Preprint
Myeloid HDAC7 drives liver inflammation and systemic glucose dysregulation during diet-induced obesity
bioRxiv, Vol.9 December 2025
Cold Spring Harbor Laboratory Press
2025
Abstract
Objectives: Histone deacetylase 7 (HDAC7), a member of the classical HDAC family, promotes LPS-inducible glycolysis and inflammatory mediator production in macrophages, innate immune cells that contribute to pathology in metabolic diseases. Here, we investigated myeloid HDAC7 functions in obesity-driven metabolic disease.
Methods: We used gain- and loss-of-function genetic approaches in mice to investigate myeloid HDAC7 functions in hepatic inflammation and metabolic disease, as well as associations with hepatic gene signatures characteristic of advanced chronic liver disease (CLD).
Results: Transgenic expression of Hdac7 in myeloid cells increased liver inflammation and liver mRNA levels of Ccl2 and Il1b, key inflammatory mediators linked to CLD. Liver glycogen levels were also decreased, another feature of CLD. Transgenic expression of Hdac7 in myeloid cells mimicked the hepatic inflammatory phenotype that was observed in mice fed a high fat, high cholesterol, and high sucrose (HFHCHS) diet, an obesity model that mimics some features of metabolic dysfunction-associated steatotic liver disease. In myeloid Hdac7 transgenic mice fed a HFHCHS diet, weight gain was increased, fasted glucose levels were elevated and glucose tolerance was dysregulated by comparison to control mice. Conversely, fasted blood glucose levels were reduced and glucose tolerance was improved in myeloid Hdac7-deleted mice on a HFHCHS diet. HDAC7 mRNA levels were also elevated in the livers of people with advanced CLD and spatial transcriptomics revealed that myeloid HDAC7 directs hepatic gene signatures characteristic of advanced CLD.
Conclusion: Myeloid HDAC7 contributes to hepatic inflammation and systemic glucose dysregulation in a mouse model of obesity and liver inflammation.
Details
- Title
- Myeloid HDAC7 drives liver inflammation and systemic glucose dysregulation during diet-induced obesity
- Authors
- Yizhuo Wang - The University of QueenslandDivya Ramnath - The University of QueenslandKaustav Das Gupta - The University of QueenslandGregory C Miller - The University of QueenslandPrakrithi Pavitra - The University of QueenslandZherui Xiong - The University of QueenslandYujun Wan - The University of QueenslandEllen N Tejo - The University of QueenslandJames E B Curson - The University of QueenslandRishika Abrol - The University of QueenslandSahar Keshvari - The University of QueenslandKimberley S Gunther - The University of QueenslandZhixuan Loh - The University of QueenslandJessica A Engel - QIMR Berghofer Medical Research InstituteChristian R Engwerda - QIMR Berghofer Medical Research InstituteSabrina Sofia Burgener - The University of QueenslandKate Schroder - The University of QueenslandDavid P Fairlie - The University of QueenslandAndrew D Clouston - Envoi Specialist Pathologists (Australia)Elizabeth E Powell - Princess Alexandra HospitalKatharine M Irvine - Translational Research InstituteMitchell A Sullivan - University of the Sunshine Coast, Queensland, Centre for BioinnovationQuan Nguyen - The University of QueenslandMatthew J Sweet (Corresponding Author) - The University of QueenslandDenuja Karunakaran (Corresponding Author) - The University of Queensland
- Publication details
- bioRxiv, Vol.9 December 2025
- Publisher
- Cold Spring Harbor Laboratory Press
- Date published
- 2025
- DOI
- 10.64898/2025.12.04.691405
- ISSN
- 2692-8205
- Grants
- Organisation Unit
- School of Health - Biomedicine; Centre for Bioinnovation
- Language
- English
- Record Identifier
- 991192342002621
- Output Type
- Preprint
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