Second-hand smoke stimulates lipid accumulation in the liver by modulating AMPK and SREBP-1

Background/Aims: The underlying mechanisms of steatosis, the first stage of non-alcoholic fatty liver disease (NAFLD) that is characterized by the accumulation of lipids in hepatocytes, remain unclear. Our study aimed to investigate the hypothesis that cigarette smoke is known to change circulating lipid profiles and thus may also contribute to the accumulation of lipids in the liver. Methods: Mice and cultured hepatocytes were exposed to sidestream whole smoke (SSW), a major component of second-hand smoke and a variety of cellular and molecular approaches were used to study the effects of cigarette smoke on lipid metabolism. Results: SSW increases lipid accumulation in hepatocytes by modulating the activity of 5'-AMP-activated protein kinase (AMPK) and sterol response element binding protein-1 (SREBP-1), two critical molecules involved in lipid synthesis. SSW causes dephosphorylation/inactivation of AMPK, which contributes to increased activation of SREBP-1. These changes of activity lead to accumulation of triglycerides in hepatocytes. Conclusion: These novel findings are important because they point to another risk factor of smoking, i.e., that of contributing to NAFLD. In addition, our results showing that both AMPK and SREBP are critically involved in these effects of smoke point to the potential use of these molecules as targets for treatment of cigarette smoke-induced metabolic diseases. (C) 2009 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.