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

in Journal of Endocrinology
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  • 1 Department of Nutrition and Food Science, Texas A&M University, College Station, Texas, USA
  • 2 Department of Endocrinology, Renmin Hospital, Wuhan University, Wuhan, Hubei, China
  • 3 Department of Endocrinology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
  • 4 The Laboratory of Lipid & Glucose Metabolism, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
  • 5 Department of Geriatrics, Nanjing Drum Tower Hospital, the Affiliated Nanjing Hospital of Nanjing University Medical School, Nanjing, Jiangshu, China
  • 6 Department of Endocrinology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
  • 7 Department of Cardiology, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China
  • 8 Vascular Biology Center, Department of Cellular Biology and Anatomy, Medical College of Georgia, Augusta University, Augusta, Georgia, USA
  • 9 Beijing Advanced Innovation Center for Food Nutrition and Human Health, College of Food Science & Nutritional Engineering, China Agricultural University, Beijing, China
  • 10 Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station, Texas, USA
  • 11 Nebraska Center for Virology, School of Biological Sciences, University of Nebraska-Lincoln, Lincoln, Nebraska, USA

Correspondence should be addressed to C Wu: cdwu@tamu.edu

*(J Zhou and H Li contributed equally to this work)

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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 lipopolysaccharide-induced 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.

 

      Society for Endocrinology

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