کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
---|---|---|---|---|
8258571 | 1534610 | 2018 | 35 صفحه PDF | دانلود رایگان |
عنوان انگلیسی مقاله ISI
Mechanisms of canalicular transporter endocytosis in the cholestatic rat liver
ترجمه فارسی عنوان
مکانیسم اندوسیتوز حمل کننده کانالیکولار در کبد رت کلستاتیک
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کلمات کلیدی
isolated rat hepatocyte coupletsCVAMDCIRHCMrp2IPLCGamFSCRHBSEPDNP-SGSmall interfering RNA - RNA تداخل کوچکsiRNA - siRNACME - آموزش مداومClathrin-mediated endocytosis - اندوسیتوز مداخله می کند Clathrintaurocholate - تاوروکولاتMonodansylcadaverine - مونودانسیل کاداورینBile salts - نمک صفاقیmultidrug resistance-associated protein 2 - پروتئین مرتبط با مقاومت چند دارویی 2Bile salt export pump - پمپ صادرات نمک صفرClathrin mediated endocytosis - کلاترین عامل اندوسیتوز استLipid rafts - گستره چربی، کلک چربی یا لیپید رفت
موضوعات مرتبط
علوم زیستی و بیوفناوری
بیوشیمی، ژنتیک و زیست شناسی مولکولی
سالمندی
چکیده انگلیسی
Impaired canalicular secretion due to increased endocytosis and intracellular retention of canalicular transporters such as BSEP and MRP2 is a main, common pathomechanism of cholestasis. Nevertheless, the mechanisms governing this process are unknown. We characterized this process in estradiol 17 β-d-glucuronide (E17G)-induced cholestasis, an experimental model which partially mimics pregnancy-induced cholestasis. Inhibitors of clathrin-mediated endocytosis (CME) such as monodansylcadaverine (MDC) or K+ depletion, but not the caveolin-mediated endocytosis inhibitors filipin and genistein, prevented E17G-induced endocytosis of BSEP and MRP2, and the associated impairment of activity of these transporters in isolated rat hepatocyte couplets (IRHC). Immunofluorescence and confocal microscopy studies showed that, in E17G-treated IRHC, there was a significant increase in the colocalization of MRP2 with clathrin, AP2, and Rab5, three essential members of the CME machinery. Knockdown of AP2 by siRNA in sandwich-cultured rat hepatocytes completely prevented E17G-induced endocytosis of BSEP and MRP2. MDC significantly prevented this endocytosis, and the impairment of bile flow and biliary secretion of BSEP and MRP2 substrates, in isolated and perfused livers. BSEP and MRP2, which were mostly present in raft (caveolin-enriched) microdomains in control rats, were largely found in non-raft (clathrin-enriched) microdomains in livers from E17G-treated animals, from where they can be readily recruited for CME. In conclusion, our findings show that CME is the mechanism responsible for the internalization of the canalicular transporters BSEP and MRP2 in E17G-induced cholestasis. The shift of these transporters from raft to non-raft microdomains could be a prerequisite for the transporters to be endocytosed under cholestatic conditions.
ناشر
Database: Elsevier - ScienceDirect (ساینس دایرکت)
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease - Volume 1864, Issue 4, Part A, April 2018, Pages 1072-1085
Journal: Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease - Volume 1864, Issue 4, Part A, April 2018, Pages 1072-1085
نویسندگان
Gisel S. Miszczuk, Ismael R. Barosso, MarÃa Cecilia Larocca, Julieta Marrone, Raúl A. Marinelli, Andrea C. Boaglio, Enrique J. Sánchez Pozzi, Marcelo G. Roma, Fernando A. Crocenzi,