Sortilin Deficiency Reduces Ductular Reaction, Hepatocyte Apoptosis, and Liver Fibrosis in Cholestatic-Induced Liver Injury
DC Field | Value | Language |
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dc.contributor.author | Hubel, Einav | - |
dc.contributor.author | Saroha, Ashish | - |
dc.contributor.author | Park, Woo-Jae | - |
dc.contributor.author | Pewzner-Jung, Yael | - |
dc.contributor.author | Lavoie, Elise G. | - |
dc.contributor.author | Futerman, Anthony H. | - |
dc.contributor.author | Bruck, Rafael | - |
dc.contributor.author | Fishman, Sigal | - |
dc.contributor.author | Dranoff, Jonathan A. | - |
dc.contributor.author | Shibolet, Oren | - |
dc.contributor.author | Zvibel, Isabel | - |
dc.date.available | 2020-02-27T19:44:59Z | - |
dc.date.created | 2020-02-07 | - |
dc.date.issued | 2017-01 | - |
dc.identifier.issn | 0002-9440 | - |
dc.identifier.uri | https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/6507 | - |
dc.description.abstract | Sortilin, a member of the vacuolar protein sorting 10 domain receptor family, traffics newly synthesized proteins from the trans-Golgi network to secretory pathways, endosomes, and cell surface. Sortilin-trafficked molecules, including IL-6 and acid sphingomyelinase (aSMase), mediate cholangiocyte proliferation and Liver inflammation, hepatic stellate cell activation, hepatocyte apoptosis, and fibrosis. Based on these sortilin-regulated functions, we investigated its role in biliary damage Leading to hepatocellular injury and fibrosis. Sortilin(-/-) mice displayed impaired inflammation and ductular reaction 3 days after bile duct Ligation (BDL), as demonstrated by reduced cholangiocyte proliferation and activation and reduced serum IL-6. Interestingly, liver fibrosis was reduced in Sortilin(-/-) mice after both BDL and carbon tetrachloride treatment, in line with attenuated in vitro activation of Sortilin(-/-) hepatic stellate cells. Sortilin(-/-) hepatic aSMase activity was reduced in the BDL and carbon tetrachloride models and accompanied by reduced in vivo hepatocyte apoptosis. In addition, wild type (WT), but not Sortilin(-/-) hepatocytes, had increased aSMase-dependent susceptibility to bile acid-induced apoptosis in vitro. Mechanistically, short-term IL-6 neutralization in bile duct-ligated WT mice decreased hepatic inflammation and reactive cholangiocyte-derived cytokines and chemokines, without affecting fibrosis, whereas pharmacological inhibition of aSMase activity was not sufficient to attenuate hepatic fibrosis. Only combined IL-6 and aSMase inhibition significantly reduced fibrosis in bile-duct ligated WT mice. We conclude that sortilin regulates cholestatic liver damage and fibrosis via effects on both aSMase activity and serum IL-6. | - |
dc.language | 영어 | - |
dc.language.iso | en | - |
dc.publisher | ELSEVIER SCIENCE INC | - |
dc.relation.isPartOf | AMERICAN JOURNAL OF PATHOLOGY | - |
dc.subject | SPHINGOMYELINASE-CERAMIDE SYSTEM | - |
dc.subject | CORONARY ENDOTHELIAL-CELLS | - |
dc.subject | ACID SPHINGOMYELINASE | - |
dc.subject | CHOLANGIOCYTE PROLIFERATION | - |
dc.subject | HEPATIC STEATOSIS | - |
dc.subject | RECEPTOR SORTILIN | - |
dc.subject | GROWTH-FACTOR | - |
dc.subject | MICE | - |
dc.subject | ACTIVATION | - |
dc.subject | DISEASE | - |
dc.title | Sortilin Deficiency Reduces Ductular Reaction, Hepatocyte Apoptosis, and Liver Fibrosis in Cholestatic-Induced Liver Injury | - |
dc.type | Article | - |
dc.type.rims | ART | - |
dc.description.journalClass | 1 | - |
dc.identifier.wosid | 000390829300013 | - |
dc.identifier.doi | 10.1016/j.ajpath.2016.09.005 | - |
dc.identifier.bibliographicCitation | AMERICAN JOURNAL OF PATHOLOGY, v.187, no.1, pp.122 - 133 | - |
dc.identifier.scopusid | 2-s2.0-85006515650 | - |
dc.citation.endPage | 133 | - |
dc.citation.startPage | 122 | - |
dc.citation.title | AMERICAN JOURNAL OF PATHOLOGY | - |
dc.citation.volume | 187 | - |
dc.citation.number | 1 | - |
dc.contributor.affiliatedAuthor | Park, Woo-Jae | - |
dc.type.docType | Article | - |
dc.subject.keywordPlus | SPHINGOMYELINASE-CERAMIDE SYSTEM | - |
dc.subject.keywordPlus | CORONARY ENDOTHELIAL-CELLS | - |
dc.subject.keywordPlus | ACID SPHINGOMYELINASE | - |
dc.subject.keywordPlus | CHOLANGIOCYTE PROLIFERATION | - |
dc.subject.keywordPlus | HEPATIC STEATOSIS | - |
dc.subject.keywordPlus | RECEPTOR SORTILIN | - |
dc.subject.keywordPlus | GROWTH-FACTOR | - |
dc.subject.keywordPlus | MICE | - |
dc.subject.keywordPlus | ACTIVATION | - |
dc.subject.keywordPlus | DISEASE | - |
dc.relation.journalResearchArea | Pathology | - |
dc.relation.journalWebOfScienceCategory | Pathology | - |
dc.description.journalRegisteredClass | scie | - |
dc.description.journalRegisteredClass | scopus | - |
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