The effects of restraint stress on ceramide metabolism disorders in the rat liver: the role of CerS6 in hepatocyte injury
Abstract Background Stress is implicated in various pathological conditions leading to liver injury. Existing evidence suggests that excessive stress can induce mitochondrial damage in hepatocytes, yet the underlying mechanism remains unclear. Ceramide synthase 6 (CerS6)-derived C16:0 ceramide is re...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
BMC
2024-03-01
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| Series: | Lipids in Health and Disease |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12944-024-02019-x |
| _version_ | 1797273406418190336 |
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| author | Yichang Liu Zhaoling Sun Qiuli Sun Li Wang Chuan Wang Yingmin Li Chunling Ma Weibo Shi Guozhong Zhang Yiming Dong Xiaojing Zhang Bin Cong |
| author_facet | Yichang Liu Zhaoling Sun Qiuli Sun Li Wang Chuan Wang Yingmin Li Chunling Ma Weibo Shi Guozhong Zhang Yiming Dong Xiaojing Zhang Bin Cong |
| author_sort | Yichang Liu |
| collection | DOAJ |
| description | Abstract Background Stress is implicated in various pathological conditions leading to liver injury. Existing evidence suggests that excessive stress can induce mitochondrial damage in hepatocytes, yet the underlying mechanism remains unclear. Ceramide synthase 6 (CerS6)-derived C16:0 ceramide is recognised as a lipotoxic substance capable of causing mitochondrial damage. However, the role of CerS6 in stress has received insufficient attention. This study aimed to explore the involvement of CerS6 in stress-induced hepatic damage and its associated mechanisms. Methods The rat restraint stress model and a corticosterone (CORT)-induced hepatocyte stress model were employed for in vivo and in vitro experimental analyses, respectively. Changes in mitochondrial damage and ceramide metabolism in hepatocytes induced by stress were evaluated. The impact of CORT on mitochondrial damage and ceramide metabolism in hepatocytes was assessed following CerS6 knockdown. Mitochondria were isolated using a commercial kit, and ceramides in liver tissue and hepatocytes were detected by LC–MS/MS. Results In comparison to the control group, rats subjected to one week of restraint exhibited elevated serum CORT levels. The liver displayed significant signs of mitochondrial damage, accompanied by increased CerS6 and mitochondrial C16:0 ceramide, along with activation of the AMPK/p38 MAPK pathway. In vitro studies demonstrated that CORT treatment of hepatocytes resulted in mitochondrial damage, concomitant with elevated CerS6 and mitochondrial C16:0 ceramide. Furthermore, CORT induced sequential phosphorylation of AMPK and p38 MAPK proteins, and inhibition of the p38 MAPK pathway using SB203580 mitigated the CORT-induced elevation in CerS6 protein. Knocking down CerS6 in hepatocytes inhibited both the increase in C16:0 ceramide and the release of mitochondrial cytochrome c induced by CORT. Conclusions CerS6-associated C16:0 ceramide plays a mediating role in stress-induced mitochondrial damage in hepatocytes. The molecular mechanism is linked to CORT-induced activation of the AMPK/p38 MAPK pathway, leading to upregulated CerS6. |
| first_indexed | 2024-03-07T14:43:54Z |
| format | Article |
| id | doaj.art-a4c8be35be334ab1a5b9811a5a2f737d |
| institution | Directory Open Access Journal |
| issn | 1476-511X |
| language | English |
| last_indexed | 2024-03-07T14:43:54Z |
| publishDate | 2024-03-01 |
| publisher | BMC |
| record_format | Article |
| series | Lipids in Health and Disease |
