Interleukin-33 / Cyclin D1 imbalance in severe liver steatosis predicts susceptibility to ischemia reperfusion injury

PLoS One. 2019 Apr 29;14(4):e0216242. doi: 10.1371/journal.pone.0216242. eCollection 2019.


Transplanting donor livers with severe macrosteatosis is associated with increased risk of primary non-function (PNF). The purpose of this study was to identify steatosis-driven biomarkers as a predisposition to severe liver damage and delayed recovery following ischemia reperfusion injury. Wistar rats were fed a methionine- and choline-deficient (MCD) diet for up to three weeks to achieve severe macrosteatosis (>90%). Animals underwent diet withdrawal to control chow and/or underwent ischemia reperfusion and partial hepatectomy injury (I/R-PHx) and reperfused out to 7 days on control chow. For animals with severe macrosteatosis, hepatic levels of IL-33 decreased while Cyclin D1 levels increased in the absence of NF-κB p65 phosphorylation. Animals with high levels of nuclear Cyclin D1 prior to I/R-PHx either did not survive or had persistent macrosteatosis after 7 days on control chow. Survival 7 days after I/R-PHx fell to 57% which correlated with increased Cyclin D1 and decreased liver IL-33 levels. In the absence of I/R-PHx, withdrawing the MCD diet normalized IL-33, Cyclin D1 levels, and I/R-PHx survival back to baseline. In transplanted grafts with macrosteatosis, higher Cyclin D1 mRNA expression was observed. Shifts in Cyclin D1 and IL-33 expression may identify severely macrosteatotic livers with increased failure risk if subjected to I/R injury. Clinical validation of the panel in donor grafts with macrosteatosis revealed increased Cyclin D1 expression corresponding to delayed graft function. This pre-surgical biomarker panel may identify the subset of livers with increased susceptibility to PNF.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Biomarkers / metabolism
  • Cyclin D1 / metabolism*
  • Diet
  • Disease Models, Animal
  • Disease Susceptibility
  • Fatty Liver / metabolism*
  • Humans
  • Interleukin-33 / metabolism*
  • Liver / metabolism
  • Liver / pathology
  • Liver Failure / metabolism
  • Liver Transplantation
  • Male
  • Middle Aged
  • Rats, Wistar
  • Reperfusion Injury / metabolism*
  • Survival Analysis


  • Biomarkers
  • Interleukin-33
  • Cyclin D1

Grants and funding

This research was funded by Ochsner Health System, OTMRI to PT and AC. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.