Hyperlipidemia and fatty infiltration of the liver are characteristics of chronic alcohol abuse these pathological manifestations are due to 1. increased VLDL synthesis 2. defective catabolism of triglyceride-rich (TGR) lipoproteins both in the liver and peripheral tissues. 3. Production of abnormal remnants which show defective feed-back regulation of hepatic lipid synthesis 4. impaired binding and uptake of remnants by the liver and 5. defective hepatic catabolism of the lipid moieties of the remnants recently, W-3 fatty acid feeding has been shown to be very effective in the treatment of genetic hyperlipidemia such as type IIB and type V by lowering plasma lipids. The possible mechanisms of action of W-3 fatty acids are to cause (A) decreased synthesis of VLDL and chylomicrons and (B) increased rates of degradation of VLDL and chylomicrons. Thus, the actions of W-3 fatty acids seen to be just the opposite of those of ethanol abuse. Therefore, it would be pertinent and clinically relevant to test whether W-3 fatty acid feeding would reverse many of the adverse effects of alcohol abuse on lipid and lipoprotein metabolism using the rat as the animal model. The present proposal seeks to explore not only the hypolipidemic effects of W-3 fatty acid but also their possible mechanisms of action with respect to alcoholic hyperlipidemia by answering the following key questions: 1a. Does the isocaloric replacement of normal dietary fat with fish oils prevent the development of fatty liver and hyperlipidemia associated with chronic ethanol feeding? 1b. How do these results correlate with the effects of fish oil in control rats? 2. Conversely, can the ethanol induced fatty liver and hyperlipidemia be restored to normolipidemic state by fish oils? 3. Does W-3 fatty acid feeding affect the rate of production of chylomicrons in chronic ethanol-fed & control rats? 4. How does W-3 fatty acid feeding affect the extra-hepatic metabolism of TGR lipoproteins in chronic ethanol-fed control rats? 5. How does W- 3 fatty acid feeding affect the hepatic metabolism of TGR lipoproteins in chronic ethanol-fed & control rats? 6. Does the feeding of W-3 fatty acids alter the normal feed-back regulation of hepatic lipid synthesis by chylomicron remnants in chronic ethanol-fed & control rats? The following experimental systems and procedures, in which the PI has expertise, will be employed to accomplish the above goals and objectives: A. in vivo systems involving cannulate of the thoracic duct, jugular vein, carotid artery, and other techniques described in proposal. B. In vitro systems such as perfused liver, perfused heart, and hepatocytes. C. Polyacrylamide gel electrophoresis. D. tracer techniques, and E. Immunonephelometry.
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