Oncotarget

Research Papers: Pathology:

Oleoylethanolamide, an endogenous PPAR-α ligand, attenuates liver fibrosis targeting hepatic stellate cells

Ling Chen, Long Li, Junde Chen, Lei Li, Zihan Zheng, Jie Ren and Yan Qiu _

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Oncotarget. 2015; 6:42530-42540. https://doi.org/10.18632/oncotarget.6466

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Abstract

Ling Chen1,4,*, Long Li1,3,*, Junde Chen2, Lei Li1, Zihan Zheng5, Jie Ren1 and Yan Qiu1

1 Department of Medical Sciences, Medical College, Xiamen University, Xiamen, Fujian, China

2 Marine Biological Resource Comprehensive Utilization Engineering Research Center of the State Oceanic Administration, The Third Institute of Oceanography of the State Oceanic Administration, Xiamen, Fujian, China

3 Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China

4 Clinical Research Institute, The First Affiliated Hospital, University of South China, Hengyang, Hunan, China

5 College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA

* These authors have contributed equally to this work

Correspondence to:

Yan Qiu, email:

Keywords: liver fibrosis, OEA, PPAR-α, TGF-β1, hepatic stellate cells, Pathology Section

Received: May 29, 2015 Accepted: November 16, 2015 Published: December 04, 2015

Abstract

Oleoylethanolamide (OEA), an endocannabinoid-like molecule, was revealed to modulate lipid metabolism through a peroxisome proliferator-activated receptor-α (PPAR-α) mediated mechanism. In present study, we further investigated the activities and mechanisms of OEA in ameliorating hepatic fibrosis in Sv/129 mice induced by a methionine choline-deficient (MCD) diet or thioacetamide (TAA) treatment. Liver fibrosis development was assessed by Hematoxylin-eosin and Sirius red staining. Treatment with OEA (5 mg/kg/day, intraperitoneal injection, i.p.) significantly attenuated the progress of liver fibrosis in both two experimental animal models by blocking the activation of hepatic stellate cells (HSCs). Gene expression analysis of hepatic tissues indicated that OEA inhibited the expression of α-smooth muscle action (α-SMA) and collagen matrix, fibrosis markers, and genes involved in inflammation and extracellular matrix remodeling. In vitro studies showed that OEA inhibited transforming growth factor β1-stimulated HSCs activation through suppressing Smad2/3 phosphorylation, α-SMA expression and myofibroblast transformation. These improvements could not be observed in PPAR-α knockout mice models with OEA administration, which suggested all the anti-fibrotic effects of OEA in vivo and in vitro were mediated by PPAR-α activation. Collectively, our results suggested that OEA exerted a pharmacological effect on modulating hepatic fibrosis development through the inhibition of HSCs activation in liver and therefore may be a potential therapeutic agent for liver fibrosis.


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