Peroxidation of n-3 Polyunsaturated Fatty Acids Inhibits the Induction of iNOS Gene Expression in Proinflammatory Cytokine-Stimulated Hepatocytes

Yoshiro Araki,Mikio Nishizawa,Hideho Takada,Masaki Kaibori,A-Hon Kwon,Tadayoshi Okumura,Masaharu Oishi,Takashi Matsuura,Miho Matsumiya

doi:10.1155/2011/374542

Yoshiro Araki, Mikio Nishizawa + Show 7 more

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https://doi.org/10.1155/2011/374542

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Abstract

Eicosapentaenoic acid and docosahexaenoic acid (EPA/DHA), n-3 polyunsaturated fatty acids (PUFAs), have a variety of biological activities including anti-inflammatory and anticancer effects. We hypothesized that their peroxidized products contributed in part to anti-inflammatory effects. In the liver, the production of nitric oxide (NO) by inducible nitric oxide synthase (iNOS) has been implicated as one of the factors in hepatic inflammation and injury. We examined whether the peroxidation of EPA/DHA influences the induction of iNOS and NO production in proinflammatory cytokine-stimulated cultured hepatocytes, which is in vitro liver inflammation model. Peroxidized EPA/DHA inhibited the induction of iNOS and NO production in parallel with the increased levels of their peroxidation, whereas unoxidized EPA/DHA had no effects at all. Peroxidized EPA/DHA reduced the activation of transcription factor, NF-κB, and the expression of the iNOS antisense transcript, which are involved in iNOS promoter transactivation (mRNA synthesis) and its mRNA stabilization, respectively. These findings demonstrated that peroxidized products of EPA/DHA suppressed the induction of iNOS gene expression through both of the transcriptional and posttranscriptional steps, leading to the prevention of hepatic inflammation.

Highlights

Accumulated evidence indicates that eicosapentaenoic acid and docosahexaenoic acid (EPA/DHA), which are n-3 polyunsaturated fatty acids (PUFAs) and are abundant in fish oil, have a variety of biological activities such as antioxidative, anti-inflammatory, and anticancer effects
These findings demonstrated that peroxidized products of Eicosapentaenoic acid and docosahexaenoic acid (EPA/DHA) suppressed the induction of inducible nitric oxide synthase (iNOS) gene expression through both of the transcriptional and posttranscriptional steps, leading to the prevention of hepatic inflammation
The peroxidation levels of EPA/DHA increased to 2–7 μM of MDA time dependently, which are near the ranges seen in the plasma of human (1.5–3.5 μM of MDA) fed fish oil diets [8, 28]

Summary

Introduction

Accumulated evidence indicates that eicosapentaenoic acid and docosahexaenoic acid (EPA/DHA), which are n-3 polyunsaturated fatty acids (PUFAs) and are abundant in fish oil, have a variety of biological activities such as antioxidative, anti-inflammatory, and anticancer effects. We previously reported the anti-inflammatory and anticancer effects of various PUFAs both in vivo and in vitro [1, 2]. Since n-3 PUFAs are peroxidized spontaneously in the air, it cannot negate the possibility that their peroxidized products are involved partly in anti-inflammatory and anticancer effects. Several studies demonstrated that the anticancer effect of PUFAs depended on their peroxidized levels [3,4,5]. Sethi [6] reported that anti-inflammatory effects of n-3 PUFAs were due to their peroxidized products. Sethi et al [7] showed that peroxidized EPA diminished the upregulation of endothelial cell adhesion molecules such as VCAM-1 and ELAM-1 through the inhibition of NFκB activation in lipopolysaccharide- (LPS-) or cytokinestimulated human umbilical vein endothelial cell, while unoxidized EPA had no effect. Sethi and coworkers demonstrated that peroxidized EPA inhibited the expression of chemokines such as monocyte chemoattractant protein(MCP-) 1 and interleukin (IL-) 8 in cytokine-stimulated endothelial cells [8, 9]

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