S-ADENOSYL-L-METHIONINE ATTENUATES LIVER INJURY IN AN ALCOHOL-LPS MODEL

Abstract

In vivo studies have shown that chronic alcoholism sensitizes the liver to endotoxemic shock leading to liver microcirculation disruption. Both LPS and chronic ethanol consumption increased hepatic sinusoidal contractile response to the constrictor effects of endothelin-1 (ET-1). The antioxidant S-adenosyl-L-methionine (SAMe) can attenuate and even prevent acute liver injury but very little is known about its role in chronic inflammatory disease progression. In this study we attempted to study the potential beneficial effects of SAMe on the liver microcirculation regulation in an alcohol-induced liver injury model. Male Sprague-Dawley rats were fed an alcohol liquid diet or a control isocaloric diet for 7 weeks with or without a daily injection of SAM (10 mg/kg b.w. i.p). Priming effects of ethanol were studied in a model with or without a semiweekly LPS treatment (1 mg/kg b.w. i.p.). At the end of the diet, animals receiving chronic ethanol and LPS (E-LPS) had an extensive steatosis and a mild infiltration as well as high levels of ALT and gained 66% more weight than animals under SAMe treatment (E-LPS-S). SAMe also significantly attenuated the steatohepatitis and liver injury as shown by the histology and the ALT levels. Alcohol feeding combined to a semiweekly LPS injection for 7 weeks resulted in HSC activation (upregulation of smooth muscle alpha actin, TGF beta and ET-1 RNA levels), and an upregulation of Caveolin-1. SAMe significantly decreased all these parameters when added to the alcohol and LPS treatment. In conclusion, our results demonstrate that chronic alcohol feeding combined with semiweekly LPS injection can induce a moderate liver fibrosis and injury combined with an imbalance in regulators of the liver microcirculation. Addition of SAMe to this chronic insult was able to significantly reduce hepatic injury and restore the balance of hepatic vasoregulators. These results suggest a close link between vascular dysregulation and progression of alcohol/LPS-induced liver injury. Supported by NIH grants AA14891 and DK38201.