induction by EPA in the presence of ATMs. Alox5 gene encodes 5-lipoxygenase enzyme catalyzing EPA into 5-HEPE, and inhibitor of 5-lipoxygenase down-regulated EPA-mediated induction of adipose tissue Tregs in ob/ob mice. The study findings demonstrated that both EPA and 5-HEPE enhance ATM-mediated Treg induction.

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Section: Discussionmentioning

confidence: 88%

Eicosapentaenoic acid and 5-HEPE enhance macrophage-mediated Treg induction in mice

Onodera

Fukuhara

Shin

et al. 2017

Sci Rep

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“…Yet, little is known regarding the direct impact of other EPA-derived eicosanoids on β-cell function. One EPA-derived eicosanoid, 5-hydroxy-EPA, can agonize GPR119 in a mouse insulinoma cell line, which ultimately enhances insulin secretion (37). Moreover, resolution of an immune response leads to the formation of EPA-derived metabolites termed resolvins, which promote insulin sensitivity in an obese mouse model (38).…”

Section: Discussionmentioning

confidence: 99%

Enriching Islet Phospholipids With Eicosapentaenoic Acid Reduces Prostaglandin E2 Signaling and Enhances Diabetic β-Cell Function

et al. 2017

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Prostaglandin E2 (PGE2) is derived from arachidonic acid, whereas PGE3 is derived from eicosapentaenoic acid (EPA) using the same downstream metabolic enzymes. Little is known about the impact of EPA and PGE3 on β-cell function, particularly in the diabetic state. In this work, we determined that PGE3 elicits a 10-fold weaker reduction in glucose-stimulated insulin secretion through the EP3 receptor as compared with PGE2. We tested the hypothesis that enriching pancreatic islet cell membranes with EPA, thereby reducing arachidonic acid abundance, would positively impact β-cell function in the diabetic state. EPA-enriched islets isolated from diabetic BTBR Leptinob/ob mice produced significantly less PGE2 and more PGE3 than controls, correlating with improved glucose-stimulated insulin secretion. NAD(P)H fluorescence lifetime imaging showed that EPA acts downstream and independently of mitochondrial function. EPA treatment also reduced islet interleukin-1β expression, a proinflammatory cytokine known to stimulate prostaglandin production and EP3 expression. Finally, EPA feeding improved glucose tolerance and β-cell function in a mouse model of diabetes that incorporates a strong immune phenotype: the NOD mouse. In sum, increasing pancreatic islet EPA abundance improves diabetic β-cell function through both direct and indirect mechanisms that converge on reduced EP3 signaling.

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“…A doubling of the omega-3 index is associated with a 1.7-fold increase in 15-HEPE, a product of EPA metabolism, which is known to decrease neutrophil migration during inflammation 29 . 5-HEPE, which is associated with a 1.9-fold increase with doubling of the omega-3 index, has been found to play a role in endocrine function 30 , and 4-HDHA, which is associated with a 3.6-fold increase with doubling of the omega-3 index, is thought to decrease oxygen-induced retinopathy 31 . Not all lipid mediators investigated were significantly associated with a change in the omega-3 index.…”

Section: Discussionmentioning

confidence: 99%

Relationship between the omega-3 index and specialized pro-resolving lipid mediators in patients with peripheral arterial disease taking fish oil supplements

Schaller

Zahner

Gasper

et al. 2017

Journal of Clinical Lipidology

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Background Oral supplementation with n-3 PUFA increases the omega-3 index, a biomarker of red blood cell eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), and plasma levels of biosynthesis pathway markers and potent lipid mediators involved in the resolution of inflammation among patients with peripheral arterial disease (PAD). Objective We aimed to quantify the association between an upstream change in the omega-3 index and downstream changes in lipid mediator production. Methods We conducted a secondary analysis of the OMEGA-PAD I Trial, a randomized, placebo controlled trial investigating high-dose n-3 PUFA oral supplementation in PAD patients. Eighty subjects were randomized to either 4.4g of fish oil or placebo for one month. Regression analyses using generalized estimating equation techniques were used to investigate the relationship between changes in the omega-3 index and changes in lipid mediators, pre- and post-intervention. Results In the fish oil group, there was a significant increase in the omega-3 index (5±1% to 9±2%, p<0.001) as well as in the plasma levels of several downstream lipid mediator pathway markers of resolution, which are involved with the regulation of leukocyte effector function and host defense. A doubling of the omega-3 index correlated with increases of 2.3-fold in 18-hydroxy-eicosapentaenoic acid (HEPE) (p<0.0001), 1.7-fold in 15-HEPE (p=0.03), 1.9-fold in 5-HEPE (p=0.04), and 3.6-fold in 4-hydroxy-docosahexaenoic acid (HDHA) (p<0.001). Conclusion Among subjects with symptomatic PAD who took oral fish oil supplements for one month, observed changes in the omega-3 index were strongly associated with increases in downstream mediators in the biochemical pathways of resolution.

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5-Hydroxy-eicosapentaenoic acid is an endogenous GPR119 agonist and enhances glucose-dependent insulin secretion

Cited by 57 publications

References 26 publications

Eicosapentaenoic acid and 5-HEPE enhance macrophage-mediated Treg induction in mice

Eicosapentaenoic acid and 5-HEPE enhance macrophage-mediated Treg induction in mice

Enriching Islet Phospholipids With Eicosapentaenoic Acid Reduces Prostaglandin E2 Signaling and Enhances Diabetic β-Cell Function

Relationship between the omega-3 index and specialized pro-resolving lipid mediators in patients with peripheral arterial disease taking fish oil supplements

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