- Research Paper
- Published:
Cholesterol absorption status and fasting plasma cholesterol are modulated by the microsomal triacylglycerol transfer protein −493 G/T polymorphism and the usual diet in women
Genes & Nutrition volume 6, pages 71–79 (2011)
Abstract
An important inter-individual variability in cholesterol absorption has been reported. It could result from polymorphisms in genes coding for proteins involved in the absorption process and in interaction with dietary intakes. To assess whether the extent of cholesterol absorption or synthesis is modified in adult women according to the −493 G/T polymorphism in the microsomal triglyceride transfer protein gene (MTP) and/or the habitual diet. Cholestanol and sitosterol, as well as desmosterol and lathosterol, surrogate markers of cholesterol absorption or synthesis, respectively, were analyzed in the fasting plasma of 69 middle-aged women under a Western-type diet (WD) and after 3 months on a low-saturated fat, low-cholesterol/Mediterranean-type diet (LFLCD). Genotypes for MTP −493G/T polymorphism were determined. Under an usual WD, subjects homozygous for the MTP −493 T allele exhibited higher (P < 0.05) fasting serum concentrations of cholestanol (199.0 ± 30.0 vs. 133 ± 7.4 × 102 mmol/mol cholesterol) and lathosterol (188.7 ± 21.8 vs. 147.6 ± 9.1 × 102 mmol/mol cholesterol), as well as total cholesterol (7.32 ± 0.22 vs. 6.63 ± 0.12 mmol/l) compared to G carrier subjects. After 3 months on a LFLCD, level of absorption markers decreased in TT subjects with no change in synthesis ones, leading to values comparable to those measured in G carriers. The lowering of plasma total and LDL cholesterol due to dietary change was 2.4- and 2.3-fold greater in TT women than in G carriers. The polymorphism −493G/T in MTP modulates the level of cholesterol absorption but not synthesis in women under a WD, an effect abolished under a prudent LFLCD.
Introduction
Cardiovascular disease (CVD) remains the leading cause of mortality in industrialized countries and is thus a major health outcome. Many epidemiological studies have indicated that the elevation in plasma cholesterol is a key and independent risk factor in the etiology of coronary heart disease [26]. The high incidence of CVD is partly ascribed to dietary habits [30], and more specifically, diets rich in saturated fat or cholesterol are known to increase concentrations of fasting plasma total cholesterol and LDL cholesterol [31].
Along with de novo endogenous synthesis, intestinal cholesterol absorption regulates the body cholesterol homeostasis. While the mechanisms controlling cholesterol metabolism and levels have been widely investigated during the last decades [44], they do not yet explain the large inter-individual variability observed (30–80%) in humans for the rate of cholesterol absorption by the small intestine [4, 39].
Cholesterol absorption is a complex multifactorial and polygenic process that is thought to result from an interaction between an individual’s genetic background [44] and various environmental factors. Specifically, the efficiency of intestinal cholesterol absorption depends on dietary factors such as the dose of dietary cholesterol [29], the amount of dietary phytosterols [28] and the amount or type of dietary fat [33].
Regarding genetic factors, present knowledge is limited. Upon digestion, biliary and dietary cholesterol are stepwise absorbed by the small intestinal mucosa and re-secreted into chylomicrons reaching the circulation [1]. Several cellular trans-membrane transporters such as SR-B1, NPC1L1 and ABCG5/G8 have already been implicated in the process of cholesterol absorption by the small intestine [12], but their respective roles are still under investigation. Only few studies have documented the influence of allelic variants in genes coding for such transporters on the extent of cholesterol absorption [5, 8, 36].
In fact, many other intracellular proteins play key roles in cholesterol and lipid trafficking, packaging into chylomicrons and baso-lateral secretion [12]. The microsomal triglyceride transfer protein (MTP) is a heterodimeric lipid transfer protein mainly present in hepatocytes and enterocytes. MTP has an essential role in the assembly process and secretion of very low-density lipoproteins (VLDL) and chylomicrons into the plasma [40]. Indeed, it is able to transfer cholesterol esters [13] and triglycerides from the endoplasmic reticulum membranes to nascent apo-B lipoproteins [46]. For instance, the loss of activity resulting from mutations in the coding regions of the MTP gene expresses the rare genetic disorder abetalipoproteinemia, with a suppressed chylomicron secretion and hypocholesterolemia [40, 45]. The MTP gene is polymorphic, with several genetic variants especially in the promoter region [14, 17]. A number of studies were undertaken to demonstrate associations between this single nucleotide polymorphisms (SNP) at position −493 (G/T) in the promoter region of the MTTP and the concentration of circulating cholesterol but provided inconsistent data [6, 7, 14, 19, 38, 41, 49].
