Loss of SIRT5 promotes bile acid-induced immunosuppressive microenvironment and hepatocarcinogenesis
文献类型：期刊论文
| 作者 | Sun, Renqiang1,2,3,4; Zhang, Zhiyong1,2,3,4; Bao, Ruoxuan1,2,3,4; Guo, Xiaozhen5; Gu, Yuan6; Yang, Wenjing7; Wei, Jinsong9; Chen, Xinyu1,2,3,4; Tong, Lingfeng8; Meng, Jian8 |
| 刊名 | JOURNAL OF HEPATOLOGY
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| 出版日期 | 2022-08 |
| 卷号 | 77期号:2页码:453-466 |
| ISSN号 | 0168-8278 |
| 关键词 | SIRT5 bile acid macrophage polarization immunosuppressive tumor microenvironment liver cancer |
| DOI | 10.1016/j.jhep.2022.02.030 |
| 文献子类 | Article |
| 英文摘要 | Background & Aims: The liver is a metabolically active organ and is also 'tolerogenic', exhibiting sophisticated mechanisms of immune regulation that prevent pathogen attacks and tumorigenesis. How metabolism impacts the tumor microenvironment (TME) in hepatocellular carcinoma (HCC) remains understudied. Methods: We investigated the role of the metabolic regulator SIRT5 in HCC development by conducting metabolomic analysis, gene expression profiling, flow cytometry and immunohistochemistry analyses in oncogene-induced HCC mouse models and human HCC samples. Results: We show that SIRT5 is downregulated in human primary HCC samples and that Sirt5 deficiency in mice synergizes with oncogenes to increase bile acid (BA) production, via hypersuccinylation and increased BA biosynthesis in the peroxisomes of hepatocytes. BAs act as a signaling mediator to stimulate their nuclear receptor and promote M2-like macrophage polarization, creating an immunosuppressive TME that favors tumor-initiating cells (TICs). Accordingly, high serum levels of taurocholic acid correlate with low SIRT5 expression and increased M2-like tumor-associated macrophages (TAMs) in HCC patient samples. Finally, administration of cholestyramine, a BA sequestrant and FDA-approved medication for hyperlipemia, reverses the effect of Sirt5 deficiency in promoting M2-like polarized TAMs and liver tumor growth. Conclusions: This study uncovers a novel function of SIRT5 in orchestrating BA metabolism to prevent tumor immune evasion and suppress HCC development. Our results also suggest a potential strategy of using clinically proven BA sequestrants for the treatment of patients with HCC, especially those with decreased SIRT5 and abnormally high BAs. Lay summary: Hepatocellular caricinoma (HCC) development is closely linked to metabolic dysregulation and an altered tumor microenvironment. Herein, we show that loss of the metabolic regulator Sirt5 promotes hepatocarcinogenesis, which is associated with abnormally elevated bile acids and subsequently an immunosuppressive microenvironment that favors HCC development. Targeting this mechanism could be a promising clinical strategy for HCC. (C) 2022 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved. |
| WOS关键词 | PROTEIN ; LIVER ; CELLS ; MALONYLATION ; MACROPHAGES ; ANTAGONIST ; METABOLISM ; EXPRESSION ; RECEPTOR ; LIGAND |
| WOS研究方向 | Gastroenterology & Hepatology |
| 语种 | 英语 |
| 出版者 | ELSEVIER |
| WOS记录号 | WOS:000852970600003 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309317]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Shi, Yinghong; Wang, Pu; Ye, Dan |
| 作者单位 | 1.Fudan Univ, Huashan Hosp, Shanghai 200032, Peoples R China; 2.Fudan Univ, Shanghai Key Lab Med Epigenet, Int Colab Med Epigenet & Metab, Minist Sci & Technol, Shanghai 200032, Peoples R China; 3.Fudan Univ, Key Lab Metab & Mol Med, Minist Educ, Shanghai 200032, Peoples R China; 4.Fudan Univ, Mol & Cell Biol Lab, Inst Biomed Sci, Shanghai Med Coll, Shanghai 200032, Peoples R China; 5.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 6.Fudan Univ, Inst Pediat, Childrens Hosp, Shanghai, Peoples R China; 7.Fudan Univ, Zhongshan Hosp, Dept Lab Med, Shanghai 200032, Peoples R China; 8.Shanghai Jiao Tong Univ, Dept Biochem & Mol Cell Biol, Sch Med, Shanghai 200025, Peoples R China; 9.Fudan Univ, Sch Life Sci, State Key Lab Genet Engn, Shanghai 200438, Peoples R China; 10.Fudan Univ, Shanghai Med Coll, Dept Pathol, Shanghai 200032, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Sun, Renqiang,Zhang, Zhiyong,Bao, Ruoxuan,et al. Loss of SIRT5 promotes bile acid-induced immunosuppressive microenvironment and hepatocarcinogenesis[J]. JOURNAL OF HEPATOLOGY,2022,77(2):453-466. |
| APA | Sun, Renqiang.,Zhang, Zhiyong.,Bao, Ruoxuan.,Guo, Xiaozhen.,Gu, Yuan.,...&Ye, Dan.(2022).Loss of SIRT5 promotes bile acid-induced immunosuppressive microenvironment and hepatocarcinogenesis.JOURNAL OF HEPATOLOGY,77(2),453-466. |
| MLA | Sun, Renqiang,et al."Loss of SIRT5 promotes bile acid-induced immunosuppressive microenvironment and hepatocarcinogenesis".JOURNAL OF HEPATOLOGY 77.2(2022):453-466. |
入库方式： OAI收割
来源：上海药物研究所
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