![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
* TNO Prevention and Health, Gaubius Laboratory, Leiden, The Netherlands;
Division of Human Nutrition, Wageningen University, Wageningen, The Netherlands;
** Unilever Health Institute, Unilever Research and Development, Vlaardingen, The Netherlands; and
Wageningen Centre for Food Sciences, Wageningen, The Netherlands
3To whom correspondence should be addressed. E-mail: jmg.princen{at}pg.tno.nl.
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
-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, respectively.
KEY WORDS: • CYP7A1 • polymorphism • cholesterol • cafestol • dietary interventions
The response of plasma lipids to dietary cholesterol and fat varies among individuals, but within subjects this response is to some extent reproducible (1). Several studies in humans showed that this response is associated with genetic polymorphisms (2). Variations in genes involved in cholesterol metabolism can therefore be important determinants for these interindividual differences, and identification of genetic factors that affect the response can be helpful for selecting a proper treatment for hyperlipidemic patients.
The liver plays a central role in the regulation and maintenance of the whole-body sterol balance. Conversion of cholesterol into bile acids in the liver, together with secretion of cholesterol into bile, is quantitatively the major pathway for eliminating cholesterol from the body (3). In humans, it was shown that changes in the biosynthetic pathway of bile acids lead to changes in cholesterol metabolism (4,5).
The first and rate-limiting enzyme in the catabolism of cholesterol is cholesterol 7-hydroxylase (CYP7A1) (3). An A to C conversion 278 bp upstream in the promoter was found in the CYP7A1 gene, which is related to variations in plasma lipid levels (6). A significantly elevated LDL cholesterol is observed in homozygous C subjects, in both men and women (6,7). Furthermore, women homozygous for the C-allele have significantly lower triglyceride levels than heterozygotes and than homozygotes for the A-allele (7).
Animal studies showed that there is an association between genetic differences in the synthesis of bile acids and the response of plasma lipids to dietary interventions (8–11). Because variations in cholesterol 7-hydroxylase influence cholesterol metabolism, polymorphisms in the CYP7A1 gene may be candidate genetic factors for the observed interindividual differences in the response of plasma lipids to a dietary challenge in humans. It was already shown that after a lowering of dietary fat intake, subjects with the CC genotype have a significantly larger decrease in plasma total cholesterol (12). Presently, no data are available on the effect of the CYP7A1 A-278C polymorphism on changes in plasma lipids after dietary interventions that increase plasma cholesterol.
In the present study, we investigated the effect of the A-278C promoter polymorphism in the CYP7A1 gene on the response of plasma lipids to changes in intake of dietary cholesterol, saturated fat, trans fat, and cafestol in 496 normolipidemic subjects.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
All food was supplied in the 7 trials with saturated fat, in the 2 trials with trans fat, and in 3 of the trials with dietary cholesterol. In the 4 trials of dietary cholesterol without complete food supply, subjects received eggs as a supplement during the treatment period and guidelines for a diet low in cholesterol during the control period. In 1 other trial of dietary cholesterol, subjects received all foods during the treatment period and received dietary guidelines during the control period.
We had data on the CYP7A1 and apolipoprotein (apo)E genotype and total cholesterol levels for 104 subjects participating in the dietary cholesterol trials, for 112 subjects participating in the cafestol trials, for 201 subjects participating in the saturated fat trials, and for 79 subjects participating in the trans fat trials. Because 41% of the subjects in the saturated fat trials and 56% of the subjects in the dietary cholesterol trials participated in more than 1 trial, we could calculate 209 and 291 responses of plasma total cholesterol to dietary cholesterol and saturated fat, respectively. We had data on plasma HDL cholesterol levels for 88 subjects and data on triglyceride and LDL-cholesterol levels for 25 subjects participating in the dietary cholesterol trails (resulting in 179 and 51 responses, respectively). The precision of the estimation of responses of plasma lipids to saturated fat and dietary cholesterol was high, because a large number of subjects participated in more than 1 trial with a similar treatment.
At the time of the trials, the subjects were healthy as indicated by a medical questionnaire and by the absence of anemia, glucosuria, and proteinuria. The protocols were approved by an Ethical Committee and informed consent was obtained from all subjects.
