Macrophage‐Hepatocyte Circuits Mediated by Grancalcin Aggravate the Progression of Metabolic Dysfunction Associated Steatohepatitis
Abstract The dynamic interplay between parenchymal hepatocytes and non‐parenchymal cells (NPCs), such as macrophages, is an important mechanism for liver metabolic homeostasis. Although numerous endeavors have been made to identify the mediators of metabolic dysfunction associated steatohepatitis (M...
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Wiley
2024-11-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202406500 |
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| author | Tian Su Yue He Min Wang Haiyan Zhou Yan Huang Mingsheng Ye Qi Guo Ye Xiao Guangping Cai Mingyang Zhao Jianping Wang Xianghang Luo |
| author_facet | Tian Su Yue He Min Wang Haiyan Zhou Yan Huang Mingsheng Ye Qi Guo Ye Xiao Guangping Cai Mingyang Zhao Jianping Wang Xianghang Luo |
| author_sort | Tian Su |
| collection | DOAJ |
| description | Abstract The dynamic interplay between parenchymal hepatocytes and non‐parenchymal cells (NPCs), such as macrophages, is an important mechanism for liver metabolic homeostasis. Although numerous endeavors have been made to identify the mediators of metabolic dysfunction associated steatohepatitis (MASH), the molecular underpinnings of MASH progression remain poorly understood, and therapies to arrest MASH progression remain elusive. Herein, it is revealed that the expression of grancalcin (GCA) is upregulated in the macrophages of patients and rodents with MASH and correlates with MASH progression. Notably, the administration of recombinant GCA aggravates the development of MASH, whereas, Gca deletion in myeloid cells blunts liver steatosis and inflammation in multiple MASH murine models. Mechanistically, GCA activates macrophages via TLR9‐NF‐κB signaling, and the activated macrophages promote hepatocyte lipid accumulation and apoptosis via secretion of Interleukin‐6(IL‐6), Tumor Necrosis Factor α (TNFα), and Interleukin‐1β(IL‐1β), thereby leading to hepatic steatosis and inflammation. Finally, the therapeutic administration of antibody blocking GCA effectively halts the progression of MASH. Collectively, these findings implicate GCA as a crucial mediator of MASH and clarify a new metabolic signaling axis between the hepatocytes and macrophages, implying that GCA can emerge as a particularly interesting putative therapeutic target for reversing MASH progression. |
| format | Article |
| id | doaj-art-9c8e0869ffba4652bde06b7a04717fa8 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-9c8e0869ffba4652bde06b7a04717fa82025-08-20T01:51:14ZengWileyAdvanced Science2198-38442024-11-011142n/an/a10.1002/advs.202406500Macrophage‐Hepatocyte Circuits Mediated by Grancalcin Aggravate the Progression of Metabolic Dysfunction Associated SteatohepatitisTian Su0Yue He1Min Wang2Haiyan Zhou3Yan Huang4Mingsheng Ye5Qi Guo6Ye Xiao7Guangping Cai8Mingyang Zhao9Jianping Wang10Xianghang Luo11Department of Endocrinology Endocrinology Research Center Xiangya Hospital of Central South University Changsha Hunan 410008 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital of Central South University Changsha Hunan 410008 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital of Central South University Changsha Hunan 410008 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital of Central South University Changsha Hunan 410008 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital of Central South University Changsha Hunan 410008 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital of Central South University Changsha Hunan 410008 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital of Central South University Changsha Hunan 410008 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital of Central South University Changsha Hunan 410008 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital of Central South University Changsha Hunan 410008 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital of Central South University Changsha Hunan 410008 ChinaDepartment of Endocrinology The Second Affiliated Hospital of University of South China Hengyang Hunan 421000 ChinaDepartment of Endocrinology Endocrinology Research Center Xiangya Hospital of Central South University Changsha Hunan 410008 ChinaAbstract The dynamic interplay between parenchymal hepatocytes and non‐parenchymal cells (NPCs), such as macrophages, is an important mechanism for liver metabolic homeostasis. Although numerous endeavors have been made to identify the mediators of metabolic dysfunction associated steatohepatitis (MASH), the molecular underpinnings of MASH progression remain poorly understood, and therapies to arrest MASH progression remain elusive. Herein, it is revealed that the expression of grancalcin (GCA) is upregulated in the macrophages of patients and rodents with MASH and correlates with MASH progression. Notably, the administration of recombinant GCA aggravates the development of MASH, whereas, Gca deletion in myeloid cells blunts liver steatosis and inflammation in multiple MASH murine models. Mechanistically, GCA activates macrophages via TLR9‐NF‐κB signaling, and the activated macrophages promote hepatocyte lipid accumulation and apoptosis via secretion of Interleukin‐6(IL‐6), Tumor Necrosis Factor α (TNFα), and Interleukin‐1β(IL‐1β), thereby leading to hepatic steatosis and inflammation. Finally, the therapeutic administration of antibody blocking GCA effectively halts the progression of MASH. Collectively, these findings implicate GCA as a crucial mediator of MASH and clarify a new metabolic signaling axis between the hepatocytes and macrophages, implying that GCA can emerge as a particularly interesting putative therapeutic target for reversing MASH progression.https://doi.org/10.1002/advs.202406500GCAmacrophage‐hepatocytemetabolic dysfunction associated steatohepatitis |
| spellingShingle | Tian Su Yue He Min Wang Haiyan Zhou Yan Huang Mingsheng Ye Qi Guo Ye Xiao Guangping Cai Mingyang Zhao Jianping Wang Xianghang Luo Macrophage‐Hepatocyte Circuits Mediated by Grancalcin Aggravate the Progression of Metabolic Dysfunction Associated Steatohepatitis Advanced Science GCA macrophage‐hepatocyte metabolic dysfunction associated steatohepatitis |
| title | Macrophage‐Hepatocyte Circuits Mediated by Grancalcin Aggravate the Progression of Metabolic Dysfunction Associated Steatohepatitis |
| title_full | Macrophage‐Hepatocyte Circuits Mediated by Grancalcin Aggravate the Progression of Metabolic Dysfunction Associated Steatohepatitis |
| title_fullStr | Macrophage‐Hepatocyte Circuits Mediated by Grancalcin Aggravate the Progression of Metabolic Dysfunction Associated Steatohepatitis |
| title_full_unstemmed | Macrophage‐Hepatocyte Circuits Mediated by Grancalcin Aggravate the Progression of Metabolic Dysfunction Associated Steatohepatitis |
| title_short | Macrophage‐Hepatocyte Circuits Mediated by Grancalcin Aggravate the Progression of Metabolic Dysfunction Associated Steatohepatitis |
| title_sort | macrophage hepatocyte circuits mediated by grancalcin aggravate the progression of metabolic dysfunction associated steatohepatitis |
| topic | GCA macrophage‐hepatocyte metabolic dysfunction associated steatohepatitis |
| url | https://doi.org/10.1002/advs.202406500 |
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