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

58 Pages Posted: 12 Oct 2018

See all articles by Shikun Yang

Shikun Yang

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Chao Yang

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Feng Cheng

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Yuanchang Hu

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Yongxiang Xia

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Xuyu Cheng

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Feng Zhang

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Ling Lu

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Research Unit of Liver Transplantation and Transplant Immunology; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation; NHC Key Laboratory of Living Donor Liver Transplantation

Jianhua Rao

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Xue-Hao Wang

Nanjing Medical University - Hepatobiliary Center; Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

More...

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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 STZinduced 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 Statement: 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, 81871259 and 81270583), and Basic research program-Youth Fund Project of Jiangsu Province (BK20140092).

Declaration of Interests: All authors declare no conflict of interests.

Ethics Approval Statement: Informed consent was obtained from all participants, and the study was approved by the local ethics committee of Nanjing Medical University.

Keywords: Hyperglycemia; ATF6; CHOP; β-catenin; Liver Ischemia/Reperfusion Injury

Suggested Citation

Yang, Shikun and Yang, Chao and Cheng, Feng and Hu, Yuanchang and Xia, Yongxiang and Cheng, Xuyu and Zhang, Feng and Lu, Ling and Rao, Jianhua and Wang, Xue-Hao, Hyperglycemia-Triggered ATF6-CHOP Pathway Modulates Inflammatory Responses by β-Catenin Signaling in Liver Ischemia/Reperfusion Injury (September 10, 2018). Available at SSRN: https://ssrn.com/abstract=3264967

Shikun Yang (Contact Author)

Nanjing Medical University - Hepatobiliary Center ( email )

Nanjing
China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Nanjing
China

Chao Yang

Nanjing Medical University - Hepatobiliary Center

Nanjing
China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Nanjing
China

Feng Cheng

Nanjing Medical University - Hepatobiliary Center ( email )

Nanjing
China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation ( email )

Nanjing
China

Yuanchang Hu

Nanjing Medical University - Hepatobiliary Center

Nanjing
China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Nanjing
China

Yongxiang Xia

Nanjing Medical University - Hepatobiliary Center

Nanjing
China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Nanjing
China

Xuyu Cheng

Nanjing Medical University - Hepatobiliary Center

Nanjing
China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation

Nanjing
China

Feng Zhang

Nanjing Medical University - Hepatobiliary Center ( email )

Nanjing
China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation ( email )

Nanjing
China

Ling Lu

Nanjing Medical University - Hepatobiliary Center ( email )

Nanjing
China

Chinese Academy of Medical Sciences - Research Unit of Liver Transplantation and Transplant Immunology ( email )

China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation ( email )

Nanjing
China

NHC Key Laboratory of Living Donor Liver Transplantation ( email )

Nanjing
China

Jianhua Rao

Nanjing Medical University - Hepatobiliary Center ( email )

Nanjing
China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation ( email )

Nanjing
China

Xue-Hao Wang

Nanjing Medical University - Hepatobiliary Center ( email )

Nanjing
China

Chinese Academy of Medical Sciences - Key Laboratory of Liver Transplantation ( email )

Nanjing
China

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