CYP7A1 A-278C promoter polymorphism. The polymorphism was detected using a real-time PCR approach with fluorescent TaqMan probes (31). This method was validated against a conventional measurement of the CYP7A1 A-278C polymorphism using PCR and subsequent restriction fragment analysis (6); >20% of the samples were genotyped by both methods and all samples showed the same genotype measured with either method.
Statistical analysis. The response of plasma lipids of 1 individual was calculated as the level of cholesterol at the end of the treatment that increased cholesterol minus the level of the same individual either at the end of the treatment that lowered cholesterol, the placebo treatment, or the diet without the cafestol or cholesterol supplement (depending on the design of the trial).
We first determined whether there were differences among the 3 genotype groups in sex, age, and BMI because these can be potential confounders of the relation between the CYP7A1 genotype and plasma lipid responses.
In the adjusted analysis, the response was corrected for several variables. First, responses were adjusted for the apoE genotype effect because the apoE genotype influences the response of plasma lipid levels (32). The responses were also adjusted for trial because there were background differences among the trials in diet, duration of the treatment, and time of the year the trials were performed. If a trial consisted of >1 treatment, we created factors indicating each treatment within a trial. Furthermore, in the saturated fat and cholesterol trials, the responses were adjusted for subject because 41% of the subjects in the saturated fat trials and 56% of the subjects in the dietary cholesterol trials participated in more than 1 trial with a similar treatment or in a crossover trial with 3 treatments [more details are given in (13)]. In an additional analysis, we adjusted for sex, age, BMI, and change in weight because these can be potential confounders of the relation between the CYP7A1 genotype and plasma lipid response. We also calculated which percentage of the total variance of plasma cholesterol could be explained by the CYP7A1 and apoE genotypes. This was calculated by dividing the Type III sum of squares of the specific genotype (corrected for the variables described above) by the total corrected sum of squares.
Because the CC group was the smallest, the estimate of effects in this group was the least robust and the most open to potential confounding. Therefore, in an additional analysis, we combined AC and CC subjects and examined the difference in response between AA subjects and C-carriers. From previous studies, it is known that genotype effects are different in men and women (13). For this reason, we also analyzed genotype effects separately in men and women.
We tested the adjusted differences in the response of plasma lipids among subjects with the CYP7A1 genotypes by ANOVA. In case of significant differences, group means were compared by Fisher’s Least Significant Difference test for multiple comparisons. Whenever plasma lipid values were not normally distributed, they were logarithmically transformed before analysis. Untransformed values are shown in the tables. All analyses were performed with SAS statistical software. Differences with a P-value of <0.05 were considered significant. Values are presented as means ± SEM.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
There were no significant differences in baseline plasma total cholesterol levels among the 3 CYP7A1 genotype groups in the different interventions. There were also no differences in sex, age, and BMI among the 3 CYP7A1 genotype groups.
Overall, an increased intake in dietary cholesterol increased plasma total, HDL, and LDL cholesterol (all P < 0.01). In the cafestol and trans fat interventions, there was an increase in plasma total and LDL cholesterol and triglycerides (all P < 0.01). HDL-cholesterol decreased in these interventions (P = 0.02 and P < 0.01, respectively). In the saturated fat intervention, plasma total, HDL, and LDL cholesterol increased (all P < 0.01). Plasma triglycerides showed the same trend (P = 0.07). More detailed information on the responses to these interventions is given in reference (13).
Dietary cholesterol intervention. The adjusted response of plasma HDL cholesterol was affected by the CYP7A1 genotype, and was the lowest in subjects with the genotype AA (P < 0.001) (Table 1). When we analyzed men and women separately, results did not differ between the groups (P = 0.02 for men and P = 0.02 for women) (data not shown). The effects on HDL-cholesterol and total cholesterol were even stronger when we looked at the effect of C-carriers (AC and CC combined) vs. AA subjects (P = 0.0001 and P = 0.03, respectively). The responses were not materially affected by adjustment for sex, age, BMI, and change in weight (data not shown).
|
Cafestol intervention. Subjects homozygous for the A allele had a smaller increase in plasma total cholesterol compared with homozygous C subjects (P = 0.028) (Table 1). The lower response of AA subjects for total cholesterol was also clear when we examined the effect of C-carriers (AC and CC combined) vs. AA subjects (P = 0.03). The responses were not materially affected by adjustment for sex, age, BMI, and change in weight (data not shown).
