Effect of a 2-y dietary and physical activity intervention on plasma fatty acid composition and estimated desaturase and elongase activities in children: the Physical Activity and Nutrition in Children Study.

BACKGROUND: Evidence on the effects of lifestyle interventions on plasma fatty acid composition in children is limited. OBJECTIVE: We investigated the effects of a dietary and physical activity intervention on plasma fatty acid composition of cholesteryl esters (CEs) and phospholipids and estimated desaturase and elongase activities in children. DESIGN: We conducted a 2-y controlled dietary and physical activity intervention based on Finnish nutrition and physical activity recommendations in a population sample of 506 children aged 6-8 y. We assessed plasma fatty acid composition by gas chromatography and estimated desaturase and elongase activities as the ratio of product fatty acids to precursor fatty acids. We analyzed data by using linear mixed models adjusted for age and sex. RESULTS: The proportion of total polyunsaturated fatty acids (PUFAs) in CEs tended to increase in the intervention group compared with the control group (P = 0.007 for group × time interaction). The proportion of total PUFAs in phospholipids (P = 0.019 for group × time interaction) and the proportion of linoleic acid in CEs (P = 0.038 for group × time interaction) decreased in the control group. The proportion of α-linolenic acid in CEs (P < 0.001 for group × time interaction) increased and in phospholipids (P = 0.015 for group × time interaction) tended to increase in the intervention group. The proportion of stearic acid in CEs decreased in the intervention group (P = 0.001 for group × time interaction). The proportion of oleic acid in CEs (P = 0.002 for group × time interaction) increased and in phospholipids (P = 0.023 for group × time interaction) tended to increase in the control group. Estimated elongase activity in CEs decreased in the control group (P = 0.050 for group × time interaction). Intervention had no effect on estimated desaturase activities. CONCLUSIONS: Dietary and physical activity intervention had a beneficial effect on plasma fatty acid composition in children by preventing the decrease in the proportion of total PUFAs and linoleic acid and by increasing the proportion of α-linolenic acid. This study was registered at clinicaltrials.gov as NCT01803776.

Gene-diet interaction of a common FADS1 variant with marine polyunsaturated fatty acids for fatty acid composition in plasma and erythrocytes among men.

SCOPE: Limited information exists on how the relationship between dietary intake of fat and fatty acids in erythrocytes and plasma is modulated by polymorphisms in the FADS gene cluster. We examined gene-diet interaction of total marine PUFA intake with a known gene encoding Δ-5 desaturase enzyme (FADS1) variant (rs174550) for fatty acids in erythrocyte membranes and plasma phospholipids (PL), cholesteryl esters (CE), and triglycerides (TG). METHODS AND RESULTS: In this cross-sectional study, fatty acid compositions were measured using GC, and total intake of polyunsaturated fat from fish and fish oil was estimated using a food frequency questionnaire in a subsample (n = 962) of the Metabolic Syndrome in Men Study. We found nominally significant gene-diet interactions for eicosapentaenoic acid (EPA, 20:5n-3) in erythrocytes (pinteraction = 0.032) and for EPA in plasma PL (pinteraction = 0.062), CE (pinteraction = 0.035), and TG (pinteraction = 0.035), as well as for docosapentaenoic acid (22:5n-3) in PL (pinteraction = 0.007). After excluding omega-3 supplement users, we found a significant gene-diet interaction for EPA in erythrocytes (pinteraction < 0.003). In a separate cohort of the Kuopio Obesity Surgery Study, the same locus was strongly associated with hepatic mRNA expression of FADS1 (p = 1.5 × 10(-10) ). CONCLUSION: FADS1 variants may modulate the relationship between marine fatty acid intake and circulating levels of long-chain omega-3 fatty acids.

Cholesterol synthesis prevails over absorption in metabolic syndrome.