The purpose of this study was to test for the first time the hypothesis of an association between the common MTP −493 G/T polymorphism and the extent of cholesterol absorption or synthesis in humans and its interaction with habitual diet. To that aim, we measured in 69 adult women surrogate markers of cholesterol absorption (cholestanol and sitosterol) and synthesis (desmosterol and lathosterol) [16, 23, 24], as well as plasma and lipoprotein cholesterol under two different dietary regimen, namely a Western diet (WD) or a low-saturated fat and low-cholesterol/Mediterranean-type diet (LFLCD).
Subjects and methods
Subjects
The population and the dietary intervention have previously been described for the whole Medi-RIVAGE cohort [42, 43]. In the present study, the subgroup population was composed of 69 Caucasian women with moderate and untreated cardiovascular risk factors (Table 1). Briefly, women aged 28–70 were recruited at the Center for Detection and Prevention of Atherosclerosis at La Timone University Hospital (Marseille, France). They presented at least one of the following eligibility criteria: fasting plasma cholesterol, 6.5–7.7 mmol/l; plasma triacylglycerols, 2.1–4.6 mmol/l; plasma glycemia, 6.1–6.9 mmol/l; systolic and diastolic blood pressure between 140–180 and 90–105 mm Hg, respectively; BMI > 27 kg/m2; smoking; sedentary lifestyle; family history of CVD. Hypolipidemic treatment was an exclusion criterion [43].
At entry, subjects (n = 69) were used to follow a WD as published [43] and were advised to follow, for 3 months, a Mediterranean-type diet (n = 35) or a low-fat type diet (n = 34), both intended to reduce saturated fatty acids and cholesterol intakes. The compliance to dietary recommendations was checked by dieticians, and 3-day food records were obtained at entry and after 3 months. The dietary records were analyzed by dieticians using the GENI program (Micro6, Nancy, France) based on the French REGAL food database [42].
Analytical methods (laboratory determinations)
At entry and at the end of the 3-month (3-mo) intervention period, body mass index (BMI: kg/m2) was calculated, and blood samples collected after an overnight fast. The triglyceride-rich lipoprotein (TRL) fraction (sf = 20–400) was isolated by ultracentrifugation, as previously described [10]. Biochemical analyses were performed with commercial kits on fasting plasma samples as reported in details [43]. The sum of cholesterol carried out by apoB-containing lipoproteins (LDL- plus TRL-cholesterol) was calculated. Fasting serum non-cholesterol sterols (cholestanol, sitosterol, desmosterol and lathosterol) were quantified by gas chromatography-mass spectrometry (GC–MS) on a Hewlett-Packard 6890 GC-5973 MS apparatus, using the reference method of Miettinen et al. [23] using a Zebron-1 capillary column (50 m × 0.25 mm i.d., 0.50 μm film thickness). Epicoprostanol (0.2 ml) was added to serum (0.2 ml) as an internal standard. After alkaline hydrolysis, extraction and derivatization, non-cholesterol sterol concentrations were determined from the same GC–MS run. To eliminate the effect of changing lipoprotein level, the non-cholesterol sterol values were standardized and expressed in terms of 102 mmol/mol cholesterol, as usual [21, 24].
Polymorphisms detection
Genomic DNA was prepared from white blood cells by a standard proteinase K-phenol method as reported [7]. The MTP (or MTTP) −493G/T polymorphisms (rs 1800591, chromosome 4, contig NT 016354.18 position 25043208) were genotyped by a polymerase chain reaction (PCR)-restriction fragment length polymorphism assay, the restriction cleavage being performed by Hph1 enzyme [14]. Primers used for PCR were as follows: forward 5′-AGTTTCACACATAAGGACAATCATCTA-3′ and reverse 5′-GGATTTAAATTTAAACTGTTAATTCATATCAC-3′ (mutated).
