This project will investigate the intracellular metabolism of fatty acid ethyl esters (FAEE). These lipid molecules are produced in many tissues during alcohol consumption. Experiments will focus on events in the liver, notably in hepatocytes. The cellular metabolism and transport of FAEE will also be examined in the pancreas. Effects of alcohol on the structure and function of lipid droplet subpopulations will be identified. It is hypothesized that significant amount of FAEE synthesized in the liver and pancreas are deposited in triglyceride-rich lipid droplets and that the liver secretes a fraction of its FAEE in lipoprotein particles. It is also hypothesized that FAEE are transported in cells by lipid binding proteins, which are involved in FAEE deposition and mobilization, and that the mobilization process is one of the regulators of the cellular FAEE content.
Six specific aims are projected to test these hypotheses and to dissect the molecular mechanisms. 1. To quantify the ethanol-induced deposition of FAEE and other lipids in lipid droplet subpopulations in the liver. 2. To determine the mechanisms by which FAEE are mobilized from storage sites in hepatocellular lipid droplets. 3. To determine the mechanism(s) of intracellular FAEE transport in the liver. 4. To quantify the secretion of FAEE by the liver in VLDL particles. 5. To define the cellular and metabolic dynamics of FAEE synthesis, deposition, transport and mobilization in the pancreas. 6. To determine the extent to which the metabolism and transport of fatty acid propyl esters (FAPE) and fatty acid butyl esters (FABE) resembles that of FAEE. Biochemical and electron microscopic techniques will be employed throughout. Definition of the alcohol-induced molecular and ultrastructural events in these organs should promote development of strategies for the prevention and treatment of alcoholic liver and pancreatic disease.
