Exacerbated ischemia-reperfusion injury in fatty livers is mediated by lipid peroxidation stress and ferroptosis

  • Surgery. 2024 Mar 19:S0039-6060(24)00063-1. doi: 10.1016/j.surg.2024.02.001.
Zachary P Rokop  1 ,  Wenjun Zhang  1 ,  Nandini Ghosh  2 ,  Nirupam Biswas  2 ,  Amitava Das  2 ,  Jingmei Lin  3 ,  Chandan K Sen  4 ,  Chandrashekhar Kubal  5
Affiliations
  • 1. Department of Surgery, Indiana University School of Medicine, Indianapolis, IN.
  • 2. Department of Surgery, Indiana University School of Medicine, Indianapolis, IN; IU Health Comprehensive Wound Center, Indiana University School of Medicine, Indianapolis, IN; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN.
  • 3. Department of Pathology and Laboratory Medicine, Indiana University School of Medicine, Indianapolis, IN.
  • 4. Department of Surgery, Indiana University School of Medicine, Indianapolis, IN; IU Health Comprehensive Wound Center, Indiana University School of Medicine, Indianapolis, IN; Indiana Center for Regenerative Medicine and Engineering, Indiana University School of Medicine, Indianapolis, IN. Electronic address: https://twitter.com/ChandanKSen.
  • 5. Department of Surgery, Indiana University School of Medicine, Indianapolis, IN. Electronic address: [email protected].
PMID: 38508920 DOI: 10.1016/j.surg.2024.02.001
Abstract

Background: Ischemia-Reperfusion Injury is a common problem in liver surgery and transplantation. Although Ischemia-Reperfusion Injury is known to be more pronounced in fatty Livers, the underlying mechanisms for this difference remain poorly understood. We hypothesized that Ferroptosis plays a significant role in fatty liver Ischemia-Reperfusion Injury due to increased lipid peroxidation in the presence of stored iron in the fatty liver. To test this hypothesis, the Ferroptosis pathway was evaluated in a murine fatty liver Ischemia-Reperfusion Injury model.

Methods: C57BL6 mice were fed with a normal diet or a high fat, high sucrose diet for 12 weeks. At 22 weeks of age, liver Ischemia-Reperfusion Injury was induced through partial (70%) hepatic pedicle clamping for 60 minutes, followed by 24 hours of reperfusion before tissue harvest. Acyl-coenzyme A synthetase long-chain family member 4 and 4-hydroxynonenal were quantified in the liver tissues. In separate experiments, liproxstatin-1 or vehicle control was administered for 7 consecutive days before liver Ischemia-Reperfusion Injury.

Results: Exacerbated Ischemia-Reperfusion Injury was observed in the Livers of high fat, high sucrose diet fed mice. High fat, high sucrose diet + Ischemia-Reperfusion Injury (HDF+IRI) Livers had a significantly greater abundance of acyl-coenzyme A synthetase long-chain family member 4 and 4-hydroxynonenal compared with normal diet + Ischemia-Reperfusion Injury (ND+IRI) Livers or sham fatty Livers, which indicated an increase of Ferroptosis. HFD fed Animals receiving liproxstatin-1 injections had a significant reduction in serum aspartate transaminase and alanine transaminase after Ischemia-Reperfusion Injury, consistent with attenuation of Ischemia-Reperfusion Injury in the liver.

Conclusion: Ferroptosis plays a significant role in Ischemia-Reperfusion Injury in fatty Livers. Inhibiting ferroptotic pathways in the liver may serve as a novel therapeutic strategy to protect the fatty liver in the setting of Ischemia-Reperfusion Injury.

Products