DESCRIPTION (provided by applicant): Control of hepatic lipid metabolism is regulated by the transcription factors sterol response element binding protein (SREBP) and peroxisome proliferator activated receptor (PPAR) alpha. Activation of SREBP induces a battery of enzymes involved in lipid synthesis, including acetyI-CoA carboxylase (ACC). The product of ACC, malonyI-CoA, inhibits fatty acid oxidation by inhibiting carnitine palmitoyl acyltransferase, the enzymatic step required for entry of long chain fatty acids into the mitochondrion. Conversely, PPAR activates a battery of genes encoding enzymes involved in the oxidation of fatty acids. Fatty acid synthesis proceeds when there are excess carbon atoms and energy sources, and fatty acid oxidation occurs when energy is needed. AMP kinase (AMPK) has emerged as an important sensor of the energy state and regulator of intermediary metabolism in liver. AMPK inhibits SREBP and ACC activity. Ethanol treatment of cultured cells and of mice activates SREBP and ACC and reduces the abundance and activity of AMPK. We hypothesize that the effect of ethanol on AMPK is central to its other effects on lipid metabolism. To fully understand this effect of ethanol, which may be of fundamental importance in the pathogenesis of alcoholic fatty liver, we will investigate the mechanisms of inhibition of AMPK by ethanol. There are two broad mechanisms we will study: 1) that ethanol, as a source of carbon and reducing equivalents, inhibits the enzyme via increasing the energy charge of the cell or 2) that ethanol or its metabolites alters signaling pathways that impinge on AMPK, such as oxidative stress signaling and alterations in calcium and PKC activity. We will also examine whether AMPK and PPARa are coordinately regulated by ethanol and if the inhibition of AMPK by ethanol is modulated by the presence of saturated fatty acids. These studies will illuminate this interesting new mechanism for ethanol control of liver metabolism and offers potentials for therapy of alcoholic fatty liver. It may also shed light on the pathogenesis of non-alcoholic fatty liver disease.