Statistical analyses
Statistical analyses were conducted with SPSS software (v17.0, SPSS Inc., Chicago, IL, USA). Hardy–Weinberg equilibrium between genotypes of MTP −493G/T was assessed by a chi square-test. All data are expressed as means ± SEMs.
Prior to analysis, the distribution of each outcome variable was checked for normality, and logarithmic transformations were performed on individual values of plasma and Framingham score.
Statistical significances between Mediterranean-type diet and low-fat-type diet subgroups were tested with univariate general linear models on plasma cholesterol parameters and serum non-cholesterol sterols (data not shown). These two subgroups of women did not differ according to the followed diet, in agreement with observations previously reported for the whole mixed cohort [42]. The two subgroups could thus be merged for the present analysis as done before [7].
Before testing the effect of genotypes on the dependent variables, Pearson correlation coefficients were calculated to check interrelations between absorption and synthesis markers of cholesterol.
Age, BMI, alcohol consumption, smoking status and menopausal status were identified as interfering covariables and used as adjustment factors (tested by univariate general linear models at entry). The effects of the genotypes at entry, 3-mo and on the response to the diet were tested with general linear models. Intragroup comparison between entry and 3-mo data was made with Student’s t paired test or non-parametric Wilcoxon test, as indicated. A P value <0.05 was considered statistically significant.
Results
In the women sample studied (n = 69), the frequency of MTP −493G/T genotypes was 0.43 for GG, 0.43 for GT and 0.13 for TT. The distribution of genotypes was not significantly different from that expected under the Hardy–Weinberg equilibrium (P = 0.729). The T allele frequency was 0.35 in this population and was 0.15 in a reference population presented in Hapmap for 24 European-caucasian subjects [25].
At entry (Table 1), women fasting plasma cholesterol ranged 4.26–9.54 mmol/l, 58% women having hypercholesterolemia (cholesterol >6.5 mmol/l). Moreover, 62% women had a BMI above 25, 25% had a systolic blood pressure higher than 140 mm Hg, 19% had triglyceridemia >1.7 mmol/l, and 7% had hyperglycemia (glucose >6 mmol/l).
As shown in Table 2, BMI, weight and energy intake (kJ) were not different between genotypes. Moreover, protein, carbohydrate and fat (saturated, monounsaturated and polyunsaturated) intakes were comparable at entry and after 3-mo intervention whatever the genotype. The 3-mo dietary intervention with LFLCD clearly resulted in significant changes in nutrient intakes, especially in reduction of saturated fat and cholesterol intakes (P < 0.05) independently of the allele present.
At entry under a Western diet, cholestanol and sitosterol plasma levels gradually increased from homozygous GG toward homozygous TT (Table 3). The comparison of homozygous TT with G carriers (grouping GT and GG alleles) showed higher plasma levels of cholestanol and sitosterol, along with a moderately higher level of lathosterol but not desmosterol (Table 4).
The levels of the various cholesterol parameters measured at entry were not different between genotype groups except for a trend to higher plasma cholesterol in subjects having the T allele (Table 3). In contrast, women homozygous for T allele exhibited higher values for plasma cholesterol, TRL-cholesterol and ApoB-containing lipoprotein cholesterol than the G carriers at entry (Table 4). Comparable HDL cholesterol, TRL-Triglycerides and ApoB levels were observed in TT or G carriers.
After the 3-mo dietary intervention with LFLCD, the levels of all synthesis and absorption markers were no longer significantly different between G carriers and TT women (Table 4), although values for cholestanol, sitosterol and lathosterol remained marginally higher. No differences were found between genotypes for other lipid or cholesterol or ApoB levels.
However, the effect of LFLCD appeared different according to genotypes. Indeed, TT women, but not G carrier women, showed a decrease in cholestanol and sitosterol levels (P = 0.045 and P = 0.035 adjusted to age and menopausal status; P = 0.057 and P = 0.043 adjusted to age, menopausal status and BMI, respectively; Table 4). This reduction in cholesterol absorption markers was not balanced by a noticeable elevation of desmosterol or lathosterol levels. Finally, only TT women showed a significant reduction in TRL-cholesterol level after 3-mo on the LFLCD.
