title: Adenosine: tipping the balance towards hepatic steatosis and fibrosis.
abstract: Fatty liver is commonly associated with alcohol ingestion and abuse. While the molecular pathogenesis of these fatty changes is well understood, the histochemical 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.affiliation: Division of Gastroenterology and Hepatology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
authors.forename: Simon C
authors.initials: SC
authors.lastname: Robson
authors.forename: Detlef
authors.initials: D
authors.lastname: Schuppan
references.citation: Hepatology. 2009 Oct;50(4):1294-306
references.pmid: 19711424
references.citation: Front Biosci. 2008 Jan 01;13:2588-603
references.pmid: 17981736
references.citation: Arterioscler Thromb Vasc Biol. 2007 May;27(5):1004-13
references.pmid: 17332491
references.citation: Nucleosides Nucleotides Nucleic Acids. 2008 Jun;27(6):821-4
references.pmid: 18600546
references.citation: J Clin Invest. 1993 Dec;92(6):2675-82
references.pmid: 8254024
references.citation: Mol Pharmacol. 2007 Dec;72(6):1626-36
references.pmid: 17872970
references.citation: Br J Pharmacol. 2008 Mar;153 Suppl 1:S457-64
references.pmid: 18311159
references.citation: Diabetes. 2008 Sep;57(9):2311-20
references.pmid: 18567823
references.citation: FASEB J. 2008 Jul;22(7):2263-72
references.pmid: 18263696
references.citation: J Clin Invest. 2009 Mar;119(3):582-94
references.pmid: 19221436
references.citation: Am J Physiol Gastrointest Liver Physiol. 2007 Jan;292(1):G395-401
references.pmid: 17053161
references.citation: Gastroenterology. 1999 Apr;116(4):964-79
references.pmid: 10092320
references.citation: Gastroenterology. 2008 Jan;134(1):292-305
references.pmid: 18036594
references.citation: Hepatology. 2010 Jan;51(1):201-9
references.pmid: 20034049