Slc7a11 stimulates glutathione synthesis to preserve fatty acid metabolism in primary hepatocytes
ABSTRACTPrimary hepatocytes are widely used as a tool for studying metabolic function and regulation in the liver. However, the metabolic properties of primary hepatocytes are gradually lost after isolation. Here, we illustrated that fatty acid metabolism is the major compromised metabolic process i...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2023-12-01
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| Series: | Redox Report |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/13510002.2023.2260646 |
| _version_ | 1797398790181748736 |
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| author | Yifan Liu Kaimin Wu Yinkun Fu Wenyan Li Xu-Yun Zhao |
| author_facet | Yifan Liu Kaimin Wu Yinkun Fu Wenyan Li Xu-Yun Zhao |
| author_sort | Yifan Liu |
| collection | DOAJ |
| description | ABSTRACTPrimary hepatocytes are widely used as a tool for studying metabolic function and regulation in the liver. However, the metabolic properties of primary hepatocytes are gradually lost after isolation. Here, we illustrated that fatty acid metabolism is the major compromised metabolic process in isolated primary hepatocytes, along with drastically decreased GSH and ROS content, while lipid peroxidation is increased. Gain- and loss-of-function studies revealed that Slc7a11 expression is critical in maintaining fatty acid metabolism and facilitating hormone-induced fatty acid metabolic events, which is synergistic with dexamethasone treatment. Intriguingly, Slc7a11 expression and dexamethasone treatment cooperatively upregulated AKT and AMPK signaling and mitochondrial complex expression in primary hepatocytes. Furthermore, direct treatment with reduced GSH or inhibition of ferroptosis is sufficient to drive protective effects on fatty acid metabolism in primary hepatocytes. Our results demonstrate that Slc7a11 expression in isolated primary hepatocytes induces GSH production, which protects against ferroptosis, to increase fatty acid metabolic gene expression, AKT and AMPK signaling and mitochondrial function in synergy with dexamethasone treatment, thereby efficiently preserving primary hepatocyte metabolic signatures, thus providing a promising approach to better reserve primary hepatocyte metabolic activities after isolation to potentially improve the understanding of liver biological functions from studies using primary hepatocytes. |
| first_indexed | 2024-03-09T01:30:36Z |
| format | Article |
| id | doaj.art-b344c617d49142f49f7f912b7befd78c |
| institution | Directory Open Access Journal |
| issn | 1351-0002 1743-2928 |
| language | English |
| last_indexed | 2024-03-09T01:30:36Z |
| publishDate | 2023-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Redox Report |
| spelling | doaj.art-b344c617d49142f49f7f912b7befd78c2023-12-09T20:05:02ZengTaylor & Francis GroupRedox Report1351-00021743-29282023-12-0128110.1080/13510002.2023.2260646Slc7a11 stimulates glutathione synthesis to preserve fatty acid metabolism in primary hepatocytesYifan Liu0Kaimin Wu1Yinkun Fu2Wenyan Li3Xu-Yun Zhao4Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of ChinaDepartment of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of ChinaDepartment of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of ChinaDepartment of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of ChinaDepartment of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Key Laboratory of Cell Differentiation and Apoptosis of National Ministry of Education, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of ChinaABSTRACTPrimary hepatocytes are widely used as a tool for studying metabolic function and regulation in the liver. However, the metabolic properties of primary hepatocytes are gradually lost after isolation. Here, we illustrated that fatty acid metabolism is the major compromised metabolic process in isolated primary hepatocytes, along with drastically decreased GSH and ROS content, while lipid peroxidation is increased. Gain- and loss-of-function studies revealed that Slc7a11 expression is critical in maintaining fatty acid metabolism and facilitating hormone-induced fatty acid metabolic events, which is synergistic with dexamethasone treatment. Intriguingly, Slc7a11 expression and dexamethasone treatment cooperatively upregulated AKT and AMPK signaling and mitochondrial complex expression in primary hepatocytes. Furthermore, direct treatment with reduced GSH or inhibition of ferroptosis is sufficient to drive protective effects on fatty acid metabolism in primary hepatocytes. Our results demonstrate that Slc7a11 expression in isolated primary hepatocytes induces GSH production, which protects against ferroptosis, to increase fatty acid metabolic gene expression, AKT and AMPK signaling and mitochondrial function in synergy with dexamethasone treatment, thereby efficiently preserving primary hepatocyte metabolic signatures, thus providing a promising approach to better reserve primary hepatocyte metabolic activities after isolation to potentially improve the understanding of liver biological functions from studies using primary hepatocytes.https://www.tandfonline.com/doi/10.1080/13510002.2023.2260646Slc7a11GSHferroptosisprimary hepatocytesfatty acid metabolismdexamethasone |
| spellingShingle | Yifan Liu Kaimin Wu Yinkun Fu Wenyan Li Xu-Yun Zhao Slc7a11 stimulates glutathione synthesis to preserve fatty acid metabolism in primary hepatocytes Redox Report Slc7a11 GSH ferroptosis primary hepatocytes fatty acid metabolism dexamethasone |
| title | Slc7a11 stimulates glutathione synthesis to preserve fatty acid metabolism in primary hepatocytes |
| title_full | Slc7a11 stimulates glutathione synthesis to preserve fatty acid metabolism in primary hepatocytes |
| title_fullStr | Slc7a11 stimulates glutathione synthesis to preserve fatty acid metabolism in primary hepatocytes |
| title_full_unstemmed | Slc7a11 stimulates glutathione synthesis to preserve fatty acid metabolism in primary hepatocytes |
| title_short | Slc7a11 stimulates glutathione synthesis to preserve fatty acid metabolism in primary hepatocytes |
| title_sort | slc7a11 stimulates glutathione synthesis to preserve fatty acid metabolism in primary hepatocytes |
| topic | Slc7a11 GSH ferroptosis primary hepatocytes fatty acid metabolism dexamethasone |
| url | https://www.tandfonline.com/doi/10.1080/13510002.2023.2260646 |
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