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ObjectiveTo investigate whether milk polar lipids (PL) impact human intestinal lipid