Cell Mol Gastroenterol Hepatol. 2021 Aug 11. pii: S2352-345X(21)00169-7. [Epub ahead of print]
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.
BACKGROUND AND AIMS: Non-alcoholic steatohepatitis (NASH) is a leading cause of chronic liver disease, characterized by steatosis and hallmark liver neutrophil infiltration. NASH is also associated with adipose tissue (AT) inflammation, but the role of AT inflammation in NASH pathogenesis remains obscure. The aim of this study is to investigate the interplay between neutrophil recruitment in AT 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 E-selectin (Sele) and treatment with an S100A9 inhibitor (Paquinimod) were investigated using this model.
RESULTS: By analyzing transcriptomic datasets of AT 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 AT of NASH patients compared to those in patients with simple steatosis. A marked upregulation of Sele in AT was also 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 AT, which resulted in decreased serum free fatty acids and proinflammatory adipokines. S100A8/A9, a major proinflammatory protein secreted by neutrophils was highly elevated in AT of HFD+AdCxcl1 mice. This elevation was blunted in the Sele KO 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 AT, which subsequently promotes inflammation and lipolysis via the production of S100A8/A9, thereby exacerbating the steatosis-to-NASH progression. Targeting AT inflammation may therefore represent a potential novel therapy for treatment of NASH.
Keywords: CXCL1; Non-alcoholic fatty liver disease (NAFLD); Paquinimod; neutrophils; steatohepatitis