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

Jing Zhou, Honggui Li, Yuli Cai, Linqiang Ma, Destiny Matthews, Bangchao Lu, Bilian Zhu, Yanming Chen, Xiaoxian Qian, Xiaoqiu Xiao, Qifu Li, Shaodong Guo, Yuqing Huo, Liang Zhao, Yanan Tian, Qingsheng Li, Chaodong Wu

Research output: Contribution to journalArticle

3 Scopus citations

Abstract

Adenosine 2A receptor (A2AR) exerts a protective role in obesity-related non-alcoholic fatty liver disease. Here, we examined whether A2AR 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 A2AR-positive macrophages/Kupffer cells in liver sections although decreasing A2AR amount in liver lysates compared with chow diet feeding. Next, MCD-induced NASH phenotype was examined in A2AR-disrupted mice and control mice. Upon MCD feeding, A2AR-disruptd mice and control mice displayed comparable decreases in body weight and fat mass. However, MCD-fed A2AR-disrupted mice revealed greater liver weight and increased severity of hepatic steatosis compared with MCD-fed control mice. Moreover, A2AR-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. In vitro, 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 lipopolysaccharideinduced phosphorylation states of p38 and NFκB p65 in A2AR-deficient macrophages, but insignificantly decreased lipopolysaccharide-induced phosphorylation states of JNK p46 and NFκB p65 in A2AR-deficient hepatocytes. Collectively, these results suggest that A2AR disruption exacerbates MCD-induced NASH, which is attributable to, in large part, increased inflammatory responses in macrophages.

Original languageEnglish (US)
Pages (from-to)199-209
Number of pages11
JournalJournal of Endocrinology
Volume243
Issue number3
DOIs
StatePublished - Dec 2019

Keywords

  • Adenosine 2A Receptor
  • Lipodystrophy
  • Macrophage
  • Non-Alcoholic Steatohepatitis

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Endocrinology

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  • Cite this

    Zhou, J., Li, H., Cai, Y., Ma, L., Matthews, D., Lu, B., Zhu, B., Chen, Y., Qian, X., Xiao, X., Li, Q., Guo, S., Huo, Y., Zhao, L., Tian, Y., Li, Q., & Wu, C. (2019). Mice lacking adenosine 2A receptor reveal increased severity of MCD-induced NASH. Journal of Endocrinology, 243(3), 199-209. https://doi.org/10.1530/JOE-19-0198