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Polarized release of hepatic micro RNA s into bile and serum in response to cellular injury and impaired liver function
Author(s) -
Verhoeven Cornelia J.,
Farid Waqar R. R.,
Roest Henk P.,
Ramakrishnaiah Vedashree,
Ruiter Petra E.,
Jonge Jeroen,
Kwekkeboom Jaap,
Metselaar Herold J.,
Tilanus Hugo W.,
Kazemier Geert,
Ijzermans Jan N. M.,
Laan Luc J. W.
Publication year - 2016
Publication title -
liver international
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.873
H-Index - 110
eISSN - 1478-3231
pISSN - 1478-3223
DOI - 10.1111/liv.12955
Subject(s) - medicine , liver injury , bile duct , liver function , hepatocyte , liver function tests , microrna , mir 122 , endocrinology , biology , biochemistry , gene , in vitro
Background & Aims Extracellular micro RNA s (mi RNA s) in serum and bile are currently under intense investigation for biomarker purposes in liver disease. However, the directions and pathways by which mi RNA s are released from hepatic cells remains largely unknown. Here, we investigated the release of hepatocyte and cholangiocyte‐derived mi RNA s ( HD miRs and CD miRs) into blood and bile during various (patho)physiological hepatic conditions. Methods Mi RNA release was analysed using longitudinally collected tissue and paired bile and serum samples ( n = 124) that were obtained from liver transplant recipients during follow‐up. Results Cell‐type specificity of HD miRs and CD miRs was confirmed in liver and common bile duct biopsies ( P < 0.001). Analysis of paired bile and serum samples showed up to 20‐times higher mi RNA ‐levels in bile compared to serum ( P < 0.0001). Fractionation of bile showed the majority of mi RNA s being present in the unpelletable supernatant, where protein conjunctions protect mi RNA s against degradation ( P < 0.0001). During episodes of liver injury and histologically proven rejection in liver transplant recipients, relative HD miR‐levels in bile decreased while its levels in serum increased ( P ≤ 0.015). Simultaneously, relative CD miR‐levels in bile significantly increased, while their levels in serum decreased. Related to liver excretory function, a strong positive correlation was observed between HD miR‐122 levels and bilirubin excretion into bile ( R = 0.694, P < 0.0001), whereas CD miRs showed an inverse correlation ( P < 0.05). Conclusion During impaired excretory function and injury, the liver shows polarized release of extracellular HD miRs and CD miRs. This sheds new light on the biology of hepatic mi RNA release which is relevant for the interpretation of hepatic mi RNA s as biomarkers.