Alcohol produces dose-dependent antiatherogenic and atherogenic plasma lipoprotein responses.

A comprehensive assessment of lipoprotein compositional/metabolic response to incremental caloric ethanol (EtOH) doses ranging from low to moderate to high was undertaken using male squirrel monkeys. Control monkeys were maintained on a chemically defined, isocaloric liquid diet, while experimental primates wee fed increasing doses of alcohol (6, 12, 18, 24, 30, and 36% of energy) substituted isocalorically for carbohydrate at 3-month intervals. Liver function tests and plasma triglyceride were normal for all animals. Plasma cholesterol showed a transient increase at the 12% caloric dose that was attributed solely to an increase in high density lipoprotein (HDL). A more pronounced increase in plasma sterol, beginning at 24% and continuing to 36% EtOH, was the result of increments in both HDL and low density lipoprotein (LDL) cholesterol, although the contribution by the latter was substantial primarily at the 36% dose. Plasma apolipoprotein elevations (HDL apolipoprotein A-I, LDL apolipoprotein B) generally accompanied the lipoprotein lipid increases, although the first atherogenic response for LDL became manifest as a significant increase in apolipoprotein B at 18% EtOH calories. Postheparin plasma lipoprotein lipase was not affected by dietary alcohol, whereas hepatic triglyceride lipase activity showed significant increases at higher (24 and 36%) EtOH doses. Plasma lecithin-cholesterol acyltransferase activity was normal at the 6 and 12% EtOH doses, but exhibited a significant reduction beginning at 18% and continuing to 36% EtOH. Alterations in these key lipoprotein regulatory enzymes may represent the underlying metabolic basis for the observed changes in lipoprotein levels and our earlier findings of HDL2/HDL3 subfraction modifications. Results from our study indicate that in squirrel monkeys, moderate (12%) EtOH caloric intake favors an antiatherogenic lipoprotein profile (increases HDL, normal LDL levels, and lecithin-cholesterol acyltransferase activity), whereas higher doses (24-36%) produce both coronary-protective (increases HDL) and atherogenic (increases LDL) responses. Moreover, the 18% EtOH level represents an important transition dose which signals early adverse alterations in lipoprotein composition (increases apolipoprotein B) and metabolism (decreases lecithin-cholesterol acyltransferase).

Effect of ethanol on low density lipoprotein and platelet composition.

The present study was designed to investigate the effect of ethanol (EtOH) dose on low density lipoprotein (LDL) and platelet composition. Male squirrel monkeys were divided into three groups designated Control, Low, and High EtOH, and fed isocaloric liquid diets containing 0%, 12%, and 24% of calories as EtOH, respectively. After four months of treatment, monkeys fed the 12% alcohol dose had LDL and platelet cholesterol concentrations similar to Controls. By contrast, platelet membranes from High EtOH animals contained significantly more cholesterol which was associated with higher levels of plasma LDL cholesterol and apolipoprotein B. Blood platelet count, size, and mass were similar for all groups and circulating platelet aggregates were absent in the two alcohol cohorts. Despite elevations in platelet cholesterol mass and thromboxane A2 (TXA2) precursor, phospholipid arachidonate, platelet responsiveness, measured as thromboxane formed in response to a collagen challenge in vitro, and the cholesterol/phospholipid molar ratio, were not significantly altered by high dose alcohol. Normal platelet activity in High EtOH monkeys may have resulted from a significant increase in the platelet phospholipid polyunsaturated/saturated fatty acid ratio and a non-significant increase in platelet phospholipid mass, both of which would have a fluidizing effect on platelet membranes. Our data indicate that low EtOH intake has no effect on platelet composition and function while unfavorable platelet cholesterol enrichment following consumption of high dose ethanol may arise from elevations in plasma LDL.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of drinking pattern on plasma lipoproteins and body weight.

