Loss of Splicing Factor SRSF3 Impairs Lipophagy Through Ubiquitination and Degradation of Syntaxin17 in Hepatocytes
Lipid accumulation in hepatocytes is the distinctive characteristic of nonalcoholic fatty liver disease. Serine/arginine-rich splicing factor 3 (SRSF3) is highly expressed in the liver and expression decreases in high-fat conditions. However, the role of SRSF3 in hepatic lipid metabolism needs to be...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2023-03-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227523000159 |
| _version_ | 1797859732954808320 |
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| author | Yun Li Tao Wang Qiumin Liao Xiaoting Luo Xing Wang Shu Zeng Mengyue You Yaxi Chen Xiong Z. Ruan |
| author_facet | Yun Li Tao Wang Qiumin Liao Xiaoting Luo Xing Wang Shu Zeng Mengyue You Yaxi Chen Xiong Z. Ruan |
| author_sort | Yun Li |
| collection | DOAJ |
| description | Lipid accumulation in hepatocytes is the distinctive characteristic of nonalcoholic fatty liver disease. Serine/arginine-rich splicing factor 3 (SRSF3) is highly expressed in the liver and expression decreases in high-fat conditions. However, the role of SRSF3 in hepatic lipid metabolism needs to be clarified. Here, we showed that loss of SRSF3 was associated with lipid accumulation. We determined that SRSF3 regulated lipophagy, the process of selective degradation of lipid droplets by autophagy. Mechanistically, loss of SRSF3 impaired the fusion of the autophagosome and lysosome by promoting the proteasomal degradation of syntaxin 17 (STX17), a key autophagosomal SNARE protein. We found that ubiquitination of STX17 was increased and upregulation of seven in absentia homolog 1 was responsible for the increased posttranslational modification of STX17. Taken together, our data primarily demonstrate that loss of SRSF3 weakens the clearance of fatty acids by impairing lipophagy in the progression of nonalcoholic fatty liver disease, indicating a novel potential therapeutic target for fatty liver disease treatment. |
| first_indexed | 2024-04-09T21:34:21Z |
| format | Article |
| id | doaj.art-116e75ed52a54741a49f4e746fac1bd5 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-04-09T21:34:21Z |
| publishDate | 2023-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-116e75ed52a54741a49f4e746fac1bd52023-03-27T04:02:48ZengElsevierJournal of Lipid Research0022-22752023-03-01643100342Loss of Splicing Factor SRSF3 Impairs Lipophagy Through Ubiquitination and Degradation of Syntaxin17 in HepatocytesYun Li0Tao Wang1Qiumin Liao2Xiaoting Luo3Xing Wang4Shu Zeng5Mengyue You6Yaxi Chen7Xiong Z. Ruan8Centre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), the Second Affiliated Hospital, Chongqing Medical University, Chongqing, ChinaCentre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), the Second Affiliated Hospital, Chongqing Medical University, Chongqing, ChinaCentre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), the Second Affiliated Hospital, Chongqing Medical University, Chongqing, ChinaCentre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), the Second Affiliated Hospital, Chongqing Medical University, Chongqing, ChinaCentre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), the Second Affiliated Hospital, Chongqing Medical University, Chongqing, ChinaCentre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), the Second Affiliated Hospital, Chongqing Medical University, Chongqing, ChinaCentre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), the Second Affiliated Hospital, Chongqing Medical University, Chongqing, ChinaCentre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China; For correspondence: Yaxi Chen; Xiong Z. RuanCentre for Lipid Research & Key Laboratory of Molecular Biology for Infectious Diseases (Ministry of Education), the Second Affiliated Hospital, Chongqing Medical University, Chongqing, China; John Moorhead Research Laboratory, Centre for Nephrology, University College London Medical School, Royal Free Campus, University College London, London, United Kingdom; For correspondence: Yaxi Chen; Xiong Z. RuanLipid accumulation in hepatocytes is the distinctive characteristic of nonalcoholic fatty liver disease. Serine/arginine-rich splicing factor 3 (SRSF3) is highly expressed in the liver and expression decreases in high-fat conditions. However, the role of SRSF3 in hepatic lipid metabolism needs to be clarified. Here, we showed that loss of SRSF3 was associated with lipid accumulation. We determined that SRSF3 regulated lipophagy, the process of selective degradation of lipid droplets by autophagy. Mechanistically, loss of SRSF3 impaired the fusion of the autophagosome and lysosome by promoting the proteasomal degradation of syntaxin 17 (STX17), a key autophagosomal SNARE protein. We found that ubiquitination of STX17 was increased and upregulation of seven in absentia homolog 1 was responsible for the increased posttranslational modification of STX17. Taken together, our data primarily demonstrate that loss of SRSF3 weakens the clearance of fatty acids by impairing lipophagy in the progression of nonalcoholic fatty liver disease, indicating a novel potential therapeutic target for fatty liver disease treatment.http://www.sciencedirect.com/science/article/pii/S0022227523000159lipid dropletslivertriglycerideobesitylipid/oxidationNAFLD |
| spellingShingle | Yun Li Tao Wang Qiumin Liao Xiaoting Luo Xing Wang Shu Zeng Mengyue You Yaxi Chen Xiong Z. Ruan Loss of Splicing Factor SRSF3 Impairs Lipophagy Through Ubiquitination and Degradation of Syntaxin17 in Hepatocytes Journal of Lipid Research lipid droplets liver triglyceride obesity lipid/oxidation NAFLD |
| title | Loss of Splicing Factor SRSF3 Impairs Lipophagy Through Ubiquitination and Degradation of Syntaxin17 in Hepatocytes |
| title_full | Loss of Splicing Factor SRSF3 Impairs Lipophagy Through Ubiquitination and Degradation of Syntaxin17 in Hepatocytes |
| title_fullStr | Loss of Splicing Factor SRSF3 Impairs Lipophagy Through Ubiquitination and Degradation of Syntaxin17 in Hepatocytes |
| title_full_unstemmed | Loss of Splicing Factor SRSF3 Impairs Lipophagy Through Ubiquitination and Degradation of Syntaxin17 in Hepatocytes |
| title_short | Loss of Splicing Factor SRSF3 Impairs Lipophagy Through Ubiquitination and Degradation of Syntaxin17 in Hepatocytes |
| title_sort | loss of splicing factor srsf3 impairs lipophagy through ubiquitination and degradation of syntaxin17 in hepatocytes |
| topic | lipid droplets liver triglyceride obesity lipid/oxidation NAFLD |
| url | http://www.sciencedirect.com/science/article/pii/S0022227523000159 |
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