Verhoeven, Cornelia J.;
Farid, Waqar R. R.;
Roest, Henk P.;
Ramakrishnaiah, Vedashree;
de Ruiter, Petra E.;
de Jonge, Jeroen;
Kwekkeboom, Jaap;
Metselaar, Herold J.;
Tilanus, Hugo W.;
Kazemier, Geert;
Ijzermans, Jan N. M.;
van der Laan, Luc J. W.
Polarized release of hepatic microRNAs into bile and serum in response to cellular injury and impaired liver function
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Medientyp:
E-Artikel
Titel:
Polarized release of hepatic microRNAs into bile and serum in response to cellular injury and impaired liver function
Beteiligte:
Verhoeven, Cornelia J.;
Farid, Waqar R. R.;
Roest, Henk P.;
Ramakrishnaiah, Vedashree;
de Ruiter, Petra E.;
de Jonge, Jeroen;
Kwekkeboom, Jaap;
Metselaar, Herold J.;
Tilanus, Hugo W.;
Kazemier, Geert;
Ijzermans, Jan N. M.;
van der Laan, Luc J. W.
Beschreibung:
<jats:title>Abstract</jats:title><jats:sec><jats:title>Background & Aims</jats:title><jats:p>Extracellular micro<jats:styled-content style="fixed-case">RNA</jats:styled-content>s (mi<jats:styled-content style="fixed-case">RNA</jats:styled-content>s) in serum and bile are currently under intense investigation for biomarker purposes in liver disease. However, the directions and pathways by which mi<jats:styled-content style="fixed-case">RNA</jats:styled-content>s are released from hepatic cells remains largely unknown. Here, we investigated the release of hepatocyte and cholangiocyte‐derived mi<jats:styled-content style="fixed-case">RNA</jats:styled-content>s (<jats:styled-content style="fixed-case">HD</jats:styled-content>miRs and <jats:styled-content style="fixed-case">CD</jats:styled-content>miRs) into blood and bile during various (patho)physiological hepatic conditions.</jats:p></jats:sec><jats:sec><jats:title>Methods</jats:title><jats:p>Mi<jats:styled-content style="fixed-case">RNA</jats:styled-content> release was analysed using longitudinally collected tissue and paired bile and serum samples (<jats:italic>n</jats:italic> = 124) that were obtained from liver transplant recipients during follow‐up.</jats:p></jats:sec><jats:sec><jats:title>Results</jats:title><jats:p>Cell‐type specificity of <jats:styled-content style="fixed-case">HD</jats:styled-content>miRs and <jats:styled-content style="fixed-case">CD</jats:styled-content>miRs was confirmed in liver and common bile duct biopsies (<jats:italic>P</jats:italic> < 0.001). Analysis of paired bile and serum samples showed up to 20‐times higher mi<jats:styled-content style="fixed-case">RNA</jats:styled-content>‐levels in bile compared to serum (<jats:italic>P</jats:italic> < 0.0001). Fractionation of bile showed the majority of mi<jats:styled-content style="fixed-case">RNA</jats:styled-content>s being present in the unpelletable supernatant, where protein conjunctions protect mi<jats:styled-content style="fixed-case">RNA</jats:styled-content>s against degradation (<jats:italic>P</jats:italic> < 0.0001). During episodes of liver injury and histologically proven rejection in liver transplant recipients, relative <jats:styled-content style="fixed-case">HD</jats:styled-content>miR‐levels in bile decreased while its levels in serum increased (<jats:italic>P</jats:italic> ≤ 0.015). Simultaneously, relative <jats:styled-content style="fixed-case">CD</jats:styled-content>miR‐levels in bile significantly increased, while their levels in serum decreased. Related to liver excretory function, a strong positive correlation was observed between <jats:styled-content style="fixed-case">HD</jats:styled-content>miR‐122 levels and bilirubin excretion into bile (<jats:italic>R</jats:italic> = 0.694, <jats:italic>P</jats:italic> < 0.0001), whereas <jats:styled-content style="fixed-case">CD</jats:styled-content>miRs showed an inverse correlation (<jats:italic>P</jats:italic> < 0.05).</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>During impaired excretory function and injury, the liver shows polarized release of extracellular <jats:styled-content style="fixed-case">HD</jats:styled-content>miRs and <jats:styled-content style="fixed-case">CD</jats:styled-content>miRs. This sheds new light on the biology of hepatic mi<jats:styled-content style="fixed-case">RNA</jats:styled-content> release which is relevant for the interpretation of hepatic mi<jats:styled-content style="fixed-case">RNA</jats:styled-content>s as biomarkers.</jats:p></jats:sec>