E-Selectin-Dependent Inflammation and Lipolysis in Adipose Tissue Exacerbate Steatosis-to-NASH Progression via S100A8/9
Abstract
Background & Aims Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease, characterized by steatosis and hallmark liver neutrophil infiltration. NASH also is associated with adipose tissue inflammation, but the role of adipose tissue inflammation in NASH pathogenesis remains obscure. The aim of this study was to investigate the interplay between neutrophil recruitment in adipose tissue and the progression of NASH. Methods A mouse model of NASH was obtained by high-fat diet (HFD) feeding plus adenovirus- Cxcl1 overexpression (HFD +AdCxcl1 ). Genetic deletion of E-selectin ( Sele ) and treatment with an S100A9 inhibitor (Paquinimod) were investigated using this model. Results By analyzing transcriptomic data sets of adipose tissue from NASH patients, we found that E-selectin, a key adhesion molecule for neutrophils, is the highest up-regulated gene among neutrophil recruitment-related factors in adipose tissue of NASH patients compared with those in patients with simple steatosis. A marked up-regulation of Sele in adipose tissue also was observed in HFD +AdCxcl1 mice. The HFD +AdCxcl1 -induced NASH phenotype was ameliorated in Sele knockout mice and was accompanied by reduced lipolysis and inflammation in adipose tissue, which resulted in decreased serum free fatty acids and proinflammatory adipokines. S100A8/A9, a major proinflammatory protein secreted by neutrophils, was highly increased in adipose tissue of HFD +AdCxcl1 mice. This increase was blunted in the Sele knockout mice. Therapeutically, treatment with the S100A9 inhibitor Paquinimod reduced lipolysis, inflammation, and adipokine production, ameliorating the NASH phenotype in mice. Conclusions E-selectin plays an important role in inducing neutrophil recruitment in adipose tissue, which subsequently promotes inflammation and lipolysis via the production of S100A8/A9, thereby exacerbating the steatosis-to-NASH progression. Targeting adipose tissue inflammation therefore may represent a potential novel therapy for treatment of NASH.
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BibTeX
@article{rodrigues2026eselectindependent,
title = {{E-Selectin-Dependent Inflammation and Lipolysis in Adipose Tissue Exacerbate Steatosis-to-NASH Progression via S100A8/9}},
author = {Robim Rodrigues and Yong He and Seonghwan Hwang and Adeline Bertola and Bryan Mackowiak and Yeni Ait Ahmed and Wonhyo Seo and Jing Ma and Xiaolin Wang and Seol Hee Park and Yukun Guan and Yaojie Fu and Tamara Vanhaecke and Dechun Feng and Bin Gao},
journal = {Cellular and Molecular Gastroenterology and Hepatology},
year = {2026},
month = oct,
doi = {10.1016/j.jcmgh.2021.08.002},
url = {https://hal.science/hal-05795792v1},
note = {CC BY-NC-ND},
}
RIS
TY - JOUR
TI - E-Selectin-Dependent Inflammation and Lipolysis in Adipose Tissue Exacerbate Steatosis-to-NASH Progression via S100A8/9
AU - Robim Rodrigues
AU - Yong He
AU - Seonghwan Hwang
AU - Adeline Bertola
AU - Bryan Mackowiak
AU - Yeni Ait Ahmed
AU - Wonhyo Seo
AU - Jing Ma
AU - Xiaolin Wang
AU - Seol Hee Park
AU - Yukun Guan
AU - Yaojie Fu
AU - Tamara Vanhaecke
AU - Dechun Feng
AU - Bin Gao
PY - 2026
DA - 2026/10/12
JO - Cellular and Molecular Gastroenterology and Hepatology
DO - 10.1016/j.jcmgh.2021.08.002
UR - https://hal.science/hal-05795792v1
AB - Background & Aims Nonalcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease, characterized by steatosis and hallmark liver neutrophil infiltration. NASH also is associated with adipose tissue inflammation, but the role of adipose tissue inflammation in NASH pathogenesis remains obscure. The aim of this study was to investigate the interplay between neutrophil recruitment in adipose tissue and the progression of NASH. Methods A mouse model of NASH was obtained by high-fat diet (HFD) feeding plus adenovirus- Cxcl1 overexpression (HFD +AdCxcl1 ). Genetic deletion of E-selectin ( Sele ) and treatment with an S100A9 inhibitor (Paquinimod) were investigated using this model. Results By analyzing transcriptomic data sets of adipose tissue from NASH patients, we found that E-selectin, a key adhesion molecule for neutrophils, is the highest up-regulated gene among neutrophil recruitment-related factors in adipose tissue of NASH patients compared with those in patients with simple steatosis. A marked up-regulation of Sele in adipose tissue also was observed in HFD +AdCxcl1 mice. The HFD +AdCxcl1 -induced NASH phenotype was ameliorated in Sele knockout mice and was accompanied by reduced lipolysis and inflammation in adipose tissue, which resulted in decreased serum free fatty acids and proinflammatory adipokines. S100A8/A9, a major proinflammatory protein secreted by neutrophils, was highly increased in adipose tissue of HFD +AdCxcl1 mice. This increase was blunted in the Sele knockout mice. Therapeutically, treatment with the S100A9 inhibitor Paquinimod reduced lipolysis, inflammation, and adipokine production, ameliorating the NASH phenotype in mice. Conclusions E-selectin plays an important role in inducing neutrophil recruitment in adipose tissue, which subsequently promotes inflammation and lipolysis via the production of S100A8/A9, thereby exacerbating the steatosis-to-NASH progression. Targeting adipose tissue inflammation therefore may represent a potential novel therapy for treatment of NASH.
SN - 2352-345X
ER -