Hyperglycemia-Triggered ATF6-CHOP Pathway Exacerbates Liver Ischemia/Reperfusion Injury: Immunomodulation by Regulating β-Catenin Signaling
1Department of Liver Surgery/Liver Transplantation Center, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
2Division of Liver and Pancreas Transplantation, Department of Surgery, David Geffen School of Medicine at University of California Los Angeles, Los Angeles.
Meeting: 2018 American Transplant Congress
Abstract number: A80
Keywords: Hypercalcemia, Inflammation, Ischemia
Session Information
Session Name: Poster Session A: Innate Immunity; Chemokines, Cytokines, Complement
Session Type: Poster Session
Date: Saturday, June 2, 2018
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Hall 4EF
Background & Aims: Hyperglycemia is a risk factor for hepatic ischemia/reperfusion injury (IRI) during liver transplantation or hepatectomy; however, the underlying mechanism remains unclear. Our previous studies implicated endoplasmic reticulum (ER) stress in the pathophysiology of hepatic IRI. In this study, we addressed the question of whether and how hyperglycemia triggered ER stress and affected liver IRI.
Methods: Diabetic patients and streptozotocin (STZ)-induced diabetic mice were involved in vivo. Bone marrow-derived macrophages (BMDMs) were used in vitro.
Results: The ER stress-ATF6-CHOP pathway was specifically activated in liver tissues and Kuppfer cells (KCs) from diabetic patients and STZ-induced diabetic mice. The ER stress inhibitor, 4-phenylbutyrate (PBA), attenuated hyperglycemia-related liver IRI based on biochemistry and histology, and decreased TLR4-related pro-inflammatory responses based on inflammatory cytokines and macrophage/neutrophil trafficking. Furthermore, CHOP-knockout (CHOP-KO) had markedly reduced hyperglycemia-related liver IRI and inflammatory responses. Importantly, expression of β-catenin, as a negative regulator of inflammatory responses, was effectively inhibited, accompanied by activation of ATF6-CHOP pathway in diabetic mice, and was almost restored in liver tissues from PBA-treated or CHOP-KO diabetic mice. In addition, β-catenin small interfering RNA (siRNA) targeting KCs abrogated the CHOP-KO-related protective effects against hyperglycemia-related liver IRI. High glucose (HG) specifically activated ATF6-CHOP signaling, inhibited β-catenin expression, and enhanced TLR4-related inflammatory responses in BMDMs in vitro; these effects were partly reversed in PBA- or CHOP siRNA-treated/CHOP-KO BMDMs. However, the anti-inflammatory functions of CHOP-KO were almost abolished by β-catenin siRNA in BMDMs under HG conditions.
Conclusions: This study revealed that hyperglycemia specifically triggers ER stress-ATF6-CHOP signaling, inhibits β-catenin activity, promotes inflammator.
CITATION INFORMATION: Rao J., Yang C., Hu Y., Yang S., Xia Y., Zhang F., Wang X., Zhai Y., Lu L. Hyperglycemia-Triggered ATF6-CHOP Pathway Exacerbates Liver Ischemia/Reperfusion Injury: Immunomodulation by Regulating β-Catenin Signaling Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:
Rao J, Yang C, Hu Y, Yang S, Xia Y, Zhang F, Wang X, Zhai Y, Lu L. Hyperglycemia-Triggered ATF6-CHOP Pathway Exacerbates Liver Ischemia/Reperfusion Injury: Immunomodulation by Regulating β-Catenin Signaling [abstract]. https://atcmeetingabstracts.com/abstract/hyperglycemia-triggered-atf6-chop-pathway-exacerbates-liver-ischemia-reperfusion-injury-immunomodulation-by-regulating-catenin-signaling/. Accessed May 9, 2025.« Back to 2018 American Transplant Congress