Discussion
The results of the present study show, for the first time in adult women, an association of the −493G/T polymorphism in MTP gene with cholesterol absorption markers, as well as the metabolic response to a dietary challenge. This association is modulated by the chronic diet of the subjects in such a way that it is observed only under a Western-type diet (WD) and not a low-saturated fat, low-cholesterol/Mediterranean-type diet (LFLCD).
As in numerous previous studies, we measured herein serum non-cholesterol sterols as surrogate markers of cholesterol metabolism [16, 20, 23, 24]. Cholestanol and sitosterol well reflect the extent of intestinal cholesterol absorption, whereas lathosterol and desmosterol are precursors and markers of endogenous cholesterol synthesis. It is noteworthy that we found in the present study (data not shown) as expected that the two cholesterol absorption markers were positively correlated and they were both negatively correlated with synthesis markers, reflecting the well-known cholesterol homeostasis regulation [24].
It has been shown using a stable isotope method that the rate of cholesterol absorption is not different in women and men [4]. Nevertheless, some previous studies showed a sex-specific association between MTP polymorphisms and anthropometric, blood and lipid parameters [3, 48, 49]. Moreover, the effects of a dietary challenge can be differently modulated by MTP genotypes according to sex. For instance, previous results from our laboratory showed that insulinemia and Framingham score displayed a genotype by sex interaction for the −493 locus in MTP gene during this 3-mo dietary intervention [7]. This therefore highlights the importance of considering genders separately in such gene–diet interaction studies.
Our first finding was the association of the −493G/T polymorphism in MTP gene with cholesterol absorption markers, but not synthesis ones, in adult women under a Western-type diet (WD). As we did not find differences in the dietary intakes of subjects according to the gene locus at entry under the WD, this observation supports the existence of a clear effect of the polymorphism at −493 MTP gene locus on the cholesterol absorption process in this cholesterol- and saturated fat-rich dietary context. Indeed, the T allele is associated with an increased cholesterol absorption status with TT homozygotes having a significantly higher level of surrogate markers (+49.6 and +139.4% for cholestanol and sitosterol, respectively) compared to G carriers. In contrast, this locus does not seem to be noticeably associated with the extent of cholesterol synthesis. It was very interesting to observe that, under the WD, TT homozygote women showed higher fasting levels for plasma cholesterol, TRL-cholesterol and ApoB-containing lipoprotein cholesterol, illustrating the clear relationship existing between the augmented extent of intestinal cholesterol absorption and the increased levels of circulating lipoproteins carrying cholesterol derived from the small intestine, and also the liver. This is in line with previous data reporting an association of LDL cholesterol with cholesterol absorption level [20, 22, 32, 39]. It is noteworthy that fasting HDL cholesterol and TG levels were not affected by this gene locus, suggesting that it predominantly interacts with the intestinal processing of cholesterol in a WD context.
Our second finding highlighted the modulatory effect of the −493G/T MTP polymorphism on the cholesterol absorption status and the metabolic response of women to a low-saturated fat, low-cholesterol/Mediterranean-type diet (LFLCD) 3-mo challenge. As for entry, no differences in the subject’s dietary intakes according to the locus were observed after the 3-mo intervention period, but the response to LFLCD differed between homozygous TT and G carriers. The key observation was that the LFLCD resulted in a significant reduction in both cholesterol absorption markers in TT women (−12.9 and −17.4% for cholestanol and sitosterol, respectively), whereas not noticeable change was observed in G carriers. This contrasted response abolished the significant difference in absorption status as observed between TT and G carriers under the WD. This indicates that under a LFLCD, the −493G/T MTP polymorphism does not modulate the cholesterol absorption phenotype as observed under the WD. This points out that while a diet rich in saturated fat and cholesterol promotes a high-absorption status in TT women, a low-saturated fat, low-cholesterol diet does not illustrating a strong gene–diet interaction. In contrast, the endogenous cholesterol synthesis markers were not altered by the 3-mo dietary challenge, while the homozygote TT women showed an unconsistent change with comparable desmosterol and increased lathosterol levels compared with G carriers. This modest rise can likely be explained as the result of a compensatory mechanism somewhat increasing cholesterol synthesis when cholesterol absorption decreased as reported [22].
