E-Selectin-Dependent Inflammation and Lipolysis in Adipose Tissue Exacerbate Steatosis-to-NASH Progression via S100A8/9Summary

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 pathogenesi...

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Autores principales:	Robim M. Rodrigues, Yong He, Seonghwan Hwang, Adeline Bertola, Bryan Mackowiak, Yeni Ait Ahmed, Wonhyo Seo, Jing Ma, Xiaolin Wang, Seol Hee Park, Yukun Guan, Yaojie Fu, Tamara Vanhaecke, Dechun Feng, Bin Gao
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2022
Materias:	Nonalcoholic Fatty Liver Disease (NAFLD) Steatohepatitis Neutrophils Paquinimod CXCL1 Diseases of the digestive system. Gastroenterology RC799-869
Acceso en línea:	https://doaj.org/article/9bc1e20fa00e4a4fafdb662818770db4
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spelling	oai:doaj.org-article:9bc1e20fa00e4a4fafdb662818770db42021-11-14T04:34:10ZE-Selectin-Dependent Inflammation and Lipolysis in Adipose Tissue Exacerbate Steatosis-to-NASH Progression via S100A8/9Summary2352-345X10.1016/j.jcmgh.2021.08.002https://doaj.org/article/9bc1e20fa00e4a4fafdb662818770db42022-01-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2352345X21001697https://doaj.org/toc/2352-345XBackground & 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.Robim M. RodriguesYong HeSeonghwan HwangAdeline BertolaBryan MackowiakYeni Ait AhmedWonhyo SeoJing MaXiaolin WangSeol Hee ParkYukun GuanYaojie FuTamara VanhaeckeDechun FengBin GaoElsevierarticleNonalcoholic Fatty Liver Disease (NAFLD)SteatohepatitisNeutrophilsPaquinimodCXCL1Diseases of the digestive system. GastroenterologyRC799-869ENCellular and Molecular Gastroenterology and Hepatology, Vol 13, Iss 1, Pp 151-171 (2022)
institution	DOAJ
collection	DOAJ
language	EN
topic	Nonalcoholic Fatty Liver Disease (NAFLD) Steatohepatitis Neutrophils Paquinimod CXCL1 Diseases of the digestive system. Gastroenterology RC799-869
spellingShingle	Nonalcoholic Fatty Liver Disease (NAFLD) Steatohepatitis Neutrophils Paquinimod CXCL1 Diseases of the digestive system. Gastroenterology RC799-869 Robim M. Rodrigues Yong He Seonghwan Hwang Adeline Bertola Bryan Mackowiak Yeni Ait Ahmed Wonhyo Seo Jing Ma Xiaolin Wang Seol Hee Park Yukun Guan Yaojie Fu Tamara Vanhaecke Dechun Feng Bin Gao E-Selectin-Dependent Inflammation and Lipolysis in Adipose Tissue Exacerbate Steatosis-to-NASH Progression via S100A8/9Summary
description	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.
format	article
author	Robim M. Rodrigues Yong He Seonghwan Hwang Adeline Bertola Bryan Mackowiak Yeni Ait Ahmed Wonhyo Seo Jing Ma Xiaolin Wang Seol Hee Park Yukun Guan Yaojie Fu Tamara Vanhaecke Dechun Feng Bin Gao
author_facet	Robim M. Rodrigues Yong He Seonghwan Hwang Adeline Bertola Bryan Mackowiak Yeni Ait Ahmed Wonhyo Seo Jing Ma Xiaolin Wang Seol Hee Park Yukun Guan Yaojie Fu Tamara Vanhaecke Dechun Feng Bin Gao
author_sort	Robim M. Rodrigues
title	E-Selectin-Dependent Inflammation and Lipolysis in Adipose Tissue Exacerbate Steatosis-to-NASH Progression via S100A8/9Summary
title_short	E-Selectin-Dependent Inflammation and Lipolysis in Adipose Tissue Exacerbate Steatosis-to-NASH Progression via S100A8/9Summary
title_full	E-Selectin-Dependent Inflammation and Lipolysis in Adipose Tissue Exacerbate Steatosis-to-NASH Progression via S100A8/9Summary
title_fullStr	E-Selectin-Dependent Inflammation and Lipolysis in Adipose Tissue Exacerbate Steatosis-to-NASH Progression via S100A8/9Summary
title_full_unstemmed	E-Selectin-Dependent Inflammation and Lipolysis in Adipose Tissue Exacerbate Steatosis-to-NASH Progression via S100A8/9Summary
title_sort	e-selectin-dependent inflammation and lipolysis in adipose tissue exacerbate steatosis-to-nash progression via s100a8/9summary
publisher	Elsevier
publishDate	2022
url	https://doaj.org/article/9bc1e20fa00e4a4fafdb662818770db4
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E-Selectin-Dependent Inflammation and Lipolysis in Adipose Tissue Exacerbate Steatosis-to-NASH Progression via S100A8/9Summary

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