Acute Response of Hepatocyte MRP2 Internalization as an Indicator of Ischemia-reperfusion Injury in Liver Transplantation
Document Type
Article
Publication Date
9-2025
Publisher
Lippincott, Williams & Wilkins
Source Publication
Transplantation
Source ISSN
0041-1337
Original Item ID
DOI: 10.1097/TP.0000000000005418
Abstract
Background.
The introduction of normothermic machine perfusion (NMP) offers new opportunities to evaluate liver graft viability before liver transplantation (LT). Under ischemic stress, multidrug resistance-associated protein 2 (MRP2) translocates from the hepatocyte membrane to the cytoplasm, resulting in loss of function.
Methods.
We measured the cytoplasmic proportion of MRP2 (MRP2 internalization index, MII) by immunofluorescence colocalization analysis using CD13 as a canalicular membrane marker.
Results.
The data showed that MII significantly correlated with ischemia time in both in situ ischemia-reperfusion injury and NMP rat models (R2 = 0.331, P < 0.0001; R2 = 0.632, P < 0.0001, respectively). Perfusate levels of liver injury markers at the end of NMP showed a significant positive correlation with MII for aspartate aminotransferase (R² = 0.444, P = 0.0013) and arginase 1 (R² = 0.637, P < 0.0001). Conversely, bile production exhibited a significant inverse correlation with MII (R² = 0.618, P < 0.0001). The maximum transport rate of MRP2 (Vmax,MRP2), derived from kinetic modeling of sodium fluorescein biliary excretion, showed a significant inverse correlation with ischemia time (R2 = 0.326, P = 0.0086) and MII (R2 = 0.554, P = 0.0002). In human LT, MII values from donor liver biopsies preLT correlated significantly with peak postLT serum aminotransferase levels (R2 = 0.398, P = 0.0007).
Conclusions.
MRP2 is a putative biomarker for the assessment of hepatic ischemia-reperfusion injury. The biliary excretion kinetics of sodium fluorescein reflects MRP2-mediated transport activity, providing a novel diagnostic method for predicting liver graft viability after LT.
Recommended Citation
Monti, Christopher; Hong, Seung-Keun; Lee, Alice; Hong, Johnny C.; Eriksen, Calvin M.; Joshi, Amit; Dash, Ranjan K.; Audi, Said H.; Lee, Whayoung; Kumar, Suresh N.; and Kim, Joohyun, "Acute Response of Hepatocyte MRP2 Internalization as an Indicator of Ischemia-reperfusion Injury in Liver Transplantation" (2025). Biomedical Engineering Faculty Research and Publications. 687.
https://epublications.marquette.edu/bioengin_fac/687
Comments
Transplantation, Vol. 109, No. 9 (September 2025): 1495-1505. DOI.