Increased RTN3 phenocopies nonalcoholic fatty liver disease by inhibiting the AMPK–IDH2 pathway
Abstract Reticulon 3 (RTN3), an endoplasmic reticulum protein, is crucial in neurodegenerative and kidney diseases. However, the role of RTN3 in liver tissues has not been described. Here, we employed public datasets, patients, and several animal models to explore the role of RTN3 in nonalcoholic fa...
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| Format: | Article |
| Language: | English |
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Wiley
2023-04-01
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| Series: | MedComm |
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| Online Access: | https://doi.org/10.1002/mco2.226 |
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| author | Hao Huang Shuai Guo Ya‐Qin Chen Yu‐Xing Liu Jie‐Yuan Jin Yun Liang Liang‐Liang Fan Rong Xiang |
| author_facet | Hao Huang Shuai Guo Ya‐Qin Chen Yu‐Xing Liu Jie‐Yuan Jin Yun Liang Liang‐Liang Fan Rong Xiang |
| author_sort | Hao Huang |
| collection | DOAJ |
| description | Abstract Reticulon 3 (RTN3), an endoplasmic reticulum protein, is crucial in neurodegenerative and kidney diseases. However, the role of RTN3 in liver tissues has not been described. Here, we employed public datasets, patients, and several animal models to explore the role of RTN3 in nonalcoholic fatty liver disease (NAFLD). The underlying mechanisms were studied in primary hepatocytes and L02 cells in vitro. We found an increased expression of RTN3 in NAFLD patients, high‐fat diet mice, and oxidized low‐density lipoprotein‐treated L02 cells. The RTN3 transgenic mice exhibited the phenotypes of fatty liver and lipid accumulation. Single‐cell RNA sequencing analysis indicated that increased RTN3 might induce mitochondrial dysfunction. We further showed this in primary hepatocytes, the L02 cell line, and the Caenorhabditis elegans strain. Mechanistically, RTN3 regulated these events through its interactions with glucose‐regulated protein 78 (GRP78), which further inhibited the adenosine 5 monophosphate‐activated protein kinase (AMPK)–isocitrate dehydrogenase 2 (IDH2) pathway. In the end, knockout of RTN3 relieved fatty liver and mitochondrial dysfunction. Our study indicated that RTN3 was important in NAFLD and lipid catabolism and that an increase in RTN3 in the liver might be a risk factor for nonalcoholic steatohepatitis and NAFLD. |
| format | Article |
| id | doaj-art-47b697c828f8482da99d53a297452fe8 |
| institution | Kabale University |
| issn | 2688-2663 |
| language | English |
| publishDate | 2023-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | MedComm |
| spelling | doaj-art-47b697c828f8482da99d53a297452fe82025-01-24T05:36:29ZengWileyMedComm2688-26632023-04-0142n/an/a10.1002/mco2.226Increased RTN3 phenocopies nonalcoholic fatty liver disease by inhibiting the AMPK–IDH2 pathwayHao Huang0Shuai Guo1Ya‐Qin Chen2Yu‐Xing Liu3Jie‐Yuan Jin4Yun Liang5Liang‐Liang Fan6Rong Xiang7Department of Nephrology Xiangya Hospital Central South University Changsha ChinaDepartment of Cell Biology School of Life Sciences Central South University Changsha ChinaDepartment of Cardiology Second Xiangya Hospital Central South University Changsha ChinaDepartment of Cell Biology School of Life Sciences Central South University Changsha ChinaDepartment of Cell Biology School of Life Sciences Central South University Changsha ChinaDepartment of Cell Biology School of Life Sciences Central South University Changsha ChinaDepartment of Nephrology Xiangya Hospital Central South University Changsha ChinaDepartment of Nephrology Xiangya Hospital Central South University Changsha ChinaAbstract Reticulon 3 (RTN3), an endoplasmic reticulum protein, is crucial in neurodegenerative and kidney diseases. However, the role of RTN3 in liver tissues has not been described. Here, we employed public datasets, patients, and several animal models to explore the role of RTN3 in nonalcoholic fatty liver disease (NAFLD). The underlying mechanisms were studied in primary hepatocytes and L02 cells in vitro. We found an increased expression of RTN3 in NAFLD patients, high‐fat diet mice, and oxidized low‐density lipoprotein‐treated L02 cells. The RTN3 transgenic mice exhibited the phenotypes of fatty liver and lipid accumulation. Single‐cell RNA sequencing analysis indicated that increased RTN3 might induce mitochondrial dysfunction. We further showed this in primary hepatocytes, the L02 cell line, and the Caenorhabditis elegans strain. Mechanistically, RTN3 regulated these events through its interactions with glucose‐regulated protein 78 (GRP78), which further inhibited the adenosine 5 monophosphate‐activated protein kinase (AMPK)–isocitrate dehydrogenase 2 (IDH2) pathway. In the end, knockout of RTN3 relieved fatty liver and mitochondrial dysfunction. Our study indicated that RTN3 was important in NAFLD and lipid catabolism and that an increase in RTN3 in the liver might be a risk factor for nonalcoholic steatohepatitis and NAFLD.https://doi.org/10.1002/mco2.226AMPKIDH2mitochondrial dysfunctionnonalcoholic fatty liver diseaseRTN3 |
| spellingShingle | Hao Huang Shuai Guo Ya‐Qin Chen Yu‐Xing Liu Jie‐Yuan Jin Yun Liang Liang‐Liang Fan Rong Xiang Increased RTN3 phenocopies nonalcoholic fatty liver disease by inhibiting the AMPK–IDH2 pathway MedComm AMPK IDH2 mitochondrial dysfunction nonalcoholic fatty liver disease RTN3 |
| title | Increased RTN3 phenocopies nonalcoholic fatty liver disease by inhibiting the AMPK–IDH2 pathway |
| title_full | Increased RTN3 phenocopies nonalcoholic fatty liver disease by inhibiting the AMPK–IDH2 pathway |
| title_fullStr | Increased RTN3 phenocopies nonalcoholic fatty liver disease by inhibiting the AMPK–IDH2 pathway |
| title_full_unstemmed | Increased RTN3 phenocopies nonalcoholic fatty liver disease by inhibiting the AMPK–IDH2 pathway |
| title_short | Increased RTN3 phenocopies nonalcoholic fatty liver disease by inhibiting the AMPK–IDH2 pathway |
| title_sort | increased rtn3 phenocopies nonalcoholic fatty liver disease by inhibiting the ampk idh2 pathway |
| topic | AMPK IDH2 mitochondrial dysfunction nonalcoholic fatty liver disease RTN3 |
| url | https://doi.org/10.1002/mco2.226 |
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