The objective of this study was to investigate cholesterol metabolism and its association with glucose metabolism and genetic regulation in metabolic syndrome. Overall, 74 subjects with clinically defined metabolic syndrome and sex and age-matched controls (n=74) were recruited. Cholesterol metabolism was assayed with serum non-cholesterol sterols, surrogate markers of synthesis, and fractional absorption of cholesterol and was related to variables of glucose and insulin action and to the common polymorphisms of the ABCG5 and ABCG8 genes. Serum squalene and non-cholesterol sterols were analyzed with gas-liquid chromatography (GLC) and presented as ratios to cholesterol. Also, synthesis marker/absorption marker ratios were calculated. The subjects with metabolic syndrome had higher cholesterol synthesis marker ratios, including squalene, and lower absorption marker ratios than controls. When adjusted with body mass index (BMI) and waist circumference, differences in some of the absorption markers (plant sterols), but not in the synthesis markers, disappeared. Plasma glucose, serum triglycerides, and homeostasis model assessment (HOMA) index were positively associated with cholesterol synthesis/absorption marker ratios (r=0.264 to 0.353, P<0.05 for all). In multivariate analysis, the serum squalene ratio was the best variable of those of cholesterol metabolism explaining the presence of metabolic syndrome. The polymorphisms of ABCG5 and ABCG8 genes did not differ between the cases and controls. In conclusion, cholesterol synthesis prevails over absorption in metabolic syndrome. The high serum squalene ratio turned out to be associated with the prevalence of metabolic syndrome. The perturbations of cholesterol metabolism seem to be related to abdominal obesity, and weight reduction might normalize cholesterol metabolism.

Cholesterol metabolism and non-cholesterol sterol distribution in lipoproteins of type 1 diabetes: the effect of improved glycemic control.

In type 1 diabetes, the ratios to cholesterol of serum absorption markers, e.g., cholestanol, are elevated and those of synthesis markers, e.g., lathosterol, are reduced suggesting perturbed cholesterol metabolism. We studied 17 subjects with type 1 diabetes in poor glycemic control at baseline to assess whether improvement of glycemic control affects lathosterol and cholestanol ratios to cholesterol and their distribution in lipoproteins. Cholesterol and the non-cholesterol sterols were assayed directly from serum, and free and ester fractions after thin-layer chromatographic separation of lipoprotein sterols with gas-liquid chromatography. After the 2-6 months follow-up, the mean value of HbA1(c) decreased from 10.8% to 8.6% (p=0.001). Even though the concentrations of serum and lipoprotein cholesterol remained unchanged, the serum lathosterol to cholesterol ratio increased by 28% (p<0.05) and the lathosterol/cholestanol proportion by 23% (p<0.05). The ratios of total and esterified lathosterol to cholesterol in serum, chylomicrons and LDL, and free lathosterol to cholesterol in serum and IDL, were negatively associated with HbA1(c) at baseline and after follow-up, suggesting that the better glycemic control, the higher was cholesterol synthesis. The absorption markers were less consistently associated with HbA1(c). About half of the serum lathosterol and cholestanol was carried in LDL and one-fourth to one-fifth in HDL, but the lathosterol ratios were roughly similar in all lipoproteins. In contrast, cholestanol accumulated in chylomicrons and HDL. Glycemic control did not affect the distributions of lathosterol and cholestanol. In conclusion, improvement in glycemic control increased cholesterol synthesis, but had no effect on cholesterol absorption as measured by the serum or lipoprotein cholestanol to cholesterol ratio. From a clinical point of view, the better the glycemic control, the more antiatherogenic cholesterol metabolism may be in type 1 diabetes.

Interaction between cholesterol and glucose metabolism during dietary carbohydrate modification in subjects with the metabolic syndrome.

BACKGROUND: Carbohydrate modification based on rye bread and pasta enhances early insulin secretion in subjects with the metabolic syndrome. OBJECTIVE: Because the actions of insulin and cholesterol metabolism are interrelated, the question is raised of whether it is possible to alter cholesterol metabolism by means of dietary carbohydrate modification. DESIGN: We investigated the 12-wk effects of dietary carbohydrate modification on cholesterol synthesis and absorption by measuring the ratios of surrogate markers of precursor (cholestenol, desmosterol, and lathosterol) and absorption (cholestanol and plant sterols) sterols to cholesterol and their association to glucose metabolism in 74 subjects with the metabolic syndrome. The subjects were randomly assigned to diets with rye bread and pasta (RPa) or oat, wheat bread, and potato (OWPo) as the main carbohydrate source (34% and 37% of energy intake, respectively). RESULTS: During the study, serum cholesterol concentrations remained unchanged. Cholesterol synthesis was lower (6-10% for cholestenol and lathosterol; P < 0.05) and absorption higher (9%; P < 0.05 for sitosterol) with the OWPo diet than at baseline. With the RPa diet, cholesterol absorption was lower and synthesis higher than with the OWPo diet. The increment in the glucose area under the curve with the RPa diet was positively related to baseline cholesterol synthesis (eg, lathosterol; r = 0.480, P < 0.05) and negatively to absorption (for cholestanol; r = -0.520, P < 0.05). In the combined group, the changes in the cholestanol ratio and the insulinogenic index were interrelated (r = -0.464, P < 0.001). CONCLUSIONS: Carbohydrate modifications had dissimilar effects on cholesterol metabolism. Consumption of RPa, as compared with OWPo, may be clinically more favorable because it seems to inhibit the absorption of cholesterol, a factor crucial in the development of arterial atherosclerosis.

Endothelial function in hypercholesterolemic subjects: Effects of plant stanol and sterol esters.

We investigated the effects of stanol (STAEST) and sterol esters (STEEST) on endothelial function in hypercholesterolemic subjects. In addition, associations of variables of cholesterol metabolism with endothelial function were investigated. In a double-blind randomized cross-over study (n=39) with age-matched parallel control group (n=37) the subjects consumed STAEST or STEEST spread (total plant sterols and stanols 1.93-1.98g/day) for 10 weeks each. Controls consumed the spread without sterols or stanols for 20 weeks. At baseline, brachial artery diameter was positively correlated with serum triglycerides (r=0.375, p=0.001) and glucose (r=0.420, p<0.001) and with cholesterol synthesis marker ratios to cholesterol (e.g. desmosterol r=0.540, p<0.001) and negatively with HDL cholesterol (r=-0.309, p=0.008) and absorption marker ratios (e.g. campesterol r=-0.332, p=0.004). During the intervention, LDL cholesterol was reduced by 6-9% from baseline with STAEST and STEEST spreads (p<0.05), and by 9-12%, respectively, from controls (p<0.05). Flow-mediated dilatation did not change during the investigation. Brachial artery diameter was unchanged in controls and during STAEST periods, but it was reduced during STEEST by 2.2% (p=0.012) from STAEST. In conclusion, variables of cholesterol metabolism are associated with brachial artery diameter at baseline. STEEST diminishes brachial artery diameter, but its clinical relevance remains unclear.

Postprandial lipemic response and lipoprotein composition in subjects with low or high cholesterol absorption efficiency.

BACKGROUND: The purpose of this study was to investigate the effect of differences in cholesterol absorption efficiency on the postprandial lipemia and lipoprotein composition. METHODS: Fifteen healthy subjects were divided into low and high cholesterol absorbers on the basis of serum cholestanol to cholesterol ratio. A high-performance liquid chromatographic method with evaporative light scattering detection was developed for quantitation of free and esterified cholesterol, triglycerides and major phospholipids from the same lipid extract in two runs utilizing the same internal standard. RESULTS: The free cholesterol to phosphatidylcholine ratio of chylomicrons was higher in the high cholesterol absorption group. The total increase of cholesterol in combined chylomicron and very low density lipoprotein (VLDL) fraction was also higher in this group. Chylomicron free cholesterol and cholesterol ester responses correlated with fasting low density lipoprotein (LDL) cholesterol. VLDL and VLDL1 triglyceride responses correlated inversely with fasting insulin and homeostasis model assessment of insulin resistance. CONCLUSIONS: High cholesterol absorption efficiency was seen in chylomicrons as higher cholesterol to phosphatidylcholine ratio during the postprandial peak. Chylomicron cholesterol response was linked to fasting LDL cholesterol and low VLDL triglyceride response to fasting insulin.

Isolation of very low density lipoprotein phospholipids enriched in ethanolamine phospholipids from rats injected with Triton WR 1339.

Phospholipids carried by very low density lipoprotein (VLDL) are hydrolysed in circulation by lipoprotein and hepatic lipases and lecithin-cholesterol acyltransferase. We have previously demonstrated [J.J. Agren, A. Ravandi, A. Kuksis, G. Steiner, Structural and compositional changes in very low density lipoprotein triacylglycerols during basal lipolysis, Eur. J. Biochem. 269 (2002) 6223-6232] that the infusion of Triton WR 1339 (TWR), which inhibits these lipases, leads in 2 h to five-fold increase in VLDL triacylglycerol concentration along with major differences in the composition of their molecular species. The present study demonstrates that the accumulation of triacylglycerols is accompanied by major changes in the content of the VLDL phospholipids, of which the most significant is the enrichment of phosphatidylethanolamine (PtdEtn). This finding coincides with the enrichment in PtdEtn demonstrated in the VLDL of a hepatocytic Golgi fraction but it had not been demonstrated that the Golgi VLDL, along with its unusual phospholipid composition, can be directly transferred to plasma. Aside from providing an easy access to nascent plasma VLDL, the TWR infusion demonstrates that lipoprotein and hepatic lipases are also responsible for the degradation of plasma VLDL PtdEtn, as independently demonstrated for plasma phosphatidylcholine. Our results indicate also, with the exception of lysophosphatidylcholine, that preferential basal hydrolysis no dot lead to major differences in molecular species composition between circulating and newly secreted VLDL phospholipids. The comparison of the molecular species composition of VLDL and liver phospholipids suggests a selective secretion of PtdEtn and sphingomyelin molecular species during VLDL secretion.

Structural and compositional changes in very low density lipoprotein triacylglycerols during basal lipolysis.

Triacylglycerols secreted by liver and carried by very low density lipoprotein (VLDL) are hydrolysed in circulation by lipoprotein and hepatic lipases. These enzymes have been shown to have positional and fatty acid specificity in vitro. If there were specificity in basal lipolysis in vivo, triacylglycerol compositions of circulating and newly secreted VLDL would be different. To study this we compared the composition of normal fasting VLDL triacylglycerol of Wistar rats to that obtained after blocking lipolysis by Triton WR1339, which increased plasma VLDL triacylglycerol concentration about 4.7-fold in 2 h. Analyses of molecular species of sn-1,2- and sn-2,3-diacylglycerol moieties and stereospecific triacylglycerol analysis revealed major differences between the groups in the VLDL triacylglycerol composition. In nontreated rats, the proportion of 16:0 was higher and that of 18:2n-6 lower in the sn-1 position. The proportion of 14:0 was lower in all positions and that of 18:0 was lower in the sn-1 and sn-3 positions in nontreated rats whereas the proportions of 20:4n-6, 20:5n-3, 22:5n-3 and 22:6n-3 were higher in the sn-1 and lower in the sn-2 position. These results suggest that the fatty acid of the sn-1 position is the most decisive factor in determining the sensitivity for hydrolysis of the triacylglycerol. In addition, triacylglycerol species with highly unsaturated fatty acids in the sn-2 position also favoured hydrolysis. The in vivo substrate specificity followed only partly that obtained in in vitro studies indicating that the nature of molecular association of fatty acids in natural triacylglycerol affects its susceptibility to lipolysis. To conclude, our results indicate that preferential basal lipolysis leads to major structural differences between circulating and newly secreted VLDL triacylglycerol. These differences extend beyond those anticipated from analysis of total fatty acids and constitute a previously unrecognized feature of VLDL triacylglycerol metabolism.