The decrease observed in cholesterol absorption status in TT women after the LFLCD was accompanied by a 26.3% lowering of TRL-cholesterol levels which are the primary circulating cholesterol carriers derived from both the small intestine (chylomicrons) and the liver (VLDL). This well supports the concept that the T allele at −493 MTP gene locus could favor the packaging of cholesterol into TRL particles.
Overall, the low-saturated fat, low-cholesterol/Mediterranean-type diet (LFLCD) promoted a lower cholesterol absorption status which can explain, at least partly, the observed beneficial reductions in total, TRL-cholesterol and ApoB-containing lipoprotein cholesterol. In contrast, it has recently been reported that a restricted weight-loss diet led to a reduction in cholesterol synthesis without changes in absorption capacity in women [35]. Moreover, variations in intakes of dietary fat or cholesterol were not accompanied by noticeable changes in cholesterol absorption markers in a short-term study in men [27].
The mechanisms behind the observed effects of the −493G/T MTP polymorphism deserve more specific comments. In fact, some other studies have highlighted that polymorphisms in MTP gene can alter various health-related indexes such as circulating cholesterol [2, 14, 17, 19] and insulinemia [7]. Both functional genetic variant in the MTP gene and diet are likely to alter the expression and intracellular concentration of MTP and subsequently, the amount of assembled chylomicrons in the small intestine. The lower level of cholesterol absorption in G carrier versus TT women could likely result from the twofold lower activity of the MTP gene promoter bearing the G allele versus T as found in vitro [14]. It has also been reported that the activity of the MTP gene promoter could also be modulated by the −164T > C polymorphism [34] which was not studied herein. On the other hand, the MTP gene is up-regulated by cholesterol [9] and down regulated by insulin [18] and the transcription factor SREBP1 [9, 37]. We can thus suggest that a higher intake of dietary cholesterol, as occurring under the Western diet (WD) period, could enhance the expression of MTP in human intestinal cells and hypothesize that this could preferentially occur in the presence of the T allele in the −493 locus of the MTP gene promoter. When changing for a low-cholesterol-type diet as herein, homozygous TT women would more markedly than G carriers lower the intracellular MTP gene transcription through lowering of cholesterol intake and decreasing insulinemia resulting in lower MTP expression, and finally lower cholesterol uptake and chylomicron assembly. Further studies should aim to validate this hypothesis.
The present data raise questions in terms of public health nutrition and cardiovascular risk. It has largely been described that upon controlled dietary interventions dedicated to lower plasma or LDL cholesterol, part of subjects showed a marked response, while others did not exhibit any change [5, 11, 15, 50], thus highly suggesting an important gene–diet interaction. According to other authors, the minor variant −493T allele in MTP promoter has been associated with lower serum LDL cholesterol [2, 14, 17, 19] but not in all studies [38, 49]. Finally, a higher cholesterol absorption level in subjects with elevated risk of CHD [32, 20] has recently been reported. Taken together, these data and our present findings support the concept of a strong link between usual diet, gene polymorphisms, ApoB-containing lipoprotein cholesterol and CHD risk. This is reinforced by the higher frequency of TT homozygotes found as herein in cohorts of subjects at moderate/high cardiovascular risk [1, 14, 38] compared to healthy subjects [14, 17, 38]. Large-scale intervention studies are needed to confirm our findings owing to the low frequency of minor allelic variants and possible sex-specific associations. Nevertheless, the present observation that 13% women at moderate cardiovascular risk are TT homozygote for the −493G/T MTP polymorphism and have a high-absorber cholesterol status under a unbalanced diet raises the need for more targeted dietary recommendations in the perspective of personalized nutrition based on nutrigenetics [47].
References
Beaumier-Gallon G, Dubois C, Senft M, Vergnes MF, Pauli AM, Portugal H, Lairon D (2001) Dietary cholesterol is secreted in intestinally derived chylomicrons during several subsequent postprandial phases in healthy humans. Am J Clin Nutr 73:870–877
Bjorn L, Leren TP, Ose L, Hamsten A, Karpe F (2000) A functional polymorphism in the promoter region of the microsomal triglyceride transfer protein (MTP −493G/T) influences lipoprotein phenotype in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol 20:1784–1788
Bohme M, Grallert H, Fischer A, Gieger C, Nitz I, Heid I, Kohl C, Wichmann HE, Illig T, Doring F (2008) MTTP variants and body mass index, waist circumference and serum cholesterol level: association analyses in 7582 participants of the KORA study cohort. Mol Genet Metab 95:229–232
Bosner MS, Lange LG, Stenson WF, Ostlund RE Jr (1999) Percent cholesterol absorption in normal women and men quantified with dual stable isotopic tracers and negative ion mass spectrometry. J Lipid Res 40:302–308
Cohen JC, Pertsemlidis A, Fahmi S, Esmail S, Vega GL, Grundy SM, Hobbs HH (2006) Multiple rare variants in NPC1L1 associated with reduced sterol absorption and plasma low-density lipoprotein levels. Proc Natl Acad Sci USA 103:1810–1815
Couture P, Otvos JD, Cupples LA, Wilson PW, Schaefer EJ, Ordovas JM (2000) Absence of association between genetic variation in the promoter of the microsomal triglyceride transfer protein gene and plasma lipoproteins in the Framingham offspring study. Atherosclerosis 148:337–343
Gastaldi M, Diziere S, Defoort C, Portugal H, Lairon D, Darmon M, Planells R (2007) Sex-specific association of fatty acid binding protein 2 and microsomal triacylglycerol transfer protein variants with response to dietary lipid changes in the 3-mo Medi-RIVAGE primary intervention study. Am J Clin Nutr 86:1633–1641
Gylling H, Hallikainen M, Pihlajamaki J, Agren J, Laakso M, Rajaratnam RA, Rauramaa R, Miettinen TA (2004) Polymorphisms in the ABCG5 and ABCG8 genes associate with cholesterol absorption and insulin sensitivity. J Lipid Res 45:1660–1665
Hagan DL, Kienzle B, Jamil H, Hariharan N (1994) Transcriptional regulation of human and hamster microsomal triglyceride transfer protein genes. Cell type-specific expression and response to metabolic regulators. J Biol Chem 269:28737–28744
Harbis A, Defoort C, Narbonne H, Juhel C, Senft M, Latge C, Delenne B, Portugal H, Atlan-Gepner C, Vialettes B et al (2001) Acute hyperinsulinism modulates plasma apolipoprotein B-48 triglyceride-rich lipoproteins in healthy subjects during the postprandial period. Diabetes 50:462–469
Herron KL, McGrane MM, Waters D, Lofgren IE, Clark RM, Ordovas JM, Fernandez ML (2006) The ABCG5 polymorphism contributes to individual responses to dietary cholesterol and carotenoids in eggs. J Nutr 136:1161–1165
Iqbal J, Hussain MM (2009) Intestinal lipid absorption. Am J Physiol Endocrinol Metab 296:E1183–E1194
Iqbal J, Rudel LL, Hussain MM (2008) Microsomal triglyceride transfer protein enhances cellular cholesteryl esterification by relieving product inhibition. J Biol Chem 283:19967–19980
Karpe F, Lundahl B, Ehrenborg E, Eriksson P, Hamsten A (1998) A common functional polymorphism in the promoter region of the microsomal triglyceride transfer protein gene influences plasma LDL levels. Arterioscler Thromb Vasc Biol 18:756–761
Katan MB, Beynen AC (1987) Characteristics of human hypo- and hyperresponders to dietary cholesterol. Am J Epidemiol 125:387–399
Kempen HJ, Glatz JF, Gevers Leuven JA, van der Voort HA, Katan MB (1988) Serum lathosterol concentration is an indicator of whole-body cholesterol synthesis in humans. J Lipid Res 29:1149–1155
Ledmyr H, Karpe F, Lundahl B, McKinnon M, Skoglund-Andersson C, Ehrenborg E (2002) Variants of the microsomal triglyceride transfer protein gene are associated with plasma cholesterol levels and body mass index. J Lipid Res 43:51–58
Lin MC, Gordon D, Wetterau JR (1995) Microsomal triglyceride transfer protein (MTP) regulation in HepG2 cells: insulin negatively regulates MTP gene expression. J Lipid Res 36:1073–1081
Lundahl B, Skoglund-Andersson C, Caslake M, Bedford D, Stewart P, Hamsten A, Packard CJ, Karpe F (2006) Microsomal triglyceride transfer protein −493T variant reduces IDL plus LDL apoB production and the plasma concentration of large LDL particles. Am J Physiol Endocrinol Metab 290:E739–E745
Matthan NR, Pencina M, Larocque JM, Jacques PF, D’Agostino RB, Schaefer EJ, Lichtenstein AH (2009) Alterations in cholesterol absorption and synthesis characterize Framingham offspring study participants with coronary heart disease. J Lipid Res 50:1927–1935
Miettinen TA (1982) Diurnal variation of cholesterol precursor’s squalene and methyl sterols in human plasma lipoproteins. J Lipid Res 23:466–473
Miettinen TA, Kesaniemi YA (1989) Cholesterol absorption: regulation of cholesterol synthesis and elimination and within-population variations of serum cholesterol levels. Am J Clin Nutr 49:629–635
Miettinen TA, Tilvis RS, Kesaniemi YA (1989) Serum cholestanol and plant sterol levels in relation to cholesterol metabolism in middle-aged men. Metabolism 38:136–140
Miettinen TA, Tilvis RS, Kesaniemi YA (1990) Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population. Am J Epidemiol 131:20–31
NCBI (2010) Reference SNP(refSNP) cluster report: rs1800591 http://www.ncbi.nlm.nih.gov/projects/SNP/snp_ref.cgi?rs=1800591
EP NC (2002) Third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III) final report. Circulation 106:3143–3421
Nissinen MJ, Gylling H, Miettinen TA (2008) Responses of surrogate markers of cholesterol absorption and synthesis to changes in cholesterol metabolism during various amounts of fat and cholesterol feeding among healthy men. Br J Nutr 99:370–378
Ostlund RE Jr (2007) Phytosterols, cholesterol absorption and healthy diets. Lipids 42:41–45
Ostlund RE Jr, Bosner MS, Stenson WF (1999) Cholesterol absorption efficiency declines at moderate dietary doses in normal human subjects. J Lipid Res 40:1453–1458
Panagiotakos DB, Pitsavos C, Chrysohoou C, Vlismas K, Skoumas Y, Palliou K, Stefanadis C (2008) Dietary habits mediate the relationship between socio-economic status and CVD factors among healthy adults: the ATTICA study. Public Health Nutr 11:1342–1349
Puska P (2009) Fat and heart disease: yes we can make a change—the case of North Karelia (Finland). Ann Nutr Metab 54(Suppl 1):33–38
Rajaratnam RA, Gylling H, Miettinen TA (2000) Independent association of serum squalene and noncholesterol sterols with coronary artery disease in postmenopausal women. J Am Coll Cardiol 35:1185–1191
Ros E (2000) Intestinal absorption of triglyceride and cholesterol. Dietary and pharmacological inhibition to reduce cardiovascular risk. Atherosclerosis 151:357–379
Rubin D, Schneider-Muntau A, Klapper M, Nitz I, Helwig U, Folsch UR, Schrezenmeir J, Doring F (2008) Functional analysis of promoter variants in the microsomal triglyceride transfer protein (MTTP) gene. Hum Mutat 29:123–129
Santosa S, Demonty I, Lichtenstein AH, Jones PJ (2007) Cholesterol metabolism and body composition in women: the effects of moderate weight loss. Int J Obes (Lond) 31:933–941
Santosa S, Demonty I, Lichtenstein AH, Ordovas JM, Jones PJ (2007) Single nucleotide polymorphisms in ABCG5 and ABCG8 are associated with changes in cholesterol metabolism during weight loss. J Lipid Res 48:2607–2613
Sato R, Miyamoto W, Inoue J, Terada T, Imanaka T, Maeda M (1999) Sterol regulatory element-binding protein negatively regulates microsomal triglyceride transfer protein gene transcription. J Biol Chem 274:24714–24720
Schgoer W, Eller P, Mueller T, Tancevski I, Wehinger A, Ulmer H, Sandhofer A, Ritsch A, Haltmayer M, Patsch JR (2008) The MTP −493TT genotype is associated with peripheral arterial disease: results from the linz peripheral arterial disease (LIPAD) study. Clin Biochem 41:712–716
Sehayek E, Nath C, Heinemann T, McGee M, Seidman CE, Samuel P, Breslow JL (1998) U-shape relationship between change in dietary cholesterol absorption and plasma lipoprotein responsiveness and evidence for extreme interindividual variation in dietary cholesterol absorption in humans. J Lipid Res 39:2415–2422
Sharp D, Blinderman L, Combs KA, Kienzle B, Ricci B, Wager-Smith K, Gil CM, Turck CW, Bouma ME, Rader DJ (1993) Cloning and gene defects in microsomal triglyceride transfer protein associated with abetalipoproteinaemia. Nature 365:65–69
Stan S, Lambert M, Delvin E, Paradis G, O’Loughlin J, Hanley JA, Levy E (2005) Intestinal fatty acid binding protein and microsomal triglyceride transfer protein polymorphisms in French-Canadian youth. J Lipid Res 46:320–327
Vincent-Baudry S, Defoort C, Gerber M, Bernard MC, Verger P, Helal O, Portugal H, Planells R, Grolier P, Amiot-Carlin MJ et al (2005) The Medi-RIVAGE study: reduction of cardiovascular disease risk factors after a 3-mo intervention with a Mediterranean-type diet or a low-fat diet. Am J Clin Nutr 82:964–971
Vincent S, Gerber M, Bernard MC, Defoort C, Loundou A, Portugal H, Planells R, Juhan-Vague I, Charpiot P, Grolier P et al (2004) The Medi-RIVAGE study (mediterranean diet, cardiovascular risks and gene polymorphisms): rationale, recruitment, design, dietary intervention and baseline characteristics of participants. Public Health Nutr 7:531–542
Wang DQ (2007) Regulation of intestinal cholesterol absorption. Annu Rev Physiol 69:221–248
Wetterau JR, Aggerbeck LP, Bouma ME, Eisenberg C, Munck A, Hermier M, Schmitz J, Gay G, Rader DJ, Gregg RE (1992) Absence of microsomal triglyceride transfer protein in individuals with abetalipoproteinemia. Science 258:999–1001
Wetterau JR, Combs KA, Spinner SN, Joiner BJ (1990) Protein disulfide isomerase is a component of the microsomal triglyceride transfer protein complex. J Biol Chem 265:9800–9807
Williams CM, Ordovas JM, Lairon D, Hesketh J, Lietz G, Gibney M, van Ommen B (2008) The challenges for molecular nutrition research 1: linking genotype to healthy nutrition. Genes Nutr 3:41–49
Yamada Y, Ando F, Shimokata H (2006) Association of a microsomal triglyceride transfer protein gene polymorphism with blood pressure in Japanese women. Int J Mol Med 17:83–88
Zak A, Jachymova M, Tvrzicka E, Vecka M, Duffkova L, Zeman M, Slaby A, Stankova B (2008) The influence of polymorphism of −493G/T MTP gene promoter and metabolic syndrome on lipids, fatty acids and oxidative stress. J Nutr Biochem 19:634–641
Zhao HL, Houweling AH, Vanstone CA, Jew S, Trautwein EA, Duchateau GS, Jones PJ (2008) Genetic variation in ABC G5/G8 and NPC1L1 impact cholesterol response to plant sterols in hypercholesterolemic men. Lipids 43:1155–1164
Acknowledgments
Supported by the French Research Minister (AQS grant), the Institut National de la Santé et de la Recherche Médicale (IDS grant), the Provence-Alpes-Côte d’Azur Regional Council, the Bouches du Rhône General Council and the Centre Régional d’Innovation et de Transfert de Technologies-Provence-Alpes-Côte d’Azur. The authors thank MC Bernard, M. Gerber and P. Vague for their active role during the intervention study, Julien Mancini for his statistical help as well as Chantal Bideau, Danielle Iniesta and Nicole Peyrol for their technical skill in SNP determination.
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Wolff, E., Vergnes, MF., Defoort, C. et al. Cholesterol absorption status and fasting plasma cholesterol are modulated by the microsomal triacylglycerol transfer protein −493 G/T polymorphism and the usual diet in women. Genes Nutr 6, 71–79 (2011). https://doi.org/10.1007/s12263-010-0174-x
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DOI: https://doi.org/10.1007/s12263-010-0174-x