MECHANISMS OF ACTIONS OF ALCOHOL AND OMEGA3 FATTY ACIDS

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APPLICANT'S ABSTRACT: Plasma apolipoprotein E (apoE) is a glycoprotein which plays important roles in "Reverse Cholesterol Transport" (RCT) functions of HDL, viz., (i) cholesterol removal from peripheral tissues and/or (ii) its delivery to the liver. Significantly, ethanol decreased plasma HDL apoE, whereas omega3-fatty acids prevented this decrease. Our preliminary work shows that plasma HDL apoE is also reduced in human alcoholics. We have further shown that chronic ethanol inhibits hepatic sialation of apoE. Sialic acid deficiency in apoE may affect its association with HDL. In turn, the loss of apoE from HDL may impair its RCT functions. Therefore, it is important to confirm whether apoE concentration in HDL and sialic acid content of apoE are reduced in alcoholics and then show how these changes affect HDL metabolism and functions. 90% of the study will utilize humans and only the remainder will use rats:Human Study: ApoE and HDL will be from sera of human alcoholics and non-alcoholics and non-alcoholics. The specific questions are: Does the degree of sialic acid deficiency in apoE affect (I) the association of apoE with HDL and (II) dissociation of apoE from HDL & association of HDL- apoE with cholesterol. III. does the loss of apoE from HDL affect its ability to remove cholesterol from peripheral tissues? Do human alcoholics compared to non-alcoholics have decreased: IV. concentration of apoE in HDL? V. sialic acid content of HDL-apoE? VI. HDL ability to remove cholesterol from the peripheral tissues using human macrophages?VII. HDL ability to deliver cholesterol to liver using the human HepG2 liver cells?Rat Study: If apoE sialation is crucial in the above important aspects of HDL it is equally important to determine the post-translational modifications of apoE in the liver. This can only be done in experimental animals like rats.Similarly, if omega3- fatty acids do correct the above defects caused by ethanol it is simpler and less time consuming to test their effects on HDL-apoE functions in rats than in humans. Thus, the questions asked are what are the influences of ethanol and omega3-fatty acids on: VIII. the posttranslational modifications of apoE at the subcellular level? IX. the mechanism of inhibition of hepatic sialyltransferase activity? Specifically, does ethanol inhibit the synthesis of sialyltransferase and by down regulation of its hepatic mRNA levels?