title: ω-3 PUFAs ameliorate liver fibrosis and inhibit hepatic stellate cells proliferation and activation by promoting YAP/TAZ degradation.
abstract: Elevated levels of the transcriptional regulators Yes-associated protein (YAP) and transcriptional coactivators with PDZ-binding motif (TAZ), key effectors of the Hippo pathway, have been shown to play essential roles in controlling liver cell fate and the activation of hepatic stellate cells (HSCs). The dietary intake of omega-3 polyunsaturated fatty acids (ω-3 PUFAs) has been positively associated with a number of health benefits including prevention and reduction of cardiovascular diseases, inflammation and cancers. However, little is known about the impact of ω-3 PUFAs on liver fibrosis. In this study, we used CCl4-induced liver fibrosis mouse model and found that YAP/TAZ is over-expressed in the fibrotic liver and activated HSCs. Fish oil administration to the model mouse attenuates CCl4-induced liver fibrosis. Further study revealed that ω-3 PUFAs down-regulate the expression of pro-fibrogenic genes in activated HSCs and fibrotic liver, and the down-regulation is mediated via YAP, thus identifying YAP as a target of ω-3 PUFAs. Moreover, ω-3 PUFAs promote YAP/TAZ degradation in a proteasome-dependent manner. Our data have identified a mechanism of ω-3 PUFAs in ameliorating liver fibrosis.
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Kun
authors.initials: K
authors.lastname: Zhang
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Yanan
authors.initials: Y
authors.lastname: Chang
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Zhemin
authors.initials: Z
authors.lastname: Shi
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Han
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Yawei
authors.initials: Y
authors.lastname: Han
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Qingbin
authors.initials: Q
authors.lastname: Yao
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Zhimei
authors.initials: Z
authors.lastname: Hu
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Hongmei
authors.initials: H
authors.lastname: Cui
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Zheng
authors.affiliation: The Third Central Clinical College of Tianjin Medical University, Tianjin 300170, China.|Department of Hepatology, Tianjin Third Central Hospital, Tianjin 300170, China.|Tianjin Key Laboratory of Artificial Cells, Tianjin 300170, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Han
authors.affiliation: Department of Histology and Embryology, School of Basic Medical Sciences, Tianjin Medical University, Tianjin 300070, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Hong
mesh_terms: D000217:Acyltransferases; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D018797:Cell Cycle Proteins; D004195:Disease Models, Animal; D015536:Down-Regulation; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage*; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000502:physiology*; D008099:Liver / Q000473:pathology; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000473:pathology*; D008297:Male; D008807:Mice, Inbred BALB C; D010750:Phosphoproteins / Q000378:metabolism*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D014157:Transcription Factors / Q000378:metabolism*; D016896:Treatment Outcome; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018797:Cell Cycle Proteins; D015525:Fatty Acids, Omega-3; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C486223:Yap1 protein, mouse; D000217:Acyltransferases; C486363:tafazzin protein, mouse; D046988:Proteasome Endopeptidase Complex