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8-Hydroxyeicosapentaenoic Acid Decreases Plasma and Hepatic Triglycerides via Activation of Peroxisome Proliferator-Activated Receptor Alpha in High-Fat Diet-Induced Obese Mice.

ABSTRACT: PPARs regulate the expression of genes involved in lipid homeostasis. PPARs serve as molecular sensors of fatty acids, and their activation can act against obesity and metabolic syndromes. 8-Hydroxyeicosapentaenoic acid (8-HEPE) acts as a PPAR ligand and has higher activity than EPA. However, to date, the PPAR ligand activity of 8-HEPE has only been demonstrated in vitro. Here, we investigated its ligand activity in vivo by examining the effect of 8-HEPE treatment on high fat diet-induced obesity in mice. After the 4-week treatment period, the levels of plasma and hepatic triglycerides in the 8-HEPE-fed mice were significantly lower than those in the HFD-fed mice. The expression of genes regulated by PPAR? was significantly increased in 8-HEPE-fed mice compared to those that received only HFD. Additionally, the level of hepatic palmitic acid in 8-HEPE-fed mice was significantly lower than in HFD-fed mice. These results suggested that intake of 8-HEPE induced PPAR? activation and increased catabolism of lipids in the liver. We found no significant differences between EPA-fed mice and HFD-fed mice. We demonstrated that 8-HEPE has a larger positive effect on metabolic syndrome than EPA and that 8-HEPE acts by inducing PPAR? activation in the liver.

SUBMITTER: Yamada H

PROVIDER: S-EPMC4864551 | biostudies-literature | 2016

REPOSITORIES: biostudies-literature

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8-Hydroxyeicosapentaenoic Acid Decreases Plasma and Hepatic Triglycerides via Activation of Peroxisome Proliferator-Activated Receptor Alpha in High-Fat Diet-Induced Obese Mice.

Yamada Hidetoshi H Kikuchi Sayaka S Hakozaki Mayuka M Motodate Kaori K Nagahora Nozomi N Hirose Masamichi M

Journal of lipids 20160428

PPARs regulate the expression of genes involved in lipid homeostasis. PPARs serve as molecular sensors of fatty acids, and their activation can act against obesity and metabolic syndromes. 8-Hydroxyeicosapentaenoic acid (8-HEPE) acts as a PPAR ligand and has higher activity than EPA. However, to date, the PPAR ligand activity of 8-HEPE has only been demonstrated in vitro. Here, we investigated its ligand activity in vivo by examining the effect of 8-HEPE treatment on high fat diet-induced obesit ...[more]

PMID: 27239345

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Project description:AimsTo evaluate a novel tetrahydroisoquinoline derivative YR4-42 as a selective peroxisome proliferator-activated receptor γ (PPARγ) modulator (SPPARM) and explore its anti-diabetic effects in vitro and in vivo.Materials and methodsUsing two standard full PPARγ agonists rosiglitazone and pioglitazone as controls, the PPARγ binding affinity and transactivation action of YR4-42 were evaluated using biochemical and cell-based reporter gene assays. The capacity of YR4-42 to recruit coactivators of PPARγ was also assessed. The effects of YR4-42 on adipogenesis and glucose consumption and PPARγ Ser273 phosphorylation were investigated in 3T3-L1 adipocytes. The effects of YR4-42 and pioglitazone, serving as positive control, on glucose and lipids metabolism were investigated in high-fat diet-induced obese (DIO) C57BL/6J mice. The expression of PPARγ target genes involved in glucose and lipid metabolism was also assessed in vitro and in vivo.ResultsIn vitro biochemical and cell-based functional assays showed that YR4-42 has much weaker binding affinity, transactivation, and recruitment to PPARγ of the coactivators thyroid hormone receptor-associated protein complex 220 kDa component (TRAP220) and PPARγ coactivator 1-α (PGC1α) compared to full agonists. In 3 T3-L1 adipocytes, YR4-42 significantly improved glucose consumption without a lipogenesis effect, while blocking tumour necrosis factor α-mediated phosphorylation of PPARγ at Ser273, thereby upregulating the expression of the PPARγ Ser273 phosphorylation-dependent genes. Furthermore, in DIO mice, oral administration of YR4-42 ameliorated the hyperglycaemia, with a similar insulin sensitization effect to that of pioglitazone. Importantly, YR4-42 also improved hyperlipidaemia-associated hepatic steatosis without weight gain, which avoids a major side effect of pioglitazone. Thus, YR4-42 appeared to selectively modulate PPARγ responses. This finding was supported by the gene expression analysis, which showed that YR4-42 selectively targets PPARγ-regulated genes mapped to glucose and lipid metabolism in DIO mice.ConclusionsWe conclude that YR4-42 is a novel anti-diabetic drug candidate with significant advantages compared to standard PPARγ agonists. YR4-42 should be further investigated in preclinical and clinical studies.

Dataset Information

8-Hydroxyeicosapentaenoic Acid Decreases Plasma and Hepatic Triglycerides via Activation of Peroxisome Proliferator-Activated Receptor Alpha in High-Fat Diet-Induced Obese Mice.

Publications

8-Hydroxyeicosapentaenoic Acid Decreases Plasma and Hepatic Triglycerides via Activation of Peroxisome Proliferator-Activated Receptor Alpha in High-Fat Diet-Induced Obese Mice.

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