Public health officials and research scientists alike have a major responsibility to define the exact relationship between alcohol consumption, health, and morbidity. While recent evidence suggests that low to moderate alcohol intake may protect against heart disease through elevations in high density lipoproteins (HDL), it is also well established that alcohol abuse is associated with profound metabolic abnormalities. Unfortunately the dose-response relationship between ethanol (ETOH) expressed as a caloric percentage and HDL levels, and the transition point between beneficial and detrimental doses of alcohol has not been well defined. Similarly, the consequences of chronic alcohol use followed by abstinence and the effect on HDL needs further clarification. The study's long-term objective is to elucidate the molecular mechanism(s) by which ETOH can either potentiate or diminish HDL's anti-atherogenic properties. The working hypotheses are that: 1) dietary ETOH at increasing caloric concentrations causes dose-related modifications in liver function and sex hormones (estradiol/testosterone) (E/T) which alter lipoprotein synthesis and catabolism by modulating the activity of key lipolytic enzymes, hepatic triglyceride lipase (HTGL) and lipoprotein lipase (LPL), thus leading to alterations in HDL subfractions (HDL2/HDL3); and 2)abstinence reverses ethanol-induced liver and circulatory changes over a specific time sequence. The methods to test these hypotheses include: 1) feeding liquid diet plus ETOH at 6-36% of calories to male atherosclerosis-susceptible primates; 2) measuring HDL2/HDL3, apoprotein A-I, E/T, HTGL/LPL and liver function (SGOT,GGT) and relating these to blood ETOH; 3) performing two key in vivo HDL synthesis and catabolism studies; and 4) withdrawing dietary ETOH, remeasuring these parameters and defining the time sequence for regression to baseline levels. This study represents the first comprehensive effort to document the underlying biochemical events associated with low-moderate ETOH induction of a protective lipoprotein profile, and the transition to potentially pathophysiological alterations in HDL metabolism at higher alcohol doses using a nonhuman primate model with great clinical relevance to man.
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