| spelling | doaj.art-a4c8be35be334ab1a5b9811a5a2f737d2024-03-05T20:07:59ZengBMCLipids in Health and Disease1476-511X2024-03-0123111610.1186/s12944-024-02019-xThe effects of restraint stress on ceramide metabolism disorders in the rat liver: the role of CerS6 in hepatocyte injuryYichang Liu0Zhaoling Sun1Qiuli Sun2Li Wang3Chuan Wang4Yingmin Li5Chunling Ma6Weibo Shi7Guozhong Zhang8Yiming Dong9Xiaojing Zhang10Bin Cong11Department of Forensic Medicine, Hebei Medical UniversityDepartment of Forensic Medicine, Hebei Medical UniversityDepartment of Forensic Medicine, Hebei Medical UniversityDepartment of Forensic Medicine, Hebei Medical UniversityDepartment of Forensic Medicine, Hebei Medical UniversityDepartment of Forensic Medicine, Hebei Medical UniversityDepartment of Forensic Medicine, Hebei Medical UniversityDepartment of Forensic Medicine, Hebei Medical UniversityDepartment of Forensic Medicine, Hebei Medical UniversityDepartment of Forensic Medicine, Hebei Medical UniversityDepartment of Forensic Medicine, Hebei Medical UniversityDepartment of Forensic Medicine, Hebei Medical UniversityAbstract Background Stress is implicated in various pathological conditions leading to liver injury. Existing evidence suggests that excessive stress can induce mitochondrial damage in hepatocytes, yet the underlying mechanism remains unclear. Ceramide synthase 6 (CerS6)-derived C16:0 ceramide is recognised as a lipotoxic substance capable of causing mitochondrial damage. However, the role of CerS6 in stress has received insufficient attention. This study aimed to explore the involvement of CerS6 in stress-induced hepatic damage and its associated mechanisms. Methods The rat restraint stress model and a corticosterone (CORT)-induced hepatocyte stress model were employed for in vivo and in vitro experimental analyses, respectively. Changes in mitochondrial damage and ceramide metabolism in hepatocytes induced by stress were evaluated. The impact of CORT on mitochondrial damage and ceramide metabolism in hepatocytes was assessed following CerS6 knockdown. Mitochondria were isolated using a commercial kit, and ceramides in liver tissue and hepatocytes were detected by LC–MS/MS. Results In comparison to the control group, rats subjected to one week of restraint exhibited elevated serum CORT levels. The liver displayed significant signs of mitochondrial damage, accompanied by increased CerS6 and mitochondrial C16:0 ceramide, along with activation of the AMPK/p38 MAPK pathway. In vitro studies demonstrated that CORT treatment of hepatocytes resulted in mitochondrial damage, concomitant with elevated CerS6 and mitochondrial C16:0 ceramide. Furthermore, CORT induced sequential phosphorylation of AMPK and p38 MAPK proteins, and inhibition of the p38 MAPK pathway using SB203580 mitigated the CORT-induced elevation in CerS6 protein. Knocking down CerS6 in hepatocytes inhibited both the increase in C16:0 ceramide and the release of mitochondrial cytochrome c induced by CORT. Conclusions CerS6-associated C16:0 ceramide plays a mediating role in stress-induced mitochondrial damage in hepatocytes. The molecular mechanism is linked to CORT-induced activation of the AMPK/p38 MAPK pathway, leading to upregulated CerS6.https://doi.org/10.1186/s12944-024-02019-xLiverStressCeramide synthase 6CeramideMitochondriaCytochrome c |
| spellingShingle | Yichang Liu Zhaoling Sun Qiuli Sun Li Wang Chuan Wang Yingmin Li Chunling Ma Weibo Shi Guozhong Zhang Yiming Dong Xiaojing Zhang Bin Cong The effects of restraint stress on ceramide metabolism disorders in the rat liver: the role of CerS6 in hepatocyte injury Lipids in Health and Disease Liver Stress Ceramide synthase 6 Ceramide Mitochondria Cytochrome c |
| title | The effects of restraint stress on ceramide metabolism disorders in the rat liver: the role of CerS6 in hepatocyte injury |
| title_full | The effects of restraint stress on ceramide metabolism disorders in the rat liver: the role of CerS6 in hepatocyte injury |
| title_fullStr | The effects of restraint stress on ceramide metabolism disorders in the rat liver: the role of CerS6 in hepatocyte injury |
| title_full_unstemmed | The effects of restraint stress on ceramide metabolism disorders in the rat liver: the role of CerS6 in hepatocyte injury |
| title_short | The effects of restraint stress on ceramide metabolism disorders in the rat liver: the role of CerS6 in hepatocyte injury |
| title_sort | effects of restraint stress on ceramide metabolism disorders in the rat liver the role of cers6 in hepatocyte injury |
| topic | Liver Stress Ceramide synthase 6 Ceramide Mitochondria Cytochrome c |
| url | https://doi.org/10.1186/s12944-024-02019-x |
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