Sortilin Deficiency Reduces Ductular Reaction, Hepatocyte Apoptosis, and Liver Fibrosis in Cholestatic-Induced Liver Injury
- Authors
- Hubel, Einav; Saroha, Ashish; Park, Woo-Jae; Pewzner-Jung, Yael; Lavoie, Elise G.; Futerman, Anthony H.; Bruck, Rafael; Fishman, Sigal; Dranoff, Jonathan A.; Shibolet, Oren; Zvibel, Isabel
- Issue Date
- Jan-2017
- Publisher
- ELSEVIER SCIENCE INC
- Citation
- AMERICAN JOURNAL OF PATHOLOGY, v.187, no.1, pp.122 - 133
- Journal Title
- AMERICAN JOURNAL OF PATHOLOGY
- Volume
- 187
- Number
- 1
- Start Page
- 122
- End Page
- 133
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/6507
- DOI
- 10.1016/j.ajpath.2016.09.005
- ISSN
- 0002-9440
- 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.
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