The effect of drinking pattern on plasma lipoproteins and body weight was examined in three groups of squirrel monkeys: (1) controls fed isocaloric liquid diet; (2) regular drinkers given liquid diet containing ethanol (EtOH) substituted isocalorically for carbohydrate at 12% of calories daily; and (3) binge drinkers fed 6% EtOH calories daily for a four-day period followed by three days of 20% EtOH to mimic a weekend bout drinking cycle. The number of calories offered per day was the same for all groups, and the average weekly EtOH consumption (12% calories) was identical for the two alcohol treatments. The entire study lasted six months. There were no significant differences in plasma cholesterol, triglyceride or liver function tests. Regular drinkers had the highest high density lipoprotein2/high density lipoprotein3 (HDL2/HDL3) protein and apolipoprotein A-I/B ratios of any group and exhibited a significant elevation in the molar plasma lecithin:cholesterol acyltransferase (LCAT) rate (nmol/min/ml). Binge drinking produced a selective increase in low density lipoprotein (LDL) cholesterol and apolipoprotein B, and a depression in the fractional LCAT rate (% esterified/min). During the course of the study, controls ate 92% of their diet while the alcohol groups each consumed 95% of the liquid diet. Despite this difference, body weight and Quetelet index (weight/height2) decreased progressively in the order controls greater than regular drinkers greater than binge drinkers. Results from our study indicate that moderate, regular daily consumption of EtOH at 12% of calories causes a modest reduction in body weight and produces a coronary protective lipoprotein profile (increases HDL2/HDL3, increases apolipoprotein A-I/B, low LDL cholesterol). By contrast, when this same average weekly dose is concentrated in a binge cycle, unfavorable alterations in lipoprotein composition (increases LDL cholesterol, increases apolipoprotein B) and metabolism (decreases LCAT activity) occur along with weight loss and depletion of body fat. These studies point to the value of the squirrel monkey model in evaluating both favorable and pathophysiological effects of chronic EtOH intake.

Plasma lipoprotein alterations in squirrel monkeys (Saimiri sciureus) during ethanol administration and abstinence.

The time course of lipoprotein changes during ethanol (EtOH) consumption followed by abstinence was examined in 3 groups of male squirrel monkeys: 1) controls fed isocaloric liquid diet; 2) low EtOH monkeys given liquid diet with vodka substituted isocalorically for carbohydrate at 12% of calories; and 3) high EtOH animals fed diet plus vodka at 24% of calories. After 2 weeks, high EtOH monkeys showed significant elevations in total plasma cholesterol which continued to increase at 4 weeks and then declined at 8 weeks. These elevations were the result of increases in both low density (LDL)- and high density lipoprotein (HDL)-cholesterol. Low EtOH monkeys had a modest increase in total cholesterol throughout 8 weeks which was attributed to increments in HDL-cholesterol alone. During abstinence, total, HDL- and LDL-cholesterol concentrations decreased rapidly in the high EtOH group and were similar to control values after 4 days. HDL-cholesterol showed a more gradual decline in animals fed 12% EtOH while LDL-cholesterol remained low and not significantly different from controls. Liver function tests were normal for all animals. Our results indicate that low-dose EtOH favors a coronary protective lipoprotein profile (increases HDL, decreases LDL) in squirrel monkeys while the higher alcohol regimen causes both favorable and unfavorable alterations in plasma lipids which quickly revert to control levels during abstinence.

Effect of ethanol dose on low density lipoproteins and high density lipoprotein subfractions.

Male squirrel monkeys were fed increasing caloric percentages (0, 12, 24, and 36%) of ethanol (ETOH) substituted isocalorically for carbohydrate as part of a chemically defined liquid diet to assess how alcohol dose modifies plasma lipoproteins and liver function. A separate group of primates was used to define the dose at which elevations in plasma apolipoprotein B first occurred and to measure plasma alcohol levels. ETOH caused a dose-related, linear increase in high density lipoprotein (HDL) cholesterol which was primarily the result of increments in coronary protective HDL2 cholesterol. HDL2 total mass (lipid + protein) followed the pattern of HDL2 cholesterol. Animals fed the 12% regimen had plasma ETOH levels of approximately 49 mg/dl, the lowest low density lipoprotein (LDL) cholesterol, and the highest HDL2/HDL3 cholesterol ratio. Significant elevations in apolipoprotein B first appeared at 18% ETOH while higher doses (24 and 36%) caused increases in LDL cholesterol and HDL3, reduced HDL2/HDL3 ratios, and plasma alcohol levels of 142 and 202 mg/dl, respectively. Liver function tests were normal for all animals. Our results indicate that while a moderate ETOH caloric intake (12%) produces an antiatherogenic lipoprotein profile (decreases LDL/HDL, increases HDL2/HDL3), any coronary protection afforded by continued increases in HDL2 at higher doses may be attenuated by concurrent atherogenic alterations (increases LDL cholesterol, increases apolipoprotein B).

