AAV induces hepatic necroptosis and carcinoma in diabetic and obese mice dependent on Pebp1 pathway
Abstract Obesity and diabetes are risk factors for hepatocellular carcinoma (HCC); however, the underlying mechanisms are yet to be elucidated. Adeno‐associated virus (AAV) frequently infects humans and has been widely used in gene therapy, but the risk of AAV infection such as HCC should be further...
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| Format: | Article |
| Language: | English |
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Springer Nature
2023-07-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.202217230 |
| _version_ | 1797280703753224192 |
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| author | Yalan Cheng Zhentong Zhang Peidong Gao Hejin Lai Wuling Zhong Ning Feng Yale Yang Huimin Yu Yali Zhang Yumo Han Jieya Dong Zhishui He Rui Huang Qiwei Zhai |
| author_facet | Yalan Cheng Zhentong Zhang Peidong Gao Hejin Lai Wuling Zhong Ning Feng Yale Yang Huimin Yu Yali Zhang Yumo Han Jieya Dong Zhishui He Rui Huang Qiwei Zhai |
| author_sort | Yalan Cheng |
| collection | DOAJ |
| description | Abstract Obesity and diabetes are risk factors for hepatocellular carcinoma (HCC); however, the underlying mechanisms are yet to be elucidated. Adeno‐associated virus (AAV) frequently infects humans and has been widely used in gene therapy, but the risk of AAV infection such as HCC should be further evaluated. Here, we show that recombinant AAV injection caused liver injury, hepatic necroptosis, and HCC in db/db or high‐fat diet‐induced hyperglycemic and obese mice, but not in mice with only hyperglycemia or obesity. Prednisone administration or knockdown of Pebp1, highly expressed in db/db mice, alleviated hepatic injury and necroptosis induced by recombinant AAV in mice with diabetes and obesity. Inhibition of Pebp1 pathway also attenuated inflammation and necroptosis in vitro. Our findings show that AAV infection is a critical risk factor for HCC in patients with diabetes and obesity, and AAV gene therapy for these patients should be carefully evaluated. Both prednisone treatment and targeting Pebp1 pathway are promising strategies to alleviate inflammation and necroptosis that occurred in AAV gene therapy or related diseases. |
| first_indexed | 2024-03-07T16:44:58Z |
| format | Article |
| id | doaj.art-2bb4f6a424834de9b7725d4368343ee2 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2024-03-07T16:44:58Z |
| publishDate | 2023-07-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-2bb4f6a424834de9b7725d4368343ee22024-03-03T06:39:20ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-07-01157n/an/a10.15252/emmm.202217230AAV induces hepatic necroptosis and carcinoma in diabetic and obese mice dependent on Pebp1 pathwayYalan Cheng0Zhentong Zhang1Peidong Gao2Hejin Lai3Wuling Zhong4Ning Feng5Yale Yang6Huimin Yu7Yali Zhang8Yumo Han9Jieya Dong10Zhishui He11Rui Huang12Qiwei Zhai13CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences, Chinese Academy of Sciences Shanghai ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences, Chinese Academy of Sciences Shanghai ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences, Chinese Academy of Sciences Shanghai ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences, Chinese Academy of Sciences Shanghai ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences, Chinese Academy of Sciences Shanghai ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences, Chinese Academy of Sciences Shanghai ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences, Chinese Academy of Sciences Shanghai ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences, Chinese Academy of Sciences Shanghai ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences, Chinese Academy of Sciences Shanghai ChinaSchool of Life Science and Technology ShanghaiTech University Shanghai ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences, Chinese Academy of Sciences Shanghai ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences, Chinese Academy of Sciences Shanghai ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences, Chinese Academy of Sciences Shanghai ChinaCAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health University of Chinese Academy of Sciences, Chinese Academy of Sciences Shanghai ChinaAbstract Obesity and diabetes are risk factors for hepatocellular carcinoma (HCC); however, the underlying mechanisms are yet to be elucidated. Adeno‐associated virus (AAV) frequently infects humans and has been widely used in gene therapy, but the risk of AAV infection such as HCC should be further evaluated. Here, we show that recombinant AAV injection caused liver injury, hepatic necroptosis, and HCC in db/db or high‐fat diet‐induced hyperglycemic and obese mice, but not in mice with only hyperglycemia or obesity. Prednisone administration or knockdown of Pebp1, highly expressed in db/db mice, alleviated hepatic injury and necroptosis induced by recombinant AAV in mice with diabetes and obesity. Inhibition of Pebp1 pathway also attenuated inflammation and necroptosis in vitro. Our findings show that AAV infection is a critical risk factor for HCC in patients with diabetes and obesity, and AAV gene therapy for these patients should be carefully evaluated. Both prednisone treatment and targeting Pebp1 pathway are promising strategies to alleviate inflammation and necroptosis that occurred in AAV gene therapy or related diseases.https://doi.org/10.15252/emmm.202217230diabetesHCCnecroptosisobesityrAAV |
| spellingShingle | Yalan Cheng Zhentong Zhang Peidong Gao Hejin Lai Wuling Zhong Ning Feng Yale Yang Huimin Yu Yali Zhang Yumo Han Jieya Dong Zhishui He Rui Huang Qiwei Zhai AAV induces hepatic necroptosis and carcinoma in diabetic and obese mice dependent on Pebp1 pathway EMBO Molecular Medicine diabetes HCC necroptosis obesity rAAV |
| title | AAV induces hepatic necroptosis and carcinoma in diabetic and obese mice dependent on Pebp1 pathway |
| title_full | AAV induces hepatic necroptosis and carcinoma in diabetic and obese mice dependent on Pebp1 pathway |
| title_fullStr | AAV induces hepatic necroptosis and carcinoma in diabetic and obese mice dependent on Pebp1 pathway |
| title_full_unstemmed | AAV induces hepatic necroptosis and carcinoma in diabetic and obese mice dependent on Pebp1 pathway |
| title_short | AAV induces hepatic necroptosis and carcinoma in diabetic and obese mice dependent on Pebp1 pathway |
| title_sort | aav induces hepatic necroptosis and carcinoma in diabetic and obese mice dependent on pebp1 pathway |
| topic | diabetes HCC necroptosis obesity rAAV |
| url | https://doi.org/10.15252/emmm.202217230 |
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