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

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

doi:10.18632/oncotarget.6466

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.

Highlights

Liver fibrosis is a common wound healing response that may be mounted in response to chronic or repeated liver injury
Chemical analysis of serum and hepatic composition indicate that OEA treatment partially prevented the increases of Alanine transaminase (ALT), aspartate transaminase (AST) and TG levels observed in WT mice given methionine choline-deficient (MCD) diet (P < 0.01, P < 0.05, P < 0.05, respectively), but did not attenuate the increase in peroxisome proliferator-activated receptor-α (PPAR-α) knockout groups (Figure 2A, 2B and Figure S1C)
Our present study demonstrates that the endogenous Peroxisome proliferator-activated receptors (PPARs)-α ligand, OEA, can significantly suppress the pro-fibrotic cytokine TGF-β1 negatively regulate genes in the TGF-β1 signaling pathway (α-SMA, collagen 1a, and collagen 3a) in mice models of hepatic fibrosis

Summary

Introduction

Liver fibrosis is a common wound healing response that may be mounted in response to chronic or repeated liver injury. The same pathological processes behind fibrosis have been linked with hepatocellular carcinoma (HCC) [1, 2] This pathological process is characterized by excessive production and deposition of proteins of the extracellular matrix (ECM). Hepatic stellate cells (HSCs) are recognized as the main producers of matrix components in the liver, and play a critical role in regulating the production and secretion of the ECM. HSCs stay in a quiescent state, mainly serving to store vitamin A. These quiescent HSCs may trans-differentiate following liver injury changing into highly-proliferative myofibroblast-like www.impactjournals.com/oncotarget cells that are characterized by the expression of α-smooth muscle actin (α-SMA), and excessive production of type I collagen (Col1a) and type III collagen (Col3a), which are critical components of the ECM. Suppression of HSC activation has been proposed as therapeutic strategy for the treatment and prevention of liver fibrosis, and novel methods for achieving this end are still being sought [3,4,5]

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Conclusion