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Succinic Acid Ameliorates Concanavalin A-Induced Hepatitis by Altering the Inflammatory Microenvironment and Expression of BCL-2 Family Proteins

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Abstract

Autoimmune hepatitis (AIH) is a severe immune-mediated inflammatory liver disease that currently lacks feasible drug treatment methods. Our study aimed to evaluate the protective effect of succinic acid against AIH and provide a reliable method for the clinical treatment of AIH. We performed an in vivo study of the effects of succinic acid on concanavalin A (ConA)-induced liver injury in mice. We examined liver transaminase levels, performed hematoxylin and eosin (HE) staining, and observed apoptotic phenotypes in mice. We performed flow cytometry to detect changes in the number of neutrophils and monocytes, and used liposomes to eliminate the liver Kupffer cells and evaluate their role. We performed bioinformatics analysis, reverse transcription-quantitative polymerase chain reaction (RT-qPCR), and western blotting to detect mitochondrial apoptosis-induced changes in proteins from the B-cell lymphoma 2(Bcl-2) family. Succinic acid ameliorated ConA-induced AIH in a concentration-dependent manner, as reflected in the survival curve. HE and TUNEL staining and terminal deoxynucleotidyl transferase dUTP nick end labeling revealed decreased alanine transaminase and aspartate aminotransferase levels, and reduced liver inflammation and apoptosis. RT-qPCR and enzyme-linked immunosorbent assay revealed that succinic acid significantly reduced liver pro-inflammatory cytokine levels. Flow cytometry revealed significantly decreased levels of liver neutrophils. Moreover, the protective effect of succinic acid disappeared after the Kupffer cells were eliminated, confirming their important role in the effect. Bioinformatics analysis, RT-qPCR, and western blotting showed that succinic acid-induced changes in proteins from the Bcl-2 family involved mitochondrial apoptosis, indicating the molecular mechanism underlying the protective effect of succinic acid. Succinic acid ameliorated ConA-induced liver injury by regulating immune balance, inhibiting pro-inflammatory factors, and promoting anti-apoptotic proteins in the liver. This study provides novel insights into the biological functions and therapeutic potential of succinic acid in the treatment of autoimmune liver injury.

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Funding

This project was supported by Fujian Provincial Natural Science Foundation (Grant No: 2021J05278), The Health Science Foundation of Fujian Youth Program (Grant No: 2021QNB017), National Natural Science Foundation of China (Grant No: 82303109), Natural Science Foundation of Fujian Province, China (Grant No: 2022J05299), and the Cross-Strait Postdoctoral Exchange Funding Program of Fujian Province, China (Grant No: 2021B002).

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Author notes

  1. Ying Cai, Zhiyuan Chen and Ermei Chen have contributed equally to this work and share the first authorship.

Authors and Affiliations

  1. Department of Gastroenterology, Zhongshan Hospital of Xiamen University, School of Medicine, Xiamen University, Xiamen, Fujian, People’s Republic of China

    Ying Cai, Zhiyuan Chen, Ermei Chen, Dongdong Zhang, Tao Wei, Mingyang Sun & Yifan Lian

  2. Institute for Microbial Ecology, School of Medicine, Xiamen University, Xiamen, Fujian, People’s Republic of China

    Ying Cai, Zhiyuan Chen, Ermei Chen, Tao Wei, Mingyang Sun & Yifan Lian

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Contributions

YC, ZC, and EC contributed to the design of the study protocol. YC and DZ performed the statistical analysis. YC, TW, and MS drew the picture. YC, ZC, and EC contributed to the writing of the study protocol and made the final corrections to this manuscript. YL finally corrected the manuscript. All authors read and approved the final manuscript. YC, ZC, and EC have contributed equally to this work and share first authorship.

Corresponding author

Correspondence to Yifan Lian.

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Ethics Approval and Consent to Participate

The animal study protocol was approved by the Ethics Committee of Xiamen University (approval no. XMULAC2023052) and conducted in accordance with the Guide for the Care and Use of Laboratory Animals (https://www.ncbi.nlm.nih.gov/books/NBK54050/).

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The authors declare no competing interests.

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Key Messages

• Succinic acid ameliorated ConA-induced hepatitis

• Succinic acid inhibits the infiltration of liver neutrophils and the production of inflammatory factors

• Macrophages contribute to the protective role of succinic acid against ConA-induced liver injury.

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Cai, Y., Chen, Z., Chen, E. et al. Succinic Acid Ameliorates Concanavalin A-Induced Hepatitis by Altering the Inflammatory Microenvironment and Expression of BCL-2 Family Proteins. Inflammation (2024). https://doi.org/10.1007/s10753-024-02021-6

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