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UDP-glucuronate metabolism controls RIPK1-driven liver damage in nonalcoholic steatohepatitis

Tao Zhang1,2,3, Na Zhang4,5, Jing Xing6

  • 1Center for Liver Transplantation, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China.

Nature Communications
|May 11, 2023
PubMed

Insights

UDP-glucose 6-dehydrogenase (UGDH) suppresses liver damage in nonalcoholic steatohepatitis (NASH) by inhibiting RIPK1 kinase-dependent hepatocyte apoptosis. Restoring UDP-glucuronate levels can treat NASH-associated liver injury.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Hepatology

Background:

  • Hepatocyte apoptosis is crucial in nonalcoholic steatohepatitis (NASH) progression.
  • Molecular mechanisms of hepatocyte apoptosis in NASH are not fully understood.

Purpose of the Study:

  • Identify novel molecular mechanisms regulating hepatocyte apoptosis in NASH.
  • Investigate the role of UDP-glucose 6-dehydrogenase (UGDH) in NASH pathogenesis.

Main Methods:

  • Utilized mouse models of NASH.
  • Assessed the impact of UGDH deficiency and RIPK1 kinase activity on liver damage.
  • Investigated the biochemical interaction between UDP-glucuronate and RIPK1 kinase.

Main Results:

  • UGDH expression decreases with NASH severity.
  • UGDH deficiency exacerbates NASH-associated liver damage in mice.
  • UDP-glucuronate directly binds to RIPK1 kinase, inhibiting its activation and hepatocyte apoptosis.
  • Restoring UDP-glucuronate levels ameliorates liver damage in established NASH.

Conclusions:

  • UGDH acts as a suppressor of NASH-associated liver damage by inhibiting RIPK1 kinase.
  • UDP-glucuronate metabolism represents a potential therapeutic target for NASH-associated liver injury.

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