Oral nicotine induces an atherogenic lipoprotein profile.

Male squirrel monkeys were used to evaluate the effect of chronic oral nicotine intake on lipoprotein composition and metabolism. Eighteen yearling monkeys were divided into two groups: 1) Controls fed isocaloric liquid diet; and 2) Nicotine primates given liquid diet supplemented with nicotine at 6 mg/kg body wt/day. Animals were weighed biweekly, plasma lipid, glucose, and lipoprotein parameters were measured monthly, and detailed lipoprotein composition, along with postheparin plasma lipoprotein lipase (LPL) and hepatic triglyceride lipase (HTGL) activity, was assessed after 24 months of treatment. Although nicotine had no effect on plasma triglyceride or high density lipoproteins (HDL), the alkaloid caused a significant increase in plasma glucose, cholesterol, and low density lipoprotein (LDL) cholesterol plus protein while simultaneously reducing the HDL cholesterol/plasma cholesterol ratio and animal body weight. Levels of LDL precursors, very low density (VLDL) and intermediate density (IDL) lipoproteins, were also lower in nicotine-treated primates while total postheparin lipase (LPL + HTGL) activity was significantly elevated. Our data indicate that long-term consumption of oral nicotine induces an atherogenic lipoprotein profile (increases LDL, decreases HDL/total cholesterol ratio) by enhancing lipolytic conversion of VLDL to LDL. These results have important health implications for humans who use smokeless tobacco products or chew nicotine gum for prolonged periods.

Oral nicotine impairs clearance of plasma low density lipoproteins.

The effect of chronic oral nicotine intake on plasma low density lipoprotein (LDL) clearance, lipid transfer protein, and lecithin:cholesterol acyltransferase (LCAT) was examined in male atherosclerosis susceptible squirrel monkeys. Eighteen yearling primates were divided into two groups: 1) Controls fed isocaloric liquid diet; and 2) Nicotine monkeys given liquid diet supplemented with nicotine at 6 mg/kg body wt/day for a two-year period. Averaged over 24 months of treatment, animals in the Nicotine group had significantly higher levels of plasma and LDL cholesterol compared to Controls while plasma LCAT activity was similar for both groups. Following simultaneous injection of 3H LDL and 14C high density lipoprotein (HDL) cholesteryl ester (CE), removal of the latter was not altered by oral nicotine while plasma clearance of 3H LDL was dramatically delayed in Nicotine monkeys. Transfer of 14C HDL CE to very low density lipoprotein (VLDL)-LDL particles was greatly accelerated in the Nicotine group vs Controls while the reciprocal movement of 3H LDL CE to HDL was only higher in experimental animals at two time points following injection of the isotopes. Results from this study provide evidence that one major detrimental effect of long-term oral nicotine use is an increase in the circulating pool of atherogenic LDL which is due to: 1) accelerated transfer of lipid from HDL; and 2) impaired clearance of LDL from the plasma compartment. Diminished removal of LDL is of particular importance because an extended residence time of these particles in circulation would increase the likelihood of their deposition in the arterial wall.

Ethanol-induced alterations in lecithin: cholesterol acyltransferase (LCAT) activity in vitro.

Our recent experiments demonstrated that squirrel monkeys fed ethanol (ETOH) at 12% of calories (Low ETOH) had significantly higher plasma lecithin: cholesterol acyltransferase (LCAT) activity than monkeys fed ETOH at 24% of calories (High Ethanol). Control animals had LCAT activity intermediate between that of Low and High ETOH primates. To test whether alcohol directly altered cholesterol esterification in vitro, LCAT activity was measured in pooled primate plasma incubated with ETOH at final concentrations of 60, 80, 160, and 240 mg/dl. A similar experiment was performed using incremental doses of ETOH's major metabolite, acetaldehyde. Peak cholesterol esterification occurred at 60 mg/dl which was comparable to plasma alcohol levels detected in Low ETOH monkeys (63 mg/dl) while LCAT activity was significantly depressed at 160 mg/dl which was similar to blood ETOH monitored in High ETOH primates (159 mg/dl). Maximum cholesterol esterification occurred at an acetaldehyde concentration of 0.45 mumoles/l. Our data indicate that ETOH can either stimulate or inhibit LCAT activity in vitro depending upon concentration and suggest that circulating blood alcohol may induce similar alterations in cholesterol esterification in vivo.