2. Academic Validation
  3. Exacerbated ischemia-reperfusion injury in fatty livers is mediated by lipid peroxidation stress and ferroptosis

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

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.

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