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

Tao Zhang, Na Zhang, Jing Xing, Shuhua Zhang, Yulu Chen, Daichao Xu and Jinyang Gu ()
Additional contact information
Tao Zhang: Huazhong University of Science and Technology
Na Zhang: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Jing Xing: Lingang Laboratory
Shuhua Zhang: Huazhong University of Science and Technology
Yulu Chen: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Daichao Xu: Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences
Jinyang Gu: Huazhong University of Science and Technology

Nature Communications, 2023, vol. 14, issue 1, 1-18

Abstract: 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.

Date: 2023
References: View references in EconPapers View complete reference list from CitEc
Citations:

Downloads: (external link)
https://www.nature.com/articles/s41467-023-38371-2 Abstract (text/html)

Related works:
This item may be available elsewhere in EconPapers: Search for items with the same title.

Export reference: BibTeX RIS (EndNote, ProCite, RefMan) HTML/Text

Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-38371-2

Ordering information: This journal article can be ordered from
https://www.nature.com/ncomms/

DOI: 10.1038/s41467-023-38371-2

Access Statistics for this article

Nature Communications is currently edited by Nathalie Le Bot, Enda Bergin and Fiona Gillespie

More articles in Nature Communications from Nature
Bibliographic data for series maintained by Sonal Shukla () and Springer Nature Abstracting and Indexing ().