Genetic variation in the rate-limiting enzyme in cholesterol catabolism (cholesterol 7 alpha-hydroxylase) influences the progression of atherosclerosis and risk of new clinical events

CHD (coronary heart disease) is a complex disorder which is, in part, related to serum cholesterol levels. The rate-limiting enzyme in the catabolism of cholesterol into bile acids is CYP7A1 (cholesterol 7alpha-hydroxylase). The effect of the CYP7A1 A-278C promoter polymorphism on the progression of atherosclerosis, risk of a new clinical event and the influence of this variant on cholesterol-lowering therapy was investigated in 715 male patients with coronary atherosclerosis participating in REGRESS (Regression Growth Evaluation Statin Study). Genotype distributions were as follows: 283 with AA; 330 with AC and 102 with CC. There were no significant differences in baseline characteristics and serum lipids between genotypes. After 2 years, CC carriers had more progression of diffuse and focal atherosclerosis compared with AA carriers, as indicated by a larger decrease in MSD (mean segment diameter; 0.09 mm compared with 0.06 mm respectively; P=0.009) and MOD (minimum obstruction diameter; 0.09 mm compared with 0.05 mm respectively; P=0.024). Inclusion of risk factors for CHD in the model showed the same trend, although not significant for MOD (P=0.01 for MSD, and P=0.06 for MOD). In addition, CC carriers had an almost 2-fold higher risk of a new clinical event compared with AA carriers [RR (95% CI) 1.93 (1.11-3.36); P=0.02; where RR is relative risk and CI is confidence interval]. Inclusion of risk factors for CHD in the model showed the same trend, although not significant [RR (95% CI), 1.74 (0.96-3.12); P=0.06]. In conclusion, we present evidence that the CC variant of the A-278C polymorphism in the rate-limiting enzyme in the catabolism of cholesterol, CYP7A1, increases the progression of atherosclerosis and possibly the risk of a new clinical even

Coffee Oil Consumption Increases Plasma Levels of 7alpha-Hydroxy-4-cholesten-3-one in Humans

Unfiltered coffee brews such as French press and espresso contain a lipid from coffee beans named cafestol that raises serum cholesterol in humans. Cafestol decreases the expression and activity of cholesterol 7-hydroxylase, the rate-limiting enzyme in the classical pathway of bile acid synthesis, in cultured rat hepatocytes and livers of APOE3Leiden mice. Inhibition of bile acid synthesis has been suggested to be responsible for the cholesterol-raising effect of cafestol. Therefore, we assessed whether cafestol decreases the activity of cholesterol 7-hydroxylase in humans. Because liver biopsies were not feasible, we measured plasma levels of 7-hydroxy-4-cholesten-3-one, a marker for the activity of cholesterol 7-hydroxylase in the liver. Plasma 7-hydroxy-4-cholesten-3-one was measured in 2 separate periods in which healthy volunteers consumed coffee oil containing cafestol (69 mg/d) for 5 wk. Plasma levels of 7-hydroxy-4-cholesten-3-one increased by 47 ± 13% (mean ± SEM, n = 38, P = 0.001) in the first period and by 23 ± 10% (n = 31, P = 0.03) in the second treatment period. Serum cholesterol was raised by 23 ± 2% (P <0.001) in the first period and by 18 ± 2% (P <0.001) in the second period. We corrected individual 7-hydroxy-4-cholesten-3-one levels for serum cholesterol levels, because coffee oil increases serum cholesterol and 7-hydroxy-4-cholesten-3-one is probably present in the lipoprotein fraction of serum. After correction, the increase in 7-hydroxy-4-cholesten-3-one was 24 ± 11% (P = 0.04) in the first period and there was no effect in period 2. Our study showed that coffee oil did not decrease, and actually increased, plasma levels of 7-hydroxy-4-cholesten-3-one in humans in 2 separate treatment periods. Therefore, this study does not support the hypothesis that cafestol decreases bile acid synthesis in human

CYP7A1 A-278C polymorphism affects the response of plasma lipids after dietary cholesterol and cafestol interventions in humans.

The response of plasma lipids to dietary cholesterol and fat varies among individuals. Variations in genes involved in cholesterol metabolism can be important in these interindividual differences. The rate-limiting enzyme in the conversion of cholesterol into bile acids is cholesterol 7-hydroxylase (CYP7A1). We investigated the effect of the A278-C promoter polymorphism in the CYP7A1 gene on responses of plasma lipids to an increased intake in dietary cholesterol (742 ± 114 mg/d), cafestol (57 ± 6 mg/d), saturated fat [change of 8¿9 energy percent/d (en%/d)] and trans fat (change of 10¿11 en%/d) in 496 normolipidemic subjects. These responses were measured in 26 previously published dietary trials. After adjustment for the apolipoprotein E genotype effect, AA-subjects consuming a cholesterol-rich diet had a smaller increase in plasma HDL cholesterol than CC-subjects (0.00 ± 0.02 vs. 0.17 ± 0.04 mmol/L; P <0.001). Upon intake of cafestol, AA-subjects had a smaller increase in plasma total cholesterol than CC-subjects (0.69 ± 0.10 vs. 1.01 ± 0.10 mmol/L; P = 0.028). No effects of the polymorphism were found in the saturated and trans fat interventions. In conclusion, the CYP7A1 polymorphism has a small but significant effect on the increase in plasma HDL cholesterol and plasma total cholesterol after an increased intake of dietary cholesterol and cafestol, respectivel

Modulating effect of the A-278C promoter polymorphism in the cholesterol 7alpha-hydroxylase gene on serum lipid levels in normolipidaemic and hypertriglyceridaemic individuals

The rate-limiting enzyme in the conversion of cholesterol into bile acids is cholesterol 7alpha-hydroxylase (CYP7A1). An A to C substitution 278 bp upstream in the promoter of the CYP7A1 gene was found to be associated with variations in serum lipid levels in normolipidaemic populations. In the present study, we investigated the involvement of this polymorphism in four different lipid disorders: hypertriglyceridaemia (HTG), combined hyperlipidaemia (CH), familial dysbetalipoproteinaemia (FD) and familial hypercholesterolaemia (FH). In a normolipidaemic male population, homozygous for the apoE3 isoform, an association was found between the AA genotype and higher levels of serum triglycerides (AA: +34%, P=0.036). In HTG patients, the AA genotype was associated with significantly higher concentrations of total cholesterol (+23%, P=0.005). There was a tendency towards increased levels of serum triglycerides (+39%, P=0.06), VLDL-triglycerides (+48%, P=0.053) and VLDL-cholesterol (+35%, P=0.059). No significant associations were found between serum lipid levels and the CYP7A1 polymorphism in patients with CH, FD and FH. Our results show that the A-278C polymorphism in the CYP7A1 gene has an effect on triglyceride levels in normolipidaemic males and on cholesterol levels in patients with hypertriglyceridaemia