OPN‐Mediated Crosstalk Between Hepatocyte E4BP4 and Hepatic Stellate Cells Promotes MASH‐Associated Liver Fibrosis
Abstract Stressed hepatocytes promote liver fibrosis through communications with hepatic stellate cells (HSCs) during chronic liver injury. However, intra‐hepatocyte players that facilitate such cell‐to‐cell communications are largely undefined. It is previously reported that hepatocyte E4BP4 is pot...
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Wiley
2024-12-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202405678 |
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| author | Sujuan Wang Jiashi Gao Meichan Yang Gary Zhang Lei Yin Xin Tong |
| author_facet | Sujuan Wang Jiashi Gao Meichan Yang Gary Zhang Lei Yin Xin Tong |
| author_sort | Sujuan Wang |
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| description | Abstract Stressed hepatocytes promote liver fibrosis through communications with hepatic stellate cells (HSCs) during chronic liver injury. However, intra‐hepatocyte players that facilitate such cell‐to‐cell communications are largely undefined. It is previously reported that hepatocyte E4BP4 is potently induced by ER stress and hepatocyte deletion of E4bp4 protects mice from high‐fat diet‐induced liver steatosis. Here how hepatocyte E4bp4 deficiency impacts the activation of HSCs and the progression toward MASH‐associated liver fibrosis is examined. Hepatic E4BP4 is increased in mouse models of NASH diet‐ or CCl4‐induced liver fibrosis. Hepatocyte‐specific E4bp4 deletion protected mice against NASH diet‐induced liver injury, inflammation, and fibrosis without impacting liver steatosis. Hepatocyte E4BP4 overexpression activated HSCs in a medium transfer experiment, whereas hepatocyte E4bp4 depletion did the opposite. RNA‐Seq analysis identified the pro‐fibrogenic factor OPN as a critical target of E4BP4 within hepatocytes. Antibody neutralization or shRNA depletion of Opn abrogated hepatocyte E4BP4‐induced HSC activation. E4BP4 interacted with and stabilized YAP, an established activator of OPN. Loss of hepatic Yap blocked OPN induction in the liver of Ad‐E4bp4‐injected mice. Hepatocyte E4BP4 induces OPN via YAP to activate HSCs and promote liver fibrosis during diet‐induced MASH. Inhibition of the hepatocyte E4BP4‐OPN pathway could offer a novel therapeutic avenue for treating MASLD/MASH. |
| format | Article |
| id | doaj-art-56570a7fb4dc4d5d83f3e1109b841b11 |
| institution | OA Journals |
| issn | 2198-3844 |
| language | English |
| publishDate | 2024-12-01 |
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| spelling | doaj-art-56570a7fb4dc4d5d83f3e1109b841b112025-08-20T01:58:42ZengWileyAdvanced Science2198-38442024-12-011147n/an/a10.1002/advs.202405678OPN‐Mediated Crosstalk Between Hepatocyte E4BP4 and Hepatic Stellate Cells Promotes MASH‐Associated Liver FibrosisSujuan Wang0Jiashi Gao1Meichan Yang2Gary Zhang3Lei Yin4Xin Tong5Department of Infectious Diseases The Second Xiangya Hospital Central South University 139 Renmin Middle Rd, Furong District Changsha Hunan 410011 P. R. ChinaDepartment of Infectious Diseases The Second Xiangya Hospital Central South University 139 Renmin Middle Rd, Furong District Changsha Hunan 410011 P. R. ChinaDepartment of Radiology Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences) Southern Medical University 106 Zhongshan 2nd Road Guangzhou Guangdong 51008 P. R. ChinaDepartment of Molecular & Integrative Physiology University of Michigan Medical School NCRC 20–3843, 2800 Plymouth Road Ann Arbor MI 48105 USADepartment of Molecular & Integrative Physiology University of Michigan Medical School NCRC 20–3843, 2800 Plymouth Road Ann Arbor MI 48105 USADepartment of Molecular & Integrative Physiology University of Michigan Medical School NCRC 20–3843, 2800 Plymouth Road Ann Arbor MI 48105 USAAbstract Stressed hepatocytes promote liver fibrosis through communications with hepatic stellate cells (HSCs) during chronic liver injury. However, intra‐hepatocyte players that facilitate such cell‐to‐cell communications are largely undefined. It is previously reported that hepatocyte E4BP4 is potently induced by ER stress and hepatocyte deletion of E4bp4 protects mice from high‐fat diet‐induced liver steatosis. Here how hepatocyte E4bp4 deficiency impacts the activation of HSCs and the progression toward MASH‐associated liver fibrosis is examined. Hepatic E4BP4 is increased in mouse models of NASH diet‐ or CCl4‐induced liver fibrosis. Hepatocyte‐specific E4bp4 deletion protected mice against NASH diet‐induced liver injury, inflammation, and fibrosis without impacting liver steatosis. Hepatocyte E4BP4 overexpression activated HSCs in a medium transfer experiment, whereas hepatocyte E4bp4 depletion did the opposite. RNA‐Seq analysis identified the pro‐fibrogenic factor OPN as a critical target of E4BP4 within hepatocytes. Antibody neutralization or shRNA depletion of Opn abrogated hepatocyte E4BP4‐induced HSC activation. E4BP4 interacted with and stabilized YAP, an established activator of OPN. Loss of hepatic Yap blocked OPN induction in the liver of Ad‐E4bp4‐injected mice. Hepatocyte E4BP4 induces OPN via YAP to activate HSCs and promote liver fibrosis during diet‐induced MASH. Inhibition of the hepatocyte E4BP4‐OPN pathway could offer a novel therapeutic avenue for treating MASLD/MASH.https://doi.org/10.1002/advs.202405678E4BP4hepatic stellate cellsliver fibrosisMASHOPN |
| spellingShingle | Sujuan Wang Jiashi Gao Meichan Yang Gary Zhang Lei Yin Xin Tong OPN‐Mediated Crosstalk Between Hepatocyte E4BP4 and Hepatic Stellate Cells Promotes MASH‐Associated Liver Fibrosis Advanced Science E4BP4 hepatic stellate cells liver fibrosis MASH OPN |
| title | OPN‐Mediated Crosstalk Between Hepatocyte E4BP4 and Hepatic Stellate Cells Promotes MASH‐Associated Liver Fibrosis |
| title_full | OPN‐Mediated Crosstalk Between Hepatocyte E4BP4 and Hepatic Stellate Cells Promotes MASH‐Associated Liver Fibrosis |
| title_fullStr | OPN‐Mediated Crosstalk Between Hepatocyte E4BP4 and Hepatic Stellate Cells Promotes MASH‐Associated Liver Fibrosis |
| title_full_unstemmed | OPN‐Mediated Crosstalk Between Hepatocyte E4BP4 and Hepatic Stellate Cells Promotes MASH‐Associated Liver Fibrosis |
| title_short | OPN‐Mediated Crosstalk Between Hepatocyte E4BP4 and Hepatic Stellate Cells Promotes MASH‐Associated Liver Fibrosis |
| title_sort | opn mediated crosstalk between hepatocyte e4bp4 and hepatic stellate cells promotes mash associated liver fibrosis |
| topic | E4BP4 hepatic stellate cells liver fibrosis MASH OPN |
| url | https://doi.org/10.1002/advs.202405678 |
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