کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
5596142 | 1573359 | 2017 | 13 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Sortilin Deficiency Reduces Ductular Reaction, Hepatocyte Apoptosis, and Liver Fibrosis in Cholestatic-Induced Liver Injury
دانلود مقاله + سفارش ترجمه
دانلود مقاله ISI انگلیسی
رایگان برای ایرانیان
موضوعات مرتبط
علوم پزشکی و سلامت
پزشکی و دندانپزشکی
کاردیولوژی و پزشکی قلب و عروق
پیش نمایش صفحه اول مقاله
چکیده انگلیسی
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. Sortilinâ/â 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 Sortilinâ/â mice after both BDL and carbon tetrachloride treatment, in line with attenuated in vitro activation of Sortilinâ/â hepatic stellate cells. Sortilinâ/â 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 Sortilinâ/â 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.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: The American Journal of Pathology - Volume 187, Issue 1, January 2017, Pages 122-133
Journal: The American Journal of Pathology - Volume 187, Issue 1, January 2017, Pages 122-133
نویسندگان
Einav Hubel, Ashish Saroha, Woo-Jae Park, Yael Pewzner-Jung, Elise G. Lavoie, Anthony H. Futerman, Rafael Bruck, Sigal Fishman, Jonathan A. Dranoff, Oren Shibolet, Isabel Zvibel,