The polymorphism accounted for 5% (P = 0.07) and 3% (P = 0.07) of the total variation in the response of plasma total cholesterol and LDL cholesterol, respectively. However, the apoE genotype did not contribute to the variance in the response of plasma total cholesterol after intake of cafestol.
Saturated fat and trans fat interventions. There were no differences in the response of plasma lipid levels among the 3 CYP7A1 variants after an increase in saturated or trans fatty acids (data not shown).
|
DISCUSSION |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
The molecular mechanism underlying the increased response of the CC-variant on plasma cholesterol after an increase in dietary cholesterol and cafestol is as yet unknown. Hubacek et al. (12) also showed an increased response of the CC-variant after a lowering in dietary fat intake. Studies on the transcriptional regulation of CYP7A1 revealed that the promoter region between nt –432 and –220 contains several cell-specific enhancer elements whose activity is controlled in part by HNF-3 (33). It is conceivable therefore, that the A-278C polymorphism might modulate transcriptional activity of the CYP7A1 gene and, consequently, the rate of cholesterol catabolism. Theoretically, the increased response of the CC genotype can be explained by a decrease in bile acid synthesis. When bile acid synthesis decreases, less cholesterol is catabolized in the liver; as a consequence, plasma cholesterol increases. The finding of an association between the genotype AA and a decrease in LDL cholesterol in a normolipidemic population by Wang et al. (6) concurs with this contention. In addition, large intervention studies showed that that there is a correlation between plasma LDL cholesterol and an increase in bile acid synthesis (4). Plasma LDL cholesterol decreases when the bile acid synthesis in the liver is upregulated. Similarly, in gallstone patients, Reihner et al. (34) reported a decrease in LDL cholesterol with an increase in CYP7A1 activity. However, this hypothesis has not yet been proven. It could be that the polymorphism in itself is nonfunctional, and is in complete linkage disequilibrium with another functional polymorphism in the CYP7A1 gene or in another unidentified gene close to the CYP7A1 locus. Furthermore, we cannot exclude that part of our results are due to chance because we analyzed several subgroups, which obviously increases the risk of chance associations. On the other hand, after subgroup analysis and adjustment for confounders, all associations remained in the same direction.
In the cholesterol intervention study, the higher response of plasma cholesterol in the CC subjects is caused mainly by the larger increase in HDL cholesterol in this group. Wang et al. (6) also found significantly higher plasma HDL cholesterol levels in men homozygous for the C allele. Furthermore, Machleder et al. (10) reported that cholesterol 7-hydroxylase activity segregates with plasma HDL-cholesterol concentrations in mice. However, for the moment, the relation between the CYP7A1 polymorphism and plasma HDL cholesterol remains unclear.
In this study, we also found a link between the cholesterol response to cafestol and the CYP7A1 genotype. Previous studies indicated that cafestol leads to increased levels of total and LDL cholesterol in humans (27). We showed that cafestol inhibits bile acid synthesis in mice (35) and in rat hepatocytes (36) by downregulation of CYP7A1 and CYP27 gene expression and inhibition of CYP7A1 enzyme activity. The suppression of bile acid synthesis in humans may also explain the increase in plasma cholesterol levels. However, at this moment, it is difficult to extrapolate our results physiologically.
Overall, the effects of the CYP7A1 polymorphism were mild. In the dietary cholesterol intervention, the polymorphism accounted for 3 and 20% of the total variation in the response of plasma cholesterol and LDL cholesterol, respectively. However, these percentages might be overestimated because they are based on our population and our experimental conditions only. Interestingly, the apoE genotype did not contribute to the total variation in the response of plasma cholesterol after dietary cholesterol and cafestol interventions. This lack of effect of the apoE genotype was reported in 2 earlier studies (6,12).
