Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.
Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation; Key Laboratory of Organ Transplantation, Chinese Academy of Medical Sciences, Wuhan, 430022, China.
Nat Commun. 2023 May 11;14(1):2715. doi: 10.1038/s41467-023-38371-2.
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.
肝细胞凋亡在非酒精性脂肪性肝炎（NASH）的进展中起着至关重要的作用。然而，肝细胞凋亡的分子机制尚不清楚。在这里，我们发现 UDP-葡萄糖 6-脱氢酶（UGDH）通过抑制 RIPK1 激酶依赖性肝细胞凋亡，成为抑制 NASH 相关肝损伤的一种抑制物。UGDH 的含量随着 NASH 的严重程度逐渐减少。肝细胞缺乏 UGDH 会加速 NASH 雄性小鼠肝损伤的发展，而 RIPK1 激酶失活突变可抑制其发展。在机制上，UGDH 通过将 UDP-葡萄糖转化为 UDP-葡糖醛酸来抑制 RIPK1，后者直接结合 RIPK1 的激酶结构域并抑制其激活。即使在 NASH 发病后，恢复 UDP-葡糖醛酸水平也能改善肝损伤。我们的研究结果揭示了 UGDH 和 UDP-葡糖醛酸在 NASH 发病机制中的作用，并揭示了 UDP-葡糖醛酸通过靶向 RIPK1 激酶控制肝细胞凋亡的机制，提示 UDP-葡糖醛酸代谢可能成为治疗 NASH 相关肝损伤的更具特异性的治疗靶点。
