Histidine triad nucleotide-binding protein 2 attenuates metabolic dysfunction-associated steatotic liver disease through NAD+-dependent sirtuin-3 activation
Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, but its pathogenesis is unclear. Here we focus on histidine triad nucleotide-binding protein 2 (HINT2), which is expressed in the mitochondria and is involved in hepatic lipid metaboli...
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| Format: | Article |
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Nature Publishing Group
2025-05-01
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| Series: | Experimental and Molecular Medicine |
| Online Access: | https://doi.org/10.1038/s12276-025-01445-w |
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| author | Qinqiu Wang Yanjun Guo Shenghui Chen Zhening Liu Xinyu Wang Hangkai Huang Qi-en Shen Ling Yang Meng Li Youming Li Chaohui Yu Chengfu Xu |
| author_facet | Qinqiu Wang Yanjun Guo Shenghui Chen Zhening Liu Xinyu Wang Hangkai Huang Qi-en Shen Ling Yang Meng Li Youming Li Chaohui Yu Chengfu Xu |
| author_sort | Qinqiu Wang |
| collection | DOAJ |
| description | Abstract Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, but its pathogenesis is unclear. Here we focus on histidine triad nucleotide-binding protein 2 (HINT2), which is expressed in the mitochondria and is involved in hepatic lipid metabolism and mitochondrial protein acetylation. The expression of HINT2 is downregulated in MASLD. HINT2 inhibits free fatty acid-induced lipid accumulation and impairs mitochondrial function in hepatocytes. Hint2 knockout exacerbates diet-induced hepatic steatosis, inflammation, fibrosis and mitochondrial damage in mice. The overexpression of Hint2 attenuates these alterations. Mechanistically, HINT2 regulates mitochondrial protein acetylation via SIRT3; HINT2 enhances the NAD+-dependent activation of sirtuin-3 (SIRT3) by promoting the mitochondrial influx of NAD+ through solute carrier family 25 member 51 (SLC25A51), thus ameliorating MASLD. Moreover, the downregulation of HINT2 in MASLD is due to YTH N6-methyladenosine RNA binding protein 1 (YTHDF1)-mediated regulation. Our results suggest that HINT2 may be an important therapeutic target for MASLD. |
| format | Article |
| id | doaj-art-e8b394d06d6f4ff5903d0ee74030df57 |
| institution | OA Journals |
| issn | 2092-6413 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Experimental and Molecular Medicine |
| spelling | doaj-art-e8b394d06d6f4ff5903d0ee74030df572025-08-20T02:30:44ZengNature Publishing GroupExperimental and Molecular Medicine2092-64132025-05-01575990100410.1038/s12276-025-01445-wHistidine triad nucleotide-binding protein 2 attenuates metabolic dysfunction-associated steatotic liver disease through NAD+-dependent sirtuin-3 activationQinqiu Wang0Yanjun Guo1Shenghui Chen2Zhening Liu3Xinyu Wang4Hangkai Huang5Qi-en Shen6Ling Yang7Meng Li8Youming Li9Chaohui Yu10Chengfu Xu11Department of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of MedicineDepartment of Gastroenterology, the First Affiliated Hospital, Zhejiang University School of MedicineAbstract Metabolic dysfunction-associated steatotic liver disease (MASLD) is the most common chronic liver disease, but its pathogenesis is unclear. Here we focus on histidine triad nucleotide-binding protein 2 (HINT2), which is expressed in the mitochondria and is involved in hepatic lipid metabolism and mitochondrial protein acetylation. The expression of HINT2 is downregulated in MASLD. HINT2 inhibits free fatty acid-induced lipid accumulation and impairs mitochondrial function in hepatocytes. Hint2 knockout exacerbates diet-induced hepatic steatosis, inflammation, fibrosis and mitochondrial damage in mice. The overexpression of Hint2 attenuates these alterations. Mechanistically, HINT2 regulates mitochondrial protein acetylation via SIRT3; HINT2 enhances the NAD+-dependent activation of sirtuin-3 (SIRT3) by promoting the mitochondrial influx of NAD+ through solute carrier family 25 member 51 (SLC25A51), thus ameliorating MASLD. Moreover, the downregulation of HINT2 in MASLD is due to YTH N6-methyladenosine RNA binding protein 1 (YTHDF1)-mediated regulation. Our results suggest that HINT2 may be an important therapeutic target for MASLD.https://doi.org/10.1038/s12276-025-01445-w |
| spellingShingle | Qinqiu Wang Yanjun Guo Shenghui Chen Zhening Liu Xinyu Wang Hangkai Huang Qi-en Shen Ling Yang Meng Li Youming Li Chaohui Yu Chengfu Xu Histidine triad nucleotide-binding protein 2 attenuates metabolic dysfunction-associated steatotic liver disease through NAD+-dependent sirtuin-3 activation Experimental and Molecular Medicine |
| title | Histidine triad nucleotide-binding protein 2 attenuates metabolic dysfunction-associated steatotic liver disease through NAD+-dependent sirtuin-3 activation |
| title_full | Histidine triad nucleotide-binding protein 2 attenuates metabolic dysfunction-associated steatotic liver disease through NAD+-dependent sirtuin-3 activation |
| title_fullStr | Histidine triad nucleotide-binding protein 2 attenuates metabolic dysfunction-associated steatotic liver disease through NAD+-dependent sirtuin-3 activation |
| title_full_unstemmed | Histidine triad nucleotide-binding protein 2 attenuates metabolic dysfunction-associated steatotic liver disease through NAD+-dependent sirtuin-3 activation |
| title_short | Histidine triad nucleotide-binding protein 2 attenuates metabolic dysfunction-associated steatotic liver disease through NAD+-dependent sirtuin-3 activation |
| title_sort | histidine triad nucleotide binding protein 2 attenuates metabolic dysfunction associated steatotic liver disease through nad dependent sirtuin 3 activation |
| url | https://doi.org/10.1038/s12276-025-01445-w |
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