Several polymorphisms in other genes involved in lipid metabolism were studied in relation to responses of plasma lipid levels after dietary interventions. Effects were reported for the enzymes lipoprotein lipase, hepatic lipase, lecithin cholesterol acyltransferase, and cholesterol ester transfer protein [for a review, see (2)]. However, the effects are small and often not reproducible. In addition, they account for only a small percentage of the total variance in the dietary response of plasma lipids. Therefore, it is unlikely that only 1 polymorphism is a major factor in determining the interindividual variation in the response of plasma lipid levels. It is likely that several polymorphisms in different genes together with environmental factors are involved in this response.
In conclusion, the CYP7A1 polymorphism has an effect on the response of plasma cholesterol after an increase in dietary cholesterol and cafestol, with a lower response in subjects homozygous for the A allele. The polymorphism accounts for a small but significant proportion of the genetic variability in the response of plasma lipid levels.
|
ACKNOWLEDGMENTS |
|---|
|
FOOTNOTES |
|---|
-hydroxylase gene display a lower response to a dietary challenge with cholesterol or cafestol than CC homozygotes. Atherosclerosis 3:2 (suppl.): P126. 
2 Supported by a grant from ZonMw and the Netherlands Heart Foundation (NHS) (980–10-024).
4 Information on the design of the dietary trials is available with the online posting of this paper at www.nutrition.org.
Manuscript received 26 February 2004. Initial review completed 13 April 2004. Revision accepted 2 June 2004.
|
LITERATURE CITED |
|---|
|
TOPABSTRACTMETHODSRESULTSDISCUSSIONLITERATURE CITED |
|---|
1. Katan, M. B., Beynen, A. C., de Vries, J. H. & Nobels, A. (1986) Existence of consistent hypo- and hyperresponders to dietary cholesterol in man. Am. J. Epidemiol. 123:221-234.
2. Ye, S. Q. & Kwiterovich, P.O.J. (2000) Influence of genetic polymorphisms on responsiveness to dietary fat and cholesterol. Am. J. Clin. Nutr. 72:1275S-1284S.
3. Princen, H., Post, S. M. & Twisk, J. (1997) Regulation of bile acid synthesis. Curr. Pharm. Design 3:59-84.
4. Lipid Research Clinics Program (1984) The Lipid Research Clinics Coronary Primary Prevention Trial results. II. The relationship of reduction in incidence of coronary heart disease to cholesterol lowering. J. Am. Med. Assoc. 251:365-374.[Abstract]
5. Pullinger, C. R., Eng, C., Salen, G., Shefer, S., Batta, A. K., Erickson, S. K., Verhagen, A., Rivera, C. R. & Mulvihill, S. J., et al (2002) Human cholesterol 7-hydroxylase (CYP7A1) deficiency has a hypercholesterolemic phenotype. J. Clin. Investig. 110:109-117.
6. Wang, J., Freeman, D. J., Grundy, S. M., Levine, D. M., Guerra, R. & Cohen, J. C. (1998) Linkage between cholesterol 7-hydroxylase and high plasma low-density lipoprotein cholesterol concentrations. J. Clin. Investig. 101:1283-1291.
7. Couture, P., Otvos, J. D., Cupples, L. A., Wilson, P. W., Schaefer, E. J. & Ordovas, J. M. (1999) Association of the A-204C polymorphism in the cholesterol 7-hydroxylase gene with variations in plasma low density lipoprotein cholesterol levels in the Framingham Offspring Study. J. Lipid Res. 40:1883-1889.
8. Repa, J. J., Lund, E. G., Horton, J. D., Leitersdorf, E., Russell, D. W., Dietschy, J. M. & Turley, S. D. (2000) Disruption of the sterol 27-hydroxylase gene in mice results in hepatomegaly and hypertriglyceridemia. Reversal by cholic acid feeding. J. Biol. Chem. 275:39685-39692.
