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

Abstract

E-selectin, a key adhesion molecule for neutrophils, is highly up-regulated in adipose tissue of nonalcoholic steatohepatitis patients compared with individuals with fatty liver. Deletion of the E-selectin gene or inhibition of neutrophilderived S100A9 in mice ameliorated adipose tissue inflammation, improving nonalcoholic steatohepatitis.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 þAdCxcl1 ). 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 upregulated 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 þAdCxcl1 mice. The HFD þAdCxcl1 -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 þAdCxcl1 mice. This increase was blunted in the Sele knockout mice. Therapeutically, treatment with the S100A 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.

Role of Neutrophils in the Pathogenesis of Nonalcoholic Steatohepatitis

“…S100 calcium-binding protein A8 (S100A8, also known as MRP8) and S100 calcium-binding protein A9 (S100A9, also known as MRP14) are Ca 2+ -binding proteins that constitute 40% of neutrophil cytosolic protein weight. Their roles in NASH have also been discussed ( 128 ). In addition, neutrophils can produce a large number of inflammatory cytokines, chemokines, and inflammatory mediators, which likely play an important role in controlling NASH development and progression ( 129 ).…”

“…As it has been increasingly recognized that the crosstalk between the liver and adipose tissue plays a crucial role in NASH development, it is reasonable to further examine the role of adipose tissue proteins S100A8/A9 in NASH development. Indeed, S100A8 and S100A9 are upregulated in the adipose tissue samples of NASH patients and CXCL1-induced experimental NASH models, and the administration of paquinimod, a S100A9 inhibitor, attenuated the CXCL1-induced NASH in mice ( 128 ). This finding further supports the possibility that neutrophil-derived specific molecules might be implicated in the crosstalk between organs that exacerbates NASH.…”

Exploratory Investigation of the Plasma Proteome Associated with the Endotheliopathy of Trauma

“…DAMP-induced damage can, in turn, generate DAMPs and precipitate self-perpetuating physiologic disarray in injured patients. A variety of potential pharmacological therapeutics exist with the potential to arrest these DAMP-related pathophysiological processes in trauma [ 54 , 74 , 75 , 76 , 77 , 78 , 79 , 80 , 81 , 82 , 83 , 84 , 85 , 86 ].…”

Therapeutic potential of traditional Chinese medicine for the treatment of NAFLD: A promising drug Potentilla discolor Bunge

“…Hepatocyte death is one of the crucial triggers of liver inflammation in NAFLD progression 14 . It has been recently found that E-selectin-mediated neutrophil recruitment promotes inflammation and lipolysis in adipose tissue, thereby inducing the release of free fatty acids and proinflammatory adipokines that exacerbate the steatosis-to-NASH progression 22 .…”