UDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis
Abstract Hepatocyte apoptosis plays an essential role in the progression of nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms underlying hepatocyte apoptosis remain unclear. Here, we identify UDP-glucose 6-dehydrogenase (UGDH) as a suppressor of NASH-associated liver damage by i...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-05-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-023-38371-2 |
| _version_ | 1797827448608391168 |
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| author | Tao Zhang Na Zhang Jing Xing Shuhua Zhang Yulu Chen Daichao Xu Jinyang Gu |
| author_facet | Tao Zhang Na Zhang Jing Xing Shuhua Zhang Yulu Chen Daichao Xu Jinyang Gu |
| author_sort | Tao Zhang |
| collection | DOAJ |
| description | Abstract Hepatocyte apoptosis plays an essential role in the progression of nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms underlying hepatocyte apoptosis remain unclear. Here, we identify UDP-glucose 6-dehydrogenase (UGDH) as a suppressor of NASH-associated liver damage by inhibiting RIPK1 kinase-dependent hepatocyte apoptosis. UGDH is progressively reduced in proportion to NASH severity. UGDH absence from hepatocytes hastens the development of liver damage in male mice with NASH, which is suppressed by RIPK1 kinase-dead knockin mutation. Mechanistically, UGDH suppresses RIPK1 by converting UDP-glucose to UDP-glucuronate, the latter directly binds to the kinase domain of RIPK1 and inhibits its activation. Recovering UDP-glucuronate levels, even after the onset of NASH, improved liver damage. Our findings reveal a role for UGDH and UDP-glucuronate in NASH pathogenesis and uncover a mechanism by which UDP-glucuronate controls hepatocyte apoptosis by targeting RIPK1 kinase, and suggest UDP-glucuronate metabolism as a feasible target for more specific treatment of NASH-associated liver damage. |
| first_indexed | 2024-04-09T12:48:29Z |
| format | Article |
| id | doaj.art-82c7fb2e83e7455d8e70dbc12828b84b |
| institution | Directory Open Access Journal |
| issn | 2041-1723 |
| language | English |
| last_indexed | 2024-04-09T12:48:29Z |
| publishDate | 2023-05-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj.art-82c7fb2e83e7455d8e70dbc12828b84b2023-05-14T11:21:46ZengNature PortfolioNature Communications2041-17232023-05-0114111810.1038/s41467-023-38371-2UDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitisTao Zhang0Na Zhang1Jing Xing2Shuhua Zhang3Yulu Chen4Daichao Xu5Jinyang Gu6Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesLingang LaboratoryCenter for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesInterdisciplinary Research Center on Biology and Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of SciencesCenter for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and TechnologyAbstract Hepatocyte apoptosis plays an essential role in the progression of nonalcoholic steatohepatitis (NASH). However, the molecular mechanisms underlying hepatocyte apoptosis remain unclear. Here, we identify UDP-glucose 6-dehydrogenase (UGDH) as a suppressor of NASH-associated liver damage by inhibiting RIPK1 kinase-dependent hepatocyte apoptosis. UGDH is progressively reduced in proportion to NASH severity. UGDH absence from hepatocytes hastens the development of liver damage in male mice with NASH, which is suppressed by RIPK1 kinase-dead knockin mutation. Mechanistically, UGDH suppresses RIPK1 by converting UDP-glucose to UDP-glucuronate, the latter directly binds to the kinase domain of RIPK1 and inhibits its activation. Recovering UDP-glucuronate levels, even after the onset of NASH, improved liver damage. Our findings reveal a role for UGDH and UDP-glucuronate in NASH pathogenesis and uncover a mechanism by which UDP-glucuronate controls hepatocyte apoptosis by targeting RIPK1 kinase, and suggest UDP-glucuronate metabolism as a feasible target for more specific treatment of NASH-associated liver damage.https://doi.org/10.1038/s41467-023-38371-2 |
| spellingShingle | Tao Zhang Na Zhang Jing Xing Shuhua Zhang Yulu Chen Daichao Xu Jinyang Gu UDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis Nature Communications |
| title | UDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis |
| title_full | UDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis |
| title_fullStr | UDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis |
| title_full_unstemmed | UDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis |
| title_short | UDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis |
| title_sort | udp glucuronate metabolism controls ripk1 driven liver damage in nonalcoholic steatohepatitis |
| url | https://doi.org/10.1038/s41467-023-38371-2 |
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