Myeloid HDAC7 drives liver inflammation and systemic glucose dysregulation during diet‐induced obesity

Abstract Objectives Histone deacetylase 7 (HDAC7), a classical HDAC family member, 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, relative 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.

Authors

Institutions

Publication Details

Journal
Clinical & Translational Immunology
Published
2026-05-29
DOI
https://doi.org/10.1002/cti2.70100
Primary Topic
Histone Deacetylase Inhibitors Research
Type
article
Field-Weighted Citation Impact
0.00

Funders

Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

Myeloid HDAC7 drives liver inflammation and systemic glucose dysregulation during diet‐induced obesity

Zherui Xiong, Kaustav Das Gupta, Christian Engwerda, Jessica A. Engel et al.
Clinical & Translational Immunology
Histone Deacetylase Inhibitors Research
article

Myeloid HDAC7 drives liver inflammation and systemic glucose dysregulation during diet‐induced obesity

Zherui Xiong, Kaustav Das Gupta, Christian Engwerda, Jessica A. Engel, Ellen N. Tejo, Sabrina Sofia Burgener, Elizabeth E. Powell, Kate Schroder, Denuja Karunakaran, Mitchell A. Sullivan, Kavita Bisht, Kimberley S. Gunther, Divya Ramnath, David P. Fairlie, Katharine M. Irvine, Andrew D. Clouston, Sahar Keshvari, Zhixuan Loh, Gregory Miller, Rishika Abrol, Jordan D. Atkinson, Matthew J. Sweet, Yujun Wan, James EB Curson, Yizhuo Wang, P Prakrithi, Quan Nguyen, Jean‐Pierre Lévesque
article en

Abstract

Abstract Objectives Histone deacetylase 7 (HDAC7), a classical HDAC family member, 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, relative 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.

Clinical & Translational ImmunologyVol. 15(6)
Translational Research Institute (AU), The University of Queensland (AU), University of the Sunshine Coast (AU), QIMR Berghofer Medical Research Institute (AU), Discovery Institute (US), Princess Alexandra Hospital (AU), Envoi Specialist Pathologists (AU), Mater Research (AU), Sunshine Coast University Hospital (AU), Australian Centre for Heart Health (AU), ARC Centre of Excellence for Plant Success in Nature and Agriculture (AU)
Australian Research Council, National Health and Medical Research Council
Good health and well-being
Openalex Percentile: Top 9%
Histone Deacetylase Inhibitors Research
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.