9. Kirk, E. A., Moe, G. L., Caldwell, M. T., Lernmark, J. A., Wilson, D. L. & LeBoeuf, R. C. (1995) Hyper- and hypo-responsiveness to dietary fat and cholesterol among inbred mice: searching for level and variability genes. J. Lipid Res. 36:1522-1532.[Abstract]
10. Machleder, D., Ivandic, B., Welch, C., Castellani, L., Reue, K. & Lusis, A. J. (1997) Complex genetic control of HDL levels in mice in response to an atherogenic diet. Coordinate regulation of HDL levels and bile acid metabolism. J. Clin. Investig. 99:1406-1419.
11. Davis, A. M., Pond, W. G., Wheeler, M., Ishimura-Oka, K., Su, D. R., Li, C. M. & Mersmann, H. J. (1998) Alleles of the cholesterol 7 alpha-hydroxylase (CYP7) gene in pigs selected for high or low plasma total cholesterol. Proc. Soc. Exp. Biol. Med. 217:466-470.[Abstract]
12. Hubacek, J. A., Pitha, J., Skodova, Z., Poledne, R., Lanska, V., Waterworth, D. M., Humphries, S. E. & Talmud, P. J. (2003) Polymorphisms in CYP-7A1, not APOE, influence the change in plasma lipids in response to population dietary change in an 8 year follow-up; results from the Czech MONICA study. Clin. Biochem. 36:263-267.[Medline]
13. Weggemans, R. M., Zock, P. L., Urgert, R. & Katan, M. B. (1999) Differences between men and women in the response of serum cholesterol to dietary changes. Eur. J. Clin. Investig. 29:827-834.[Medline]
14. Beynen, A. C. & Katan, M. B. (1985) Reproducibility of the variations between humans in the response of serum cholesterol to cessation of egg consumption. Atherosclerosis 57:19-31.[Medline]
15. Beynen, A. C. & Katan, M. B. (1985) Effect of egg yolk feeding on the concentration and composition of serum lipoproteins in man. Atherosclerosis 54:157-166.[Medline]
16. Katan, M. B. & Beynen, A. C. (1987) Characteristics of human hypo- and hyperresponders to dietary cholesterol. Am. J. Epidemiol. 125:387-399.
17. Glatz, J. F., Turner, P. R., Katan, M. B., Stalenhoef, A. F. & Lewis, B. (1993) Hypo- and hyperresponse of serum cholesterol level and low density lipoprotein production and degradation to dietary cholesterol in man. Ann. N.Y. Acad. Sci. 676:163-179.[Abstract]
18. Brussaard, J. H., Dallinga-Thie, G., Groot, P. H. & Katan, M. B. (1980) Effects of amount and type of dietary fat on serum lipids, lipoproteins and apolipoproteins in man. A controlled 8-week trial. Atherosclerosis 36:515-527.[Medline]
19. Katan, M. B., Berns, M. A., Glatz, J. F., Knuiman, J. T., Nobels, A. & de Vries, J. H. (1988) Congruence of individual responsiveness to dietary cholesterol and to saturated fat in humans. J. Lipid Res. 29:883-892.[Abstract]
20. Mensink, R. P. & Katan, M. B. (1987) Effect of monounsaturated fatty acids versus complex carbohydrates on high-density lipoproteins in healthy men and women. Lancet 1:122-125.[Medline]
21. Mensink, R. P. & Katan, M. B. (1989) Effect of a diet enriched with monounsaturated or polyunsaturated fatty acids on levels of low-density and high-density lipoprotein cholesterol in healthy women and men. N. Engl. J. Med. 321:436-441.[Abstract]
22. Mensink, R. P. & Katan, M. B. (1990) Effect of dietary trans fatty acids on high-density and low-density lipoprotein cholesterol levels in healthy subjects. N. Engl. J. Med. 323:439-445.[Abstract]
23. Zock, P. L. & Katan, M. B. (1992) Hydrogenation alternatives: effects of trans fatty acids and stearic acid versus linoleic acid on serum lipids and lipoproteins in humans. J. Lipid Res. 33:399-410.[Abstract]
24. Zock, P. L., de Vries, J. H. & Katan, M. B. (1994) Impact of myristic acid versus palmitic acid on serum lipid and lipoprotein levels in healthy women and men. Arterioscler. Thromb. 14:567-575.[Abstract]
25. Zock, P. L., Katan, M. B., Merkus, M. P., van Dusseldorp, M. & Harryvan, J. L. (1990) Effect of a lipid-rich fraction from boiled coffee on serum cholesterol. Lancet 335:1235-1237.[Medline]
26. Mensink, R. P., Lebbink, W. J., Lobbezoo, I. E., Weusten-Van der Wouw, M. P., Zock, P. L. & Katan, M. B. (1995) Diterpene composition of oils from Arabica and Robusta coffee beans and their effects on serum lipids in man. J. Intern. Med. 237:543-550.[Medline]
27. Weusten-Van der Wouw, M. P., Katan, M. B., Viani, R., Huggett, A. C., Liardon, R.P.G., Thelle, D. S., Ahola, I. & Aro, A. (1994) Identity of the cholesterol-raising factor from boiled coffee and its effects on liver function enzymes. J. Lipid Res. 35:721-733.[Abstract]
28. Urgert, R., Meyboom, S., Kuilman, M., Rexwinkel, H., Vissers, M. N., Klerk, M. & Katan, M. B. (1996) Comparison of effect of cafetiere and filtered coffee on serum concentrations of liver aminotransferases and lipids: six month randomised controlled trial. Br. Med. J. 313:1362-1366.
29. Urgert, R., Schulz, A. G. & Katan, M. B. (1995) Effects of cafestol and kahweol from coffee grounds on serum lipids and serum liver enzymes in humans. Am. J. Clin. Nutr. 61:149-154.
30. Urgert, R., Essed, N., van der Weg, G., Kosmeijer-Schuil, T. G. & Katan, M. B. (1997) Separate effects of the coffee diterpenes cafestol and kahweol on serum lipids and liver aminotransferases. Am. J. Clin. Nutr. 65:519-524.
31. Hofman, M. K., Groenendijk, M., Verkuijlen, P.J.J.H., Jonkers, I.J.A.M., Mohrschladt, M. F., Smelt, A.H.M. & Princen, H.M.G. (2004) Modulating effect of the A-278C promoter polymorphism in the cholesterol 7-hydroxylase gene on serum lipid levels in normolipidemic and hypertriglyceridemic individuals. Eur. J. Hum. Genet. (in press).
32. Weggemans, R. M., Zock, P. L., Ordovas, J. M., Pedro-Botet, J. & Katan, M. B. (2001) Apoprotein E genotype and the response of serum cholesterol to dietary fat, cholesterol and cafestol. Atherosclerosis 154:547-555.[Medline]
33. Molowa, D. T., Chen, W. S., Cimis, G. M. & Tan, C. P. (1992) Transcriptional regulation of the human cholesterol 7 alpha-hydroxylase gene. Biochemistry 31:2539-2544.[Medline]
34. Reihner, E., Angelin, B., Rudling, M., Ewerth, S., Bjorkhem, I. & Einarsson, K. (1990) Regulation of hepatic cholesterol metabolism in humans: stimulatory effects of cholestyramine on HMG-CoA reductase activity and low density lipoprotein receptor expression in gallstone patients. J. Lipid Res. 31:2219-2226.[Abstract]
35. Post, S. M., de Roos, B., Vermeulen, M., Afman, L., Jong, M. C., Dahlmans, V. E., Havekes, L. M., Stellaard, F., Katan, M. B. & Princen, H. M. (2000) Cafestol increases serum cholesterol levels in apolipoprotein E*3-Leiden transgenic mice by suppression of bile acid synthesis. Arterioscler. Thromb. Vasc. Biol. 20:1551-1556.
36. Post, S. M., de Wit, E. C. & Princen, H. M. (1997) Cafestol, the cholesterol-raising factor in boiled coffee, suppresses bile acid synthesis by downregulation of cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase in rat hepatocytes. Arterioscler. Thromb. Vasc. Biol. 17:3064-3070.
This article has been cited by other articles:
|
|
 |
|
  I. A. Pikuleva CHOLESTEROL-METABOLIZING CYTOCHROMES P450 Drug Metab. Dispos., April 1, 2006; 34(4): 513 - 520. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
