Hydroxyeicosapentaenoic acids from the Pacific krill show high ligand activities for PPARs

Hidetoshi Yamada,Eriko Oshiro,Sayaka Kikuchi,Mayuka Hakozaki,Hideyuki Takahashi,Ken-Ichi Kimura

doi:10.1194/jlr.m047514

Hidetoshi Yamada, Eriko Oshiro + Show 4 more

Open Access

https://doi.org/10.1194/jlr.m047514

Copy DOI

Abstract

PPARs regulate the expression of genes for energy metabolism in a ligand-dependent manner. PPARs can influence fatty acid oxidation, the level of circulating triglycerides, glucose uptake and insulin sensitivity. Here, we demonstrate that 5-hydroxyeicosapentaenoic acid (HEPE), 8-HEPE, 9-HEPE, 12-HEPE and 18-HEPE (hydroxylation products of EPA) obtained from methanol extracts of Pacific krill (Euphausia pacifica) can act as PPAR ligands. Two of these products, 8-HEPE and 9-HEPE, enhanced the transcription levels of GAL4-PPARs to a significantly greater extent than 5-HEPE, 12-HEPE, 18-HEPE, EPA, and EPA ethyl-ester. 8-HEPE also activated significantly higher transcription of GAL4-PPARα, GAL4-PPARγ, and GAL4-PPARδ than EPA at concentrations greater than 4, 64, and 64 μM, respectively. We also demonstrated that 8-HEPE increased the expression levels of genes regulated by PPARs in FaO, 3T3-F442A, and C2C12 cells. Furthermore, 8-HEPE enhanced adipogenesis and glucose uptake. By contrast, at the same concentrations, EPA showed weak or little effect, indicating that 8-HEPE was the more potent inducer of physiological effects.

Highlights

PPARs regulate the expression of genes for energy metabolism in a ligand-dependent manner
Transcription of GAL4-PPAR␣ and GAL4-PPAR␥ was activated by 5, 8, 9, 12, and 18-hydroxyeicosapentaenoic acid (HEPE) (Fig. 3A, B), while transcription of GAL4-PPAR␦ was activated by 5, 8, 9, and 12-HEPE (Fig. 3C)
We found that arachidonic acid (AA), 8-hydroxyeicosatetraenoic acids (HETEs), and 8-HEPE activated transcription of GAL4PPAR␣ and GAL4-PPAR␥ at a concentration of 5 ␮M (Fig. 4A, B), while 8-HEPE activated transcription of GAL4PPAR␦ (Fig. 4C)

Summary

Introduction

PPARs regulate the expression of genes for energy metabolism in a ligand-dependent manner. We demonstrate that 5-hydroxyeicosapentaenoic acid (HEPE), 8-HEPE, 9-HEPE, 12-HEPE and 18-HEPE (hydroxylation products of EPA) obtained from methanol extracts of Pacific krill (Euphausia pacifica) can act as PPAR ligands Two of these products, 8-HEPE and 9-HEPE, enhanced the transcription levels of GAL4-PPARs to a significantly greater extent than 5-HEPE, 12-HEPE, 18-HEPE, EPA, and EPA ethyl-ester. Journal of Lipid Research Volume 55, 2014 895 leading to the formation of leukotrienes and hydroxyeicosatetraenoic acids (HETEs), or via the cyclooxygenase pathway that produces prostaglandins and thromboxanes They can act as activators for different PPARs; for example, the prostaglandin D2 derivative, 15-deoxy-⌬12,14-PGJ2, is a ligand for PPAR␥ [17, 22]; 8-HETE, a compound associated with phorbol ester-induced inflammation, is a ligand for PPAR␣ [8, 19]; and leukotriene B4, a chemotactic inflammation mediator, binds to PPAR␣ [19, 23]. The levels of triglycerides in the livers of mice given a water-soluble extract from Pacific krill decreased [32]

Methods

Results

Conclusion