Deleting Fn14 inhibits hepatic cytokine induction, reduces steatohepatitis severity, blocks accumulation of progenitors and myofibroblasts (a.k.a, the ductular reaction), and reduces liver fibrosis. This suggests that Fn14-positive progenitors promote fibro-inflammatory responses during acute alcoholic hepatitis and identifies Tweak/Fn 14 as a potential target in this disease. Disclosures: Linda C. Burkly – Employment: Biogen Idec, Inc.; Stock Shareholder: Biogen Idec, Inc. Anna Mae Diehl – Consulting: Bristol Myers
Squibb, BTK inhibitor ic50 Synergy, GlaxoSmithKline, Norgine; Grant/Research Support: GlaxoSmithKline The following people have nothing to disclose: Gamze Karaca, Guanhua Xie, Marzena Swiderska-Syn, Gregory A. Michelotti, Steve S. Choi We previously reported that chronic ethanol intake lowers hepatocellular S-adenosylmethionine (SAM) to S-adenosylho-mocysteine Erlotinib (SAH) ratios and significantly impairs many essential liver transmethylation reactions catalyzed by specific SAM-dependent methyltransferases.
One such enzyme is guani-dinoacetate methyltransferase (GAMT) that catalyzes the transfer of a methyl group from SAM to guanidinoacetate (GAA) to form creatine. Hepatic GAMT is a major consumer of methyl groups and utilizes as much as 40% of the SAM-derived methyl groups. In the past few decades, ingestion of methyl-consuming compounds has substantially increased primarily due to pollution, food additives, niacin fortification and high meat consumption putting additional stresses on cellular methylation potential. The purpose of our study was to investigate the role that increased methyl consumption, either alone or combined with alcohol consumption, could play in the pathogenesis of liver injury. Because of our interest in GAMT-catalyzed reaction, we chose GAA as a potent methyl group
consumer. Adult male Wistar rats were pair-fed the Lieber DeCarli Ureohydrolase control or ethanol diet in the presence or absence of 0.36% GAA in these respective diets for 2 weeks. At the end of the feeding regimen, the rats were sacrificed and blood and livers were collected and processed for biochemical and histological analyses. We observed microvescicular steatosis and a 7 fold-increased triglyceride accumulation in the livers of rats fed the ethanol-alone diet for 2 weeks as compared to controls. GAA administration alone resulted in similar changes as the ethanol fed group but to a lesser extent, only a 4-fold increased triglyceride accumulation compared to controls was observed. However, supplementing GAA in the ethanol diet produced a marked decrease in the methylation potential as evident from a significantly lower hepatocellular SAM:SAH ratio, panlobular macro-and micro-vesicular steatosis and a 28-fold increased triglyceride accumulation as compared to the control group. These GAA-supplemented ethanol diet-fed rats displayed inflammatory changes as indicated by the histological presence of lipogranulomas and microgranulomas.