A Combination of Single Nucleotide Polymorphisms is Associated with the Interindividual Variability of Cholesterol Bioavailability in Healthy Adult Males.

SCOPE: Cholesterol bioavailability displays a high interindividual variability, partly due to genetic factors. Existing studies have focused on single nucleotide polymorphisms (SNPs) analyzed individually, which only explained a minor fraction of the variability of this complex phenotype. The aim is to identify a combination of SNPs associated with a significant part of the variability in cholesterol bioavailability. METHODS AND RESULTS: Thirty-nine healthy adult males are given a standard test snack containing 80 mg heptadeuterated (D7) cholesterol. The plasma D7-cholesterol concentration is measured at equilibrium 40 h after test snack intake. The D7-cholesterol response (D7-cholesterol/total cholesterol concentration) exhibits a relatively high interindividual variability (CV = 32%). The association of exonic SNPs in candidate genes (188 genes involved in or related to cholesterol metabolism) with the plasma D7-cholesterol response is assessed by univariate statistics followed by partial least squares regression. A significant model (p-value after cross-validation ANOVA = 1.64 × 10-7 ) that includes 8 SNPs (SOAT2-rs9658625, DNAH11-rs11768670, LIPC-rs690, MVK-rs2287218, GPAM-rs10787428, APOE-rs7412, CBS-rs234706, and WRN-rs1801196) explains 59.7% of the variance in cholesterol bioavailability (adjusted R²). CONCLUSION: Here a combination of SNPs is significantly associated with the variability in dietary cholesterol bioavailability in healthy adult males.

Effects of bariatric surgery on hepatic and intestinal lipoprotein particle metabolism in obese, nondiabetic humans.

OBJECTIVE: The dyslipidemia of obesity and other insulin-resistant states is characterized by the elevation of plasma triglyceride-rich lipoproteins (TRL) of both hepatic (apoB-100-containing very low-density lipoprotein) and intestinal (apoB-48-containing chylomicrons) origin. Bariatric surgery is a well-established and effective modality for the treatment of obesity and is associated with improvements in several metabolic abnormalities associated with obesity, including a reduction in plasma triglycerides. Here, we have investigated the effect of bariatric surgery on TRL metabolism. APPROACH AND RESULTS: Twenty-two nondiabetic, obese subjects undergoing bariatric surgery: sleeve gastrectomy (n=12) or gastric bypass (n=10) were studied. Each subject underwent 1 lipoprotein turnover study 1 month before surgery followed by a second study, 6 months after surgery, using established stable isotope enrichment methodology, in constant fed state. TRL-apoB-100 concentration was significantly reduced after sleeve gastrectomy, explained by a decrease (P<0.05) in TRL-apoB-100 production rate and an increase (P<0.05) in TRL-apoB-100 fractional catabolic rate. TRL-apoB-48 concentration was also significantly reduced after sleeve gastrectomy, explained by reduction in TRL-apoB-48 production rate (P<0.05). For gastric bypass, although TRL-apoB-100 concentration declined after surgery (P<0.01), without a significant decline in TRL-apoB-48, there was no significant change in either TRL-apoB-100 or TRL-apoB-48 production rate or fractional catabolic rate. The reduction in TRL-apoB-100 concentration was significantly associated with a reduction in plasma apoC-III in the pooled group of patients undergoing bariatric surgery. CONCLUSIONS: This is the first human lipoprotein kinetic study to explore the mechanism of improvement of TRL metabolism after bariatric surgery. These effects may contribute to the decrease of cardiovascular mortality after surgery. CLINICAL TRIAL REGISTRATION URL: http://www.ClinicalTrials.gov. Unique identifier: NCT01277068.

Cholesterol-absorber status modifies the LDL cholesterol-lowering effect of a Mediterranean-type diet in adults with moderate cardiovascular risk factors.

LDL-cholesterol (LDL-C) reduction may be achieved by various types of prudent diets, but their effects on surrogate markers of cholesterol absorption and synthesis have not been well studied in humans. We aimed to assess whether the extent of cholesterol absorption or synthesis, and cholesterol concentrations, are modified in adults when they shift from a Western-type diet (WD) to a combined low-fat, low-cholesterol/Mediterranean-type diet (LFCMD). Cholestanol and sitosterol, as well as desmosterol and lathosterol, surrogate markers of cholesterol absorption or synthesis, respectively, were quantified in the serum of 125 fasting, middle-aged participants at moderate cardiovascular risk. They habitually consumed a WD and then consumed a LFCMD during the 3-mo intervention. The group was stratified by serum cholestanol concentration and classified as high, intermediate, or low absorbers of cholesterol. When they consumed the WD, participants had comparable total and LDL-C concentrations, independent of absorber group and sex. After 3 mo of consuming the LFCMD, absorption and synthesis did not change or changed only slightly. The cholestanol concentration increased in low absorbers by 18% (P < 0.02) and decreased in high absorbers by 14% (P < 0.001), but these variations did not change the high- or low-absorber status. In male and female low absorbers, plasma total (-7%) and LDL-C (-9%) concentrations decreased after the 3-mo intervention and changes were 2.3- and 2.4-fold greater, respectively, than in high absorbers, independent of sex. Cholesterol synthesis/absorption status was not markedly altered by diet, but the decrease in plasma LDL-C due to the Mediterranean-type diet occurred only in low absorbers of cholesterol. This should be considered during further dietary interventions.

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.

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 × 10(2 )mmol/mol cholesterol) and lathosterol (188.7 ± 21.8 vs. 147.6 ± 9.1 × 10(2) 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.