Adenosine signaling contributes to ethanol-induced fatty liver in mice
Zhongsheng Peng, … , Giuseppe Resta, Bruce N. Cronstein
Zhongsheng Peng, … , Giuseppe Resta, Bruce N. Cronstein
Published February 16, 2009
Citation Information: J Clin Invest. 2009;119(3):582-594. https://doi.org/10.1172/JCI37409.
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Research Article Gastroenterology

Adenosine signaling contributes to ethanol-induced fatty liver in mice

Abstract

Fatty liver is commonly associated with alcohol ingestion and abuse. While the molecular pathogenesis of these fatty changes is well understood, the biochemical and pharmacological mechanisms by which ethanol stimulates these molecular changes remain unknown. During ethanol metabolism, adenosine is generated by the enzyme ecto-5′-nucleotidase, and adenosine production and adenosine receptor activation are known to play critical roles in the development of hepatic fibrosis. We therefore investigated whether adenosine and its receptors play a role in the development of alcohol-induced fatty liver. WT mice fed ethanol on the Lieber-DeCarli diet developed hepatic steatosis, including increased hepatic triglyceride content, while mice lacking ecto-5′-nucleotidase or adenosine A1 or A2B receptors were protected from developing fatty liver. Similar protection was also seen in WT mice treated with either an adenosine A1 or A2B receptor antagonist. Steatotic livers demonstrated increased expression of genes involved in fatty acid synthesis, which was prevented by blockade of adenosine A1 receptors, and decreased expression of genes involved in fatty acid metabolism, which was prevented by blockade of adenosine A2B receptors. In vitro studies supported roles for adenosine A1 receptors in promoting fatty acid synthesis and for A2B receptors in decreasing fatty acid metabolism. These results indicate that adenosine generated by ethanol metabolism plays an important role in ethanol-induced hepatic steatosis via both A1 and A2B receptors and suggest that targeting adenosine receptors may be effective in the prevention of alcohol-induced fatty liver.

Authors

Zhongsheng Peng, Pier Andrea Borea, Tuere Wilder, Herman Yee, Luis Chiriboga, Michael R. Blackburn, Gianfranco Azzena, Giuseppe Resta, Bruce N. Cronstein

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Figure 2

Deletion of adenosine A1 or A2B receptors protects mice from developing ethanol-induced fatty liver.

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Deletion of adenosine A1 or A2B receptors protects mice from developing ...
Eight-week-old male mice (WT, A1KO, A2BKO, A2AWT, and A2AKO mice) were fed a liquid diet containing ethanol or an equal caloric diet containing maltose for 6 weeks and then sacrificed. The livers and bodies of the mice were weighed on the day of sacrifice and the liver/total body weight ratio was calculated. The serum AST and triglyceride and hepatic tissue triglyceride levels were also measured, as described in Methods. The hepatic steatosis grade was based on the percentage of steatotic hepatocytes in the H&E-stained liver sections. (A) H&E-stained liver sections from maltose- and ethanol-treated A1KO, A2BKO, A2AWT, and A2AKO mice (original magnification, ×400). (B) Oil Red O–stained liver sections from ethanol-treated A1KO and A2BKO mice (original magnification, ×400). (C) Hepatic steatosis grades of ethanol-treated WT, A1KO, A2BKO, A2AWT, and A2AKO mice. Steatosis grades in maltose-treated WT, A1KO, A2BKO, A2AWT, and A2AKO mice were 0. (D) Liver/body weight ratio. (E) Serum AST levels. (F) Serum triglyceride levels. (G) Hepatic tissue triglyceride levels. #P < 0.01, A1KO mice or A2BKO mice versus WT mice, respectively; *P < 0.01, ethanol mice versus control mice in different groups, respectively; **P < 0.01, ethanol KO mice versus control KO mice or control WT mice or ethanol WT mice, respectively; n = 5–10 for each group of mice.