Hyperglycemia-Triggered ATF6-CHOP Pathway Modulates Inflammatory Responses by β-Catenin Signaling in Liver Ischemia/Reperfusion Injury

Abstract

Background: Hyperglycemia is an adverse risk factor for hepatic ischemia reperfusion injury (IRI); however, the underlying mechanism remains unclear. Herein, we addressed the question of whether and how hyperglycemia triggered endoplasmic reticulum (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. Findings: 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, and decreased TLR4-related pro-inflammatory responses. Furthermore, CHOP gene knockout (CHOP-/-) had markedly reduced hyperglycemia-related liver IRI and inflammatory responses. Importantly, expression of β-catenin, was effectively inhibited, accompanied by activation of ATF6-CHOP signaling in diabetic mice, and was almost restored in liver tissues from PBA-treated or CHOP-/- diabetic mice. Furthermore, β-catenin small interfering RNA (siRNA) targeting KCs abrogated the CHOP-/--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-/- BMDMs. However, the anti-inflammatory functions of CHOP-/- were almost abolished by β-catenin siRNA in BMDMs under HG conditions. The above results were furthermore confirmed using a chimeric mice carrying WT or CHOP-/- BMDMs by BMDMs transplantation. Interpretation: This study revealed hyperglycemia specifically triggers ER stress-ATF6-CHOP signaling, inhibits β-catenin activity, promotes inflammation, and exacerbates liver IRI, which might provide the rationale for novel therapeutic strategies aimed at managing diabetic-related liver surgery. Funding: This study was supported by the Foundation of Jiangsu Collaborative Innovation Center of Biomedical Functional Materials, the Priority Academic Program Development of Jiangsu Higher Education Institutions, the National Natural Science Foundation of China (81400650, 814700901, 81273261, and 81270583), and Basic research program-Youth Fund Project of Jiangsu Province (BK20140092). Declaration of Interest: All authors declare no conflict of interests. Ethical Approval: Informed consent was obtained from all participants, and the study was approved by the local ethics committee of Nanjing Medical University. The animal protocol was approved by the Institutional Animal Care and Use Committee (IACUC) of Nanjing Medical University (Protocol Number IACUC-1702001).