Exacerbation of NAFLD in both HFD-fed Mice and MCD-fed Mice by Adenosine 2A Receptor Deficiency Conference Paper uri icon

abstract

  • Nonalcoholic fatty liver disease (NAFLD) is an essential component of metabolic syndrome. Much evidence has demonstrated that the incidence of NAFLD is markedly increased in obese populations. In addition, adiposity and inflammation are two factors that critically contribute to the development and progression of hepatic steatosis and inflammatory damage in obesityassociated NAFLD. While mediating the antiinflammatory activity of adenosine, the 2A receptor of adenosine (A2AR) also has a protective role in NAFLD. However, it remains largely unknown about the extent to which A2AR acts through altering adiposity vs. inflammation to protect against NAFLD. In the present study, the effects of A2AR deficiency on aspects of NAFLD were investigated in both obese mice and lean mice upon feeding wildtype (WT) C57BL/6J mice and A2ARdeficent mice a highfat diet (HFD) and/or a methionine and cholinedeficient diet (MCD). Compared with lowfat dietfed mice, HFDfed WT mice displayed overt hepatic steatosis and inflammation as indicated by increased proinflammatory signaling and cytokine expression. Furthermore, the severity of HFDinduced hepatic steatosis and inflammation in A2ARdeficient mice was much greater than that in WT mice, which was accompanied with increased body weight, adiposity, and adipose tissue infiltration of proinflammatory macrophages in HFDfed A2ARdeficient mice. Unlike HFDfed mice, all MCDfed mice displayed lean phenotype due to a significant decrease in food intake. In the absence of adiposity, A2ARdeficient mice still displayed a greater increase in the severity of hepatic steatosis and inflammation compared with WT mice. In an in vitro system, A2ARdeficient macrophages showed an increase in proinflammatory responses compared with control cells. In addition, coculture of WT primary mouse hepatocytes with A2ARdeficient macrophages caused significant increases in hepatocyte fat deposition and in hepatocyte proinflammatory responses compared with WT hepatocytemacrophage cocultures. Taken together, these results suggest that A2ARdefiencyassociated inflammation is sufficient enough to bring about NAFLD aspects although A2AR deficiency can act through increasing both adiposity and inflammation to exacerbate NAFLD. Therefore, A2AR appears to protect against NAFLD mainly through its antiinflammatory activity.Support or Funding InformationThis study was support in part by NIH grants.

published proceedings

  • FASEB JOURNAL

author list (cited authors)

  • Cai, Y., Zheng, J., Guo, X., Li, H., Pei, Y. a., Botchlett, R., ... Wu, C.

citation count

  • 0

complete list of authors

  • Cai, Yuli||Zheng, Juan||Guo, Xin||Li, Honggui||Pei, Ya||Botchlett, Rachel||Woo, Shih-Lung||Liu, Mengyang||Chen, Guang||Huo, Yuqing||Wu, Chaodong

publication date

  • April 2016

publisher