Progression of Chronic Liver Inflammation and Fibrosis Driven by Activation of c-JUN Signaling in Sirt6 Mutant Mice
Abstract
The human body has a remarkable ability to regulate inflammation, a biophysical response triggered by virus infection and tissue damage. Sirt6 is critical for metabolism and lifespan; however, its role in inflammation is unknown. Here we show that Sirt6-null (Sirt6(-/-)) mice developed chronic liver inflammation starting at ∼2 months of age, and all animals were affected by 7-8 months of age. Deletion of Sirt6 in T cells or myeloid-derived cells was sufficient to induce liver inflammation and fibrosis, albeit to a lesser degree than that in the global Sirt6(-/-) mice, suggesting that Sirt6 deficiency in the immune cells is the cause. Consistently, macrophages derived from the bone marrow of Sirt6(-/-) mice showed increased MCP-1, IL-6, and TNFα expression levels and were hypersensitive to LPS stimulation. Mechanistically, SIRT6 interacts with c-JUN and deacetylates histone H3 lysine 9 (H3K9) at the promoter of proinflammatory genes whose expression involves the c-JUN signaling pathway. Sirt6-deficient macrophages displayed hyperacetylation of H3K9 and increased occupancy of c-JUN in the promoter of these genes, leading to their elevated expression. These data suggest that Sirt6 plays an anti-inflammatory role in mice by inhibiting c-JUN-dependent expression of proinflammatory genes.
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BibTeX
@article{xiao2026progression,
title = {{Progression of Chronic Liver Inflammation and Fibrosis Driven by Activation of c-JUN Signaling in Sirt6 Mutant Mice}},
author = {Cuiying Xiao and Rui-Hong Wang and Tyler Lahusen and Ogyi Park and Adeline Bertola and Takashi Maruyama and Della Reynolds and Qiang Chen and Xiaoling Xu and Howard Young and Wan-Jun Chen and Bin Gao and Chu-Xia Deng},
journal = {Journal of Biological Chemistry},
year = {2026},
month = oct,
doi = {10.1074/jbc.m112.415182},
url = {https://hal.science/hal-05795804v1},
note = {CC BY},
}
RIS
TY - JOUR
TI - Progression of Chronic Liver Inflammation and Fibrosis Driven by Activation of c-JUN Signaling in Sirt6 Mutant Mice
AU - Cuiying Xiao
AU - Rui-Hong Wang
AU - Tyler Lahusen
AU - Ogyi Park
AU - Adeline Bertola
AU - Takashi Maruyama
AU - Della Reynolds
AU - Qiang Chen
AU - Xiaoling Xu
AU - Howard Young
AU - Wan-Jun Chen
AU - Bin Gao
AU - Chu-Xia Deng
PY - 2026
DA - 2026/10/12
JO - Journal of Biological Chemistry
DO - 10.1074/jbc.m112.415182
UR - https://hal.science/hal-05795804v1
AB - The human body has a remarkable ability to regulate inflammation, a biophysical response triggered by virus infection and tissue damage. Sirt6 is critical for metabolism and lifespan; however, its role in inflammation is unknown. Here we show that Sirt6-null (Sirt6(-/-)) mice developed chronic liver inflammation starting at ∼2 months of age, and all animals were affected by 7-8 months of age. Deletion of Sirt6 in T cells or myeloid-derived cells was sufficient to induce liver inflammation and fibrosis, albeit to a lesser degree than that in the global Sirt6(-/-) mice, suggesting that Sirt6 deficiency in the immune cells is the cause. Consistently, macrophages derived from the bone marrow of Sirt6(-/-) mice showed increased MCP-1, IL-6, and TNFα expression levels and were hypersensitive to LPS stimulation. Mechanistically, SIRT6 interacts with c-JUN and deacetylates histone H3 lysine 9 (H3K9) at the promoter of proinflammatory genes whose expression involves the c-JUN signaling pathway. Sirt6-deficient macrophages displayed hyperacetylation of H3K9 and increased occupancy of c-JUN in the promoter of these genes, leading to their elevated expression. These data suggest that Sirt6 plays an anti-inflammatory role in mice by inhibiting c-JUN-dependent expression of proinflammatory genes.
SN - 0021-9258
SN - 1083-351X
ER -