E-Selectin-Dependent Inflammation and Lipolysis in Adipose Tissue Exacerbate Steatosis-to-NASH Progression via S100A8/9
| Autor: | Adeline Bertola, Yeni Ait-Ahmed, Jing Ma, Bin Gao, Yukun Guan, Dechun Feng, Tamara Vanhaecke, Robim Marcelino Rodrigues, Bryan Mackowiak, Yaojie Fu, Xiaolin Wang, Wonhyo Seo, Seonghwan Hwang, Seol Hee Park, Yong He |
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| Přispěvatelé: | Pharmaceutical and Pharmacological Sciences, Experimental in vitro toxicology and dermato-cosmetology |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
HFD
high-fat diet Neutrophils AdCxcl1 adenovirus-Cxcl1 Adipose tissue MPO myeloperoxidase RC799-869 AST aspartate aminotransferase PAQ Paquinimod Mice Rbp4 retinol binding protein 4 SELE E-selectin Non-alcoholic Fatty Liver Disease RT-qPCR reverse-transcription quantitative polymerase chain reaction Original Research Steatohepatitis biology Gastroenterology IGFBP1 insulin-like growth factor-binding protein 1 ELISA enzyme-linked immunosorbent assay Diseases of the digestive system. Gastroenterology CXCL1 mRNA messenger RNA MRP myeloid-related protein Adipose Tissue GTT glucose tolerance test medicine.symptom E-Selectin NASH nonalcoholic steatohepatitis SELP P-selectin medicine.medical_specialty TSEC immortalized liver sinusoidal endothelial cell line Lipolysis Adipokine Inflammation digestive system Proinflammatory cytokine ANGPTL3 angiopoietin-like protein 3 Internal medicine ALT alanine aminotransferase E-selectin FFA free fatty acid medicine Animals Humans ITT insulin tolerance test KO knockout Hepatology business.industry nutritional and metabolic diseases CXCL1 C-X-C motif chemokine ligand 1 medicine.disease Nonalcoholic Fatty Liver Disease (NAFLD) SELL L-selectin WT wild-type digestive system diseases IL interleukin Mice Inbred C57BL Endocrinology biology.protein NAFLD nonalcoholic fatty liver disease Steatosis Paquinimod business |
| Zdroj: | Cellular and Molecular Gastroenterology and Hepatology Cellular and Molecular Gastroenterology and Hepatology, Vol 13, Iss 1, Pp 151-171 (2022) |
| Popis: | 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. Graphical abstract |
| Databáze: | OpenAIRE |
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