Mice lacking adenosine 2A receptor reveal increased severity of MCD-induced NASH release_ljwjah5wjnbf5lhxw4kwyx47oa

by Jing Zhou, Honggui Li, Yuli Cai, Linqiang Ma, Destiny Mathews, Bangchao Lu, Bilian Zhu, Yanming Chen, Xiaoxian Qian, Xiaoqiu Xiao, Qifu Li, Shaodong Guo (+5 others)

Published in Journal of Endocrinology by Bioscientifica.

2019  

Abstract

Adenosine 2A receptor (A<jats:sub>2A</jats:sub>R) exerts a protective role in obesity-related non-alcoholic fatty liver disease. Here, we examined whether A<jats:sub>2A</jats:sub>R protects against non-alcoholic steatohepatitis (NASH). In C57BL/6J mice, feeding a methionine- and choline-deficient diet (MCD) resulted in significant weight loss, overt hepatic steatosis, and massive aggregation of macrophages in the liver compared with mice fed a chow diet. MCD feeding also significantly increased the numbers of A<jats:sub>2A</jats:sub>R-positive macrophages/Kupffer cells in liver sections although decreasing A<jats:sub>2A</jats:sub>R amount in liver lysates compared with chow diet feeding. Next, MCD-induced NASH phenotype was examined in A<jats:sub>2A</jats:sub>R-disrupted mice and control mice. Upon MCD feeding, A<jats:sub>2A</jats:sub>R-disruptd mice and control mice displayed comparable decreases in body weight and fat mass. However, MCD-fed A<jats:sub>2A</jats:sub>R-disrupted mice revealed greater liver weight and increased severity of hepatic steatosis compared with MCD-fed control mice. Moreover, A<jats:sub>2A</jats:sub>R-disupted mice displayed increased severity of MCD-induced liver inflammation, indicated by massive aggregation of macrophages and increased phosphorylation states of Jun-N terminal kinase (JNK) p46 and nuclear factor kappa B (NFκB) p65 and mRNA levels of tumor necrosis factor alpha, interleukin-1 beta, and interleukin-6. <jats:italic>In vitro,</jats:italic> incubation with MCD-mimicking media increased lipopolysaccharide (LPS)-induced phosphorylation states of JNK p46 and/or NFκB p65 and cytokine mRNAs in control macrophages and RAW264.7 cells, but not primary hepatocytes. Additionally, MCD-mimicking media significantly increased lipopolysaccharide-induced phosphorylation states of p38 and NFκB p65 in A<jats:sub>2A</jats:sub>R-deficient macrophages, but insignificantly decreased lipopolysaccharide-induced phosphorylation states of JNK p46 and NFκB p65 in A<jats:sub>2A</jats:sub>R-deficient hepatocytes. Collectively, these results suggest that A<jats:sub>2A</jats:sub>R disruption exacerbates MCD-induced NASH, which is attributable to, in large part, increased inflammatory responses in macrophages.
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Type  article-journal
Stage   published
Date   2019-09-01
Language   en ?
DOI  10.1530/joe-19-0198
PubMed  31505462
PMC  PMC7050433
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ISSN-L:  0022-0795
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