Lipidomic changes of LDL in overweight and moderately hypercholesterolemic subjects taking phytosterol- and omega-3-supplemented milk

Abstract

The prevalence of overweight and obesity is increasing and represents a primary health concern due to the relationship between obesity and a number of diseases and comorbidities including hyperlipidemia, a major risk factor for atherosclerosis and CVD. Dyslipidemias, typically characterized by high serum LDL cholesterol (LDLc), or low levels of HDL cholesterol (HDLc), and/or elevated triglyceride (TGL) levels, are common among patients with established CVD, type 2 diabetes mellitus, and the metabolic syndrome ( 1 ).Because cholesterol lowering is a major target for reducing CVD risk ( 2 ), dietary interventions to reduce LDLc levels in individuals with borderline dyslipidemia and obesity without overall cardiovascular risk are becoming mandatory. Cholesterol concentrations within the circulatory pool are products of input from gut absorption and endogenous synthesis relative to clearance through Abstract The benefi ts of dietary phytosterols (PhySs) and long-chain n-3 PUFA ( 3) have been linked to their effects as cholesterol-and triglyceride (TGL)-lowering agents. However, it remains unknown whether these compounds have further metabolic effects on LDL lipid composition. Here, we studied the effects of PhyS-or 3-supplemented low-fat milk (milk) on the LDL-lipidome. Overweight and moderately hypercholesterolemic subjects (n = 32) were enrolled in a two-arm longitudinal crossover study. Milk (250 ml/day), enriched with either 1.57 g PhyS or 375 mg 3 (EPA + DHA), was given to the participants during two sequential 28 day intervention periods. Compared with baseline, PhyS-milk induced a higher reduction in the LDL cholesterol (LDLc) level than 3-milk. LDL resistance to oxidation was signifi cantly increased after intervention with PhyS-milk. Changes in TGL and VLDL cholesterol were only evident after 3-milk intake. Lipidomic analysis revealed a differential effect of the PhyS-and 3-milk interventions on the LDL lipid metabolite pattern. Content in LDL-glycerophospholipids was reduced after PhySmilk intake, with major changes in phosphatidylcholine (PC) and phosphatidylserine subclasses, whereas 3-milk induced signifi cant changes in the long-chain polyunsaturated cholesteryl esters and in the ratio PC36:5/lysoPC16:0, associated to a reduced infl ammatory activity. In conclusion, daily intake of milk products containing PhyS or 3 supplements induce changes in the LDL-lipidome that indicate reduced infl ammatory and atherogenic effects, beyond their LDLc-and TGL-lowering effects. -Padro, T., G. Vilahur, J. S á nchez-Hern á ndez, M. Hern á ndez, R. M. Antonijoan, A. Perez, and L. Badimon. Lipidomic changes of LDL in overweight and moderately hypercholesterolemic

Systems biology approaches to understand the effects of nutrition and promote health

“…Particularly, a strong correlation was found for the PC32:0 subclass. We found a reduction in PC32:0 in those individuals under the phytosterol milk intervention as well as in PC34:1, a highly abundant PC in LDL particles . The fact that the strongest coordinated changes after phytosterol‐enriched milk were observed between PC metabolites differing by two carbon atoms in their fatty acid side chain suggests that changes result from products of elongation processes occurring in the LDL after the dietary intervention.…”

“…Another important finding of our study was the detected decrease in LDL susceptibility to oxidation after intake of phytosterol-enriched milk [40]. The susceptibility of LDL to oxidation has been linked to their content in sphingomyelines, lipid components reported as physiological inhibitors of lipoprotein oxidation due to their effects in LDL surface fluidity and propagation of the oxidation reaction in the PC monolayer [42].…”

“…Moreover, Ahmed et al [49], using a proteomic approach based on gel electrophoresis and liquid chromatography-tandem mass spectrometry, evidenced that high dietary ω3PUFA modulates proteins directly involved in lipid and carbohydrate metabolism, such as regucalcin or hepatic fructose-1 and ketohexokinase, as well as proteins involved in protein synthesis. From a metabolomic point of view we have demonstrated that intake of ω3-enriched milk for 4 weeks induces changes in the lipidomic compostion of the LDL-fraction leading to an increase in long chain polyunsaturated cholesteryl-esters CE20:5 and CE:22:6 content as well as in the ratio PC 36:5 : LysoPC16:0, thus conferring LDL particles with a lower pro-inflammatory potential [40]. In summary, dietary intake of ω3 long chain fatty acids and plant sterols seem to exert independent but interactive effects on the plasma lipid profile suggesting that their combination as food supplements may represent an improved strategy to prevent cardiovascular risk [50].…”

The effect of intakes of fish and Camelina sativa oil on atherogenic and anti-atherogenic functions of LDL and HDL particles: A randomized controlled trial

“…LDL, particularly when 34 modified, also stimulate several atherogenic processes, such as interleukin-8 (IL-8) secretion 35 of endothelial cells, which induce the chemotactic recruitment of monocytes to the arterial 36 intima [1,9,10]. Modified lipoproteins are taken up by macrophages, which leads to foam- 37 cell formation. Retained and modified lipoproteins and foam cell formation leads to the 38 release of proinflammatory cytokines and bridging molecules (e.g.…”

“…In these studies, changes in the LDL lipidome were induced 300 enzymatically and increased content of free fatty acids and lysophosphatidylcholine was 301 found to enhance IL-8 release. Instead, studies investigating dietary effects on LDL lipidome 302 are scarce [8,37], and to our knowledge, there are no previous studies investigating the 303 effects of dietary intervention on inflammatory properties of LDL particles. Padro et al [37] 304 found that milk enriched with long-chain n-3 PUFA (0.375 g/250 ml milk) did not induce 305 changes among lipid species of LDL.…”