Human and nonhuman primate studies

Apolipoprotein A-I is the most abundant protein in HDL and plays an important role in maintaining the structure of HDL and activating lecithin cholesterol acyltransferase (LCAT), an enzyme involved in converting cholesterol to cholesterol ester. HDL appears to be primarily cardioprotective by transporting cholesterol from the periphery to the liver for export as bile acids. This process is termed reverse cholesterol transport. From epidemiological studies, higher levels of HDL cholesterol are associated with a decrease in cardiovascular disease risk. Similar studies have shown that apolipoprotein A-I levels show a similar inverse relationship with risk for cardiovascular disease [4],

Consumption of moderate amounts of alcohol is associated with an increase in HDL cholesterol and apolipoprotein A-I. The increases occur in a dose-dependent fashion. As little asl5gof alcohol/day can increase apolipoprotein A-I levels in humans [5], Hojnacki et al. [6] examined the dose response of alcohol on lipids and apolipoproteins in male squirrel monkeys. Comparing diets containing 0, 6, 12, 18, 24, 30, and 36% of calories derived from alcohol, there was a dose dependent increase in apolipoprotein A-I levels (and HDL cholesterol) with a significant increase detectable at 24%.

Acute administration of alcohol has no or little effect on apolipoprotein A-I levels. Valimaki et al. examined the time course of 60 g/day of alcohol (16% of total calories were derived from alcohol) for 3 weeks in men on total apolipoprotein A-I levels [7], Apolipoprotein A-I levels did not increase until after 1 week of alcohol consumption.

In contrast, in a study using young, healthy men consuming 160 g/day of alcohol in three divided doses over three days did not change total apolipoprotein A-I levels or total HDL cholesterol. However, there were pronounced changes in the HDL subfractions. The apolipoprotein A-I content ofHDL2 increased which was mitigated by the decrease in apolipoprotein A-I content of HDL3 [8], The lipid composition of both subfractions was characterized by a relative increase in phospholipids but decrease in cholesterol. These changes in HDL composition likely have important effects on HDL function, since the conformation of apolipoprotein A-I on the surface of HDL is dependent upon the lipid composition of the particle [9,10], Alcoholics (male and female) also have increases in the apolipoprotein A-I and A-II of HDL compared to controls [11].

Other environmental factors can influence the effect of alcohol on apolipoprotein levels including level of physical activity [12] and diet. Rumpler et al. [13] examined the effect of adding alcohol to the diet of women consuming either a high fat (38% fat calories) or low fat (18% fat calories). Alcohol (5% of calories) only increased HDL cholesterol while on the high fat diet. This effect was confined to the HDL2 subfraction. Diet influences the metabolism of most apolipoproteins and is the major confounding factor in interpreting the effects of alcohol on apolipoproteins in human and animals.

The steady state concentration of apolipoprotein A-I is a balance between synthesis and catabolism. Alcohol appears to affect both processes. In a study with healthy men consuming 60-70 g/alcohol/day for two weeks, alcohol increased apolipoprotein A-I synthesis by nearly 50% [14]. Apolipoprotein A-I is synthesized and secreted primarily in the intestine and liver. No studies have examined the effect of alcohol on apolipoprotein A-I secretion in intestinal cells. In vitro, alcohol has been shown to stimulate apolipoprotein A-I secretion from two human hepatoma cell lines, HepG2 and Hep3B [15]. As little aslO mM alcohol (equivalent to 46 mg/ dl) stimulated apolipoprotein A-I synthesis and secretion in HepG2 cells [16]. This effect on synthesis appears to be a post-translational effect, since alcohol has little effect on apolipoprotein A-I mRNA steady state levels. The alcohol effect was not blocked by 4-methylphyrazole, an aldehyde dehydrogenase inhibitor, or aminotriazole, a catalase inhibitor, but was inhibited by metyrapone, a microsomal alcohol oxidizing system [15]. These results suggest that acetylaldehyde is responsible to this effect and that metabolism via cytochrome P450 2E1 is required. However, the mechanism for this alcohol effect on apolipoprotein A-I synthesis and secretion has not been elucidated. One possibility is that alcohol may increase the fraction of translatable apolipoprotein A-I mRNA. This mechanism appears to account for the effect of high fat diets to increase apolipoprotein A-I synthesis [17].

In addition, alcohol also increases the catabolism of apolipoprotein A-I. Consuming 60-70 g/day in healthy mean increased the fractional catabolic rate of apolipoprotein A-I by 30% [14]. Hence, there was an increase in the turnover of apolipoprotein A-I.

In contrast to humans, feeding male squirrel monkeys with a diet consisting of 24% alcohol-derived calories for 18 months had no effect on apolipoprotein A-I synthesis but decreased the FCR by nearly 50% [18]. It is unclear whether this represents a difference in time of treatment and/or a species differences in response to alcohol feeding.

No published work has been done to determine the mechanism for alcohol increasing catabolism of apolipoprotein A-I. It is possible that the changes in lipid composition of

HDL induced by alcohol could increase the catabolism of apolipoprotein A-I. In addition, no studies have examined the effect of alcohol on various HDL receptors including SR-B1 and cubulin. In summary, the HDL raising effects of alcohol consumption in humans appears to derive from an increase in apolipoprotein A-I secretion from hepatocytes and decreased catabolism from serum.

Animal models

The effect of alcohol consumption in various animal models can vary significantly from the effect in humans. In rats, like humans, alcohol consumption increases apolipoprotein A-I levels in serum. Lakshman et al. fed male Wistar rats a high fat (40% of calories) with or without high doses of alcohol (36% of total calories) [19], Over a 6 week feeding period, alcohol nearly doubled the total apolipoprotein A-I in serum. However, when apolipoprotein A-I synthesis was examined in perfused liver, the alcohol-fed rats had a 50% decrease in apolipoprotein A-I synthesis. This suggests that apolipoprotein A-I catabolism must have also decreased to account for the increase in serum apolipoprotein. In a study using rats, inclusion of 35% ethanol-derived calories on a high fat diet (40%) increases apolipoprotein A-I levels. However, when the fat calories were replaced with fish oil (enriched in Q-3 fatty acids), the alcohol effect was blunted [20], Mice appear to have an entirely different response to alcohol than rats. Some, but not all studies in C57BL/6 mice have shown that including alcohol in liquid diets does not increase and may even decrease serum total apolipoprotein A-I levels. The differences likely represent differences in the dietary components. C57BL/6 mice have become the standard strain for studying atherosclerosis, since this strain develops atherosclerosis when fed a high fat diet containing cholate. The cholate in the diet results in a decrease in HDL cholesterol and apolipoprotein A-I levels. This appears to occur by increasing the expression of ARP-1, a repressor protein that inhibits apolipoprotein A-I promoter activity [21], C57BL/6 mice fed a high fat (34% fat calories) containing cholate have a decrease in HDL cholesterol compared to mice fed a low fat (12% fat). In one study utilizing a liquid diet based upon the classic Lieber-DeCarli diet which included moderate (18% of total calories) or high (36% of calories) doses of alcohol over 22 weeks, there was no effect on apolipoprotein levels except at the highest dose of alcohol in the high fat group, where apolipoprotein A-I levels decreased [22].

A second study with the same strain of mice, but utilizing a modified AIN '76 liquid diet with 36% alcohol-derived calories, showed that alcohol had no effect on apolipoprotein A-I levels [23], This AIN '76 diet differed from the Lieber-DeCarli diet in that it lacks essential fatty acids and has approximately 2% of the vitamin A content. Since retinoic acid regulates apolipoprotein A-I expression [24], it is conceivable that the vitamin A content may modify the ethanol response, however this has not been examined. Genetics may also play a role in the ethanol effect. LDL receptor knockout mice fed the modified AIN '76 diet for 6 weeks did demonstrate an approximate 50% decrease in apolipoprotein A-I levels [23], However, inclusion of alcohol (36% of calories) raised apolipoprotein A-I levels to control levels. This effect does not appear to be secondary to an increase in hepatic apolipoprotein A-I synthesis (unpublished observation). However, alcohol does not increase apolipoprotein A-I levels in these mice if a diet containing essential fatty acids and vitamin A levels used in the classic Lieber-DeCarli diet (Yuan et al., manuscript submitted). These studies emphasize that the alcohol effect on apolipoprotein levels can vary depending upon dietary and genetic factors.

One possible site of action that has not been examined is the effect of alcohol on apolipoprotein A-I synthesis from the intestine. Intestinal-derived apolipoprotein A-I may be important in the atherogenic protective effect ofHDL; this is based upon the observation that staggerer mice (sg/sg), which lack the retinoic acid receptor-related orphan receptor a (RORa), have an increased atherogenic response to a high fat diet in association with decreased levels of apolipoprotein A-I [25], RORa regulates apolipoprotein A-I expression within the intestine but not the liver [26], LDL receptor knockout mice fed the modified AIN '76 diet show no change in steady state levels of apolipoprotein A-I mRNA (unpublished observation). However, this does not eliminate an alcohol effect on synthesis as described above.

It is very interesting to note that although alcohol did not increase HDL cholesterol or apolipoprotein A-I levels in the C57BL/6 mice fed a modified Lieber-DeCarli diet, atherosclerotic plaque size decreased [22], Similarily, the LDL receptor knockout mice fed either the modified AIN '76 or Lieber-DeCarli diet with or without alcohol for 6 weeks showed that alcohol intake was associated with a decrease in atherosclerotic plaque size after 6 weeks. However, if the feeding on the modified AIN '76 diet was continued for an additional 6 weeks (12 weeks total), the plaque size was comparable in the control and alcohol fed animals despite normal apolipoprotein A-I levels [23], These data suggest that alcohol may inhibit plaque development by factors other than raising HDL.

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