Acute Endoplasmic Reticulum Stress Suppresses Hepatic Gluconeogenesis by Stimulating MAPK Phosphatase 3 Degradation
Drug-induced liver injury (DILI) is a widespread and harmful disease, and is closely linked to acute endoplasmic reticulum (ER) stress. Previous reports have shown that acute ER stress can suppress hepatic gluconeogenesis and even leads to hypoglycemia. However, the mechanism is still unclear. MAPK...
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MDPI AG
2023-10-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/21/15561 |
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| author | Xiaohua Huang Heng Zhu Wei Lu Lei Cao Zhengfeng Fang Lianqiang Che Yan Lin Shengyu Xu Yong Zhuo Lun Hua Xuemei Jiang Mengmeng Sun De Wu Bin Feng |
| author_facet | Xiaohua Huang Heng Zhu Wei Lu Lei Cao Zhengfeng Fang Lianqiang Che Yan Lin Shengyu Xu Yong Zhuo Lun Hua Xuemei Jiang Mengmeng Sun De Wu Bin Feng |
| author_sort | Xiaohua Huang |
| collection | DOAJ |
| description | Drug-induced liver injury (DILI) is a widespread and harmful disease, and is closely linked to acute endoplasmic reticulum (ER) stress. Previous reports have shown that acute ER stress can suppress hepatic gluconeogenesis and even leads to hypoglycemia. However, the mechanism is still unclear. MAPK phosphatase 3 (MKP-3) is a positive regulator for gluconeogenesis. Thus, this study was conducted to investigate the role of MKP-3 in the suppression of gluconeogenesis by acute ER stress, as well as the regulatory role of acute ER stress on the expression of MKP-3. Results showed that acute ER stress induced by tunicamycin significantly suppressed gluconeogenesis in both hepatocytes and mouse liver, reduced glucose production level in hepatocytes, and decreased fasting blood glucose level in mice. Additionally, the protein level of MKP-3 was reduced by acute ER stress in both hepatocytes and mouse liver. <i>Mkp-3</i> deficiency eliminated the inhibitory effect of acute ER stress on gluconeogenesis in hepatocytes. Moreover, the reduction effect of acute ER stress on blood glucose level and hepatic glucose 6-phosphatase (<i>G6pc</i>) expression was not observed in the liver-specific <i>Mkp-3</i> knockout mice. Furthermore, activation of protein kinase R-like ER kinase (PERK) decreased the MKP-3 protein level, while inactivation of PERK abolished the reduction effect of acute ER stress on the MKP-3 protein level in hepatocytes. Taken together, our study suggested that acute ER stress could suppress hepatic gluconeogenesis by stimulating MKP-3 degradation via PERK, at least partially. Thus, MKP-3 might be a therapeutic target for DILI-related hypoglycemia. |
| first_indexed | 2024-03-11T11:29:22Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-11T11:29:22Z |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-10f3a22d64744ff284565fab6908ef712023-11-10T15:04:26ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-10-0124211556110.3390/ijms242115561Acute Endoplasmic Reticulum Stress Suppresses Hepatic Gluconeogenesis by Stimulating MAPK Phosphatase 3 DegradationXiaohua Huang0Heng Zhu1Wei Lu2Lei Cao3Zhengfeng Fang4Lianqiang Che5Yan Lin6Shengyu Xu7Yong Zhuo8Lun Hua9Xuemei Jiang10Mengmeng Sun11De Wu12Bin Feng13Animal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, ChinaAnimal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, ChinaAnimal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, ChinaAnimal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, ChinaAnimal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, ChinaAnimal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, ChinaAnimal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, ChinaAnimal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, ChinaAnimal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, ChinaAnimal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, ChinaAnimal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, ChinaCollege of Science, Sichuan Agricultural University, Chengdu 611130, ChinaAnimal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, ChinaAnimal Nutrition Institute, Sichuan Agricultural University, Chengdu 611130, ChinaDrug-induced liver injury (DILI) is a widespread and harmful disease, and is closely linked to acute endoplasmic reticulum (ER) stress. Previous reports have shown that acute ER stress can suppress hepatic gluconeogenesis and even leads to hypoglycemia. However, the mechanism is still unclear. MAPK phosphatase 3 (MKP-3) is a positive regulator for gluconeogenesis. Thus, this study was conducted to investigate the role of MKP-3 in the suppression of gluconeogenesis by acute ER stress, as well as the regulatory role of acute ER stress on the expression of MKP-3. Results showed that acute ER stress induced by tunicamycin significantly suppressed gluconeogenesis in both hepatocytes and mouse liver, reduced glucose production level in hepatocytes, and decreased fasting blood glucose level in mice. Additionally, the protein level of MKP-3 was reduced by acute ER stress in both hepatocytes and mouse liver. <i>Mkp-3</i> deficiency eliminated the inhibitory effect of acute ER stress on gluconeogenesis in hepatocytes. Moreover, the reduction effect of acute ER stress on blood glucose level and hepatic glucose 6-phosphatase (<i>G6pc</i>) expression was not observed in the liver-specific <i>Mkp-3</i> knockout mice. Furthermore, activation of protein kinase R-like ER kinase (PERK) decreased the MKP-3 protein level, while inactivation of PERK abolished the reduction effect of acute ER stress on the MKP-3 protein level in hepatocytes. Taken together, our study suggested that acute ER stress could suppress hepatic gluconeogenesis by stimulating MKP-3 degradation via PERK, at least partially. Thus, MKP-3 might be a therapeutic target for DILI-related hypoglycemia.https://www.mdpi.com/1422-0067/24/21/15561DILIER stressPERKMKP-3gluconeogenesis |
| spellingShingle | Xiaohua Huang Heng Zhu Wei Lu Lei Cao Zhengfeng Fang Lianqiang Che Yan Lin Shengyu Xu Yong Zhuo Lun Hua Xuemei Jiang Mengmeng Sun De Wu Bin Feng Acute Endoplasmic Reticulum Stress Suppresses Hepatic Gluconeogenesis by Stimulating MAPK Phosphatase 3 Degradation International Journal of Molecular Sciences DILI ER stress PERK MKP-3 gluconeogenesis |
| title | Acute Endoplasmic Reticulum Stress Suppresses Hepatic Gluconeogenesis by Stimulating MAPK Phosphatase 3 Degradation |
| title_full | Acute Endoplasmic Reticulum Stress Suppresses Hepatic Gluconeogenesis by Stimulating MAPK Phosphatase 3 Degradation |
| title_fullStr | Acute Endoplasmic Reticulum Stress Suppresses Hepatic Gluconeogenesis by Stimulating MAPK Phosphatase 3 Degradation |
| title_full_unstemmed | Acute Endoplasmic Reticulum Stress Suppresses Hepatic Gluconeogenesis by Stimulating MAPK Phosphatase 3 Degradation |
| title_short | Acute Endoplasmic Reticulum Stress Suppresses Hepatic Gluconeogenesis by Stimulating MAPK Phosphatase 3 Degradation |
| title_sort | acute endoplasmic reticulum stress suppresses hepatic gluconeogenesis by stimulating mapk phosphatase 3 degradation |
| topic | DILI ER stress PERK MKP-3 gluconeogenesis |
| url | https://www.mdpi.com/1422-0067/24/21/15561 |
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