title: Oleoylethanolamide, an endogenous PPAR-α ligand, attenuates liver fibrosis targeting hepatic stellate cells.
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.
authors.affiliation: Department of Medical Sciences, Medical College, Xiamen University, Xiamen, Fujian, China.|Clinical Research Institute, The First Affiliated Hospital, University of South China, Hengyang, Hunan, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.affiliation: Department of Medical Sciences, Medical College, Xiamen University, Xiamen, Fujian, China.|Xiamen Diabetes Institute, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, China.
authors.forename: Long
authors.initials: L
authors.lastname: Li
authors.affiliation: 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.
authors.forename: Junde
authors.initials: J
authors.lastname: Chen
authors.affiliation: Department of Medical Sciences, Medical College, Xiamen University, Xiamen, Fujian, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Li
authors.affiliation: College of Arts and Sciences, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA.
authors.forename: Zihan
authors.initials: Z
authors.lastname: Zheng
authors.affiliation: Department of Medical Sciences, Medical College, Xiamen University, Xiamen, Fujian, China.
authors.forename: Jie
authors.initials: J
authors.lastname: Ren
authors.affiliation: Department of Medical Sciences, Medical College, Xiamen University, Xiamen, Fujian, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Qiu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D004195:Disease Models, Animal; D063388:Endocannabinoids / Q000494:pharmacology*; D005455:Fluorescent Antibody Technique; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000473:pathology; D008024:Ligands; D008103:Liver Cirrhosis / Q000473:pathology*; D051379:Mice; D057507:Mice, 129 Strain; D018345:Mice, Knockout; D009829:Oleic Acids / Q000494:pharmacology*; D047493:PPAR alpha / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D063388:Endocannabinoids; D008024:Ligands; D009829:Oleic Acids; D047493:PPAR alpha; C488250:oleoylethanolamide
keywords: OEA; PPAR-α; Pathology Section; TGF-β1; hepatic stellate cells; liver fibrosis