The adiponectin-SIRT1-AMPK pathway in alcoholic fatty liver disease in the rat.

Abstract

Our previous work showed that binge drinking in the rat induced hepatic steatosis which correlated with reduced expression of AMP-activated protein kinase (AMPK). In this study, we used the rat model to investigate the role of adiponectin (Adip), sirtuin 1 (SIRT1), AMPK, and lipin 1 (LIP 1) signaling, a central controlling pathway of lipid metabolism in hepatic steatosis. The serum Adip and tumor necrosis factor-alpha (TNF-α) as well as liver Adip receptors (AdipoR1 and AdipoR2) SIRT1, AMPK, phosphorylated AMPK (p-AMPK), sterol regulatory element-binding proteins (SREBPs), acetyl-CoA carboxylase (ACC), LIP 1, lipocalin-2 (LCN2), and serum amyloid A1 were assessed in the rat model where 16weeks of gavaged alcohol were administered. In this model of ethanol (EtOH) administration, hepatic steatosis, necrosis, as well as inflammation were increased over the 16-week period. The level of TNF-α in the serum was increased while the Adip content decreased significantly, and there was an inverse relationship between the content of TNF-α and Adip. The mRNA and protein expression of AdipoR2, SIRT1, and AMPK was suppressed by EtOH in the rats' hepatic tissue. Additionally, EtOH significantly decreased p-AMPK by 90% over the 16-week period. In parallel, there was a 2.53- and 1.82-fold increase of lipogenic genes SREBP1c and ACC, and a 3.22- and 4.12-fold increase of LIP 1 and LIP 1 β mRNA expression, respectively, in the hepatic tissue of the rats. Our present observations demonstrate that the impaired Adip-SIRT1-AMPK signaling pathway contributes, at least in part, to the development of alcoholic fatty liver disease in EtOH binge rats.