title: Sortilin Deficiency Reduces Ductular Reaction, Hepatocyte Apoptosis, and Liver Fibrosis in Cholestatic-Induced Liver Injury.
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.
authors.affiliation: Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Einav
authors.initials: E
authors.lastname: Hubel
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Ashish
authors.initials: A
authors.lastname: Saroha
authors.affiliation: Department of Biochemistry, School of Medicine, Gachon University, Incheon, Republic of Korea.
authors.forename: Woo-Jae
authors.initials: WJ
authors.lastname: Park
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Yael
authors.initials: Y
authors.lastname: Pewzner-Jung
authors.affiliation: Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Elise G
authors.initials: EG
authors.lastname: Lavoie
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot, Israel.
authors.forename: Anthony H
authors.initials: AH
authors.lastname: Futerman
authors.affiliation: Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Rafael
authors.initials: R
authors.lastname: Bruck
authors.affiliation: Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Sigal
authors.initials: S
authors.lastname: Fishman
authors.affiliation: Division of Gastroenterology and Hepatology, University of Arkansas for Medical Sciences, Little Rock, Arkansas.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Dranoff
authors.affiliation: Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel.
authors.forename: Oren
authors.initials: O
authors.lastname: Shibolet
authors.affiliation: Research Center for Digestive Tract and Liver Diseases, Tel Aviv Sourasky Medical Center and the Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Electronic address: isab@tlvmc.gov.il.
authors.forename: Isabel
authors.initials: I
authors.lastname: Zvibel
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000172:deficiency* / Q000378:metabolism; D000818:Animals; D017209:Apoptosis; D001652:Bile Ducts / Q000473:pathology*; D049109:Cell Proliferation; D018925:Chemokines / Q000378:metabolism; D002779:Cholestasis / Q000150:complications* / Q000473:pathology; D055166:Hepatic Stellate Cells / Q000378:metabolism / Q000473:pathology; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D007249:Inflammation / Q000473:pathology; D015850:Interleukin-6 / Q000378:metabolism; D008026:Ligation; D008099:Liver / Q000293:injuries* / Q000378:metabolism / Q000473:pathology; D008103:Liver Cirrhosis / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D008810:Mice, Inbred C57BL; D009500:Neutralization Tests; D010641:Phenotype; D013108:Sphingomyelin Phosphodiesterase / Q000378:metabolism; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D018925:Chemokines; D015850:Interleukin-6; D013108:Sphingomyelin Phosphodiesterase; D000099183:Sortilin; C577975:ASMase, mouse