A comprehensive understanding of ethanol's (ETOH) effect on lipoproteins (LP) and coronary heart disease (CHD) must address: 1) ETOH dose; 2) drinking pattern; 3) ETOH-tobacco interaction; 4) sex hormone alterations; and 5) caloric balance/body composition changes. Consequently, the long-term study objectives are to determine how ETOH and oral nicotine (NIC) either potentiate or diminish low density lipoprotein's (LDL) atherogenic and high density lipoprotein's (HDL2)cardioprotective properties, and to identify predictive markers of disturbances in LP's sex hormones, and body composition which appear during drug administration and abstinence. This investigation has important health implications in view of differences in CHD in moderate vs. heavy drinkers, the prevalent binge drinking pattern in young men, ETOH/nutrient deficiencies (alcoholism) or excesses (obesity), resurgence in smokeless tobacco use and the residual CHD risk in ex-smokers. Conflicting results in human ETOH-tobacco studies because of variable dietary factors (fat, calories), hepatic dysfunction, and imprecise drug intake estimates point to the value of controlled regimens and primate models which closely mimic humans in drug response. Atherosclerosis-susceptible squirrel monkeys are well suited for these experiments since they have normal liver function but show divergent responses when given liquid diet plus ETOH and NIC: 1) moderate ETOH (12% kcal): HDL2/HDL3 ratio, LDL, normal testosterone (T) and growth rate, plasma ETOH 49 mg/dl; 2) high ETOH (24%): HDL2/HDL3 LDL, T, body wt.m plasma ETOH 142 mg/dl; and 3) oral NIC (6 mg/kg/d): HDL, LDL, body wt., plasma NIC 66 ng/ml. Based on thsi model, the specific aims are: 1) to assess whether favorable (12%) vs. deleterious (24%) ETOH induced LP profiles result form alterations in LDL physicochemistry (heterogeneity), in vivo receptor vs. nonrecrptor LDL clearance, and the reverse cholesterol transport process (cholesterol esterification, lipid transfer); 2) to evaluate whether 12% ETOH consumed during a binge drinking cycle adversely affects LP's and sex huormones (estrone/T); 3) to determine if concurrent use of oral NIC negates the anti-atherogenic LP effect of 12% ETOH and how these drugs modify body composition (fat/lean mass, lipoprotein lipase); and 4) to assess whether LP abnormalities persist following drug cessation. The proposed study will provide unique information on ETOH and NIC's influence on LP's and hence coronary risk, and also identify biologic indices useful in formulating drug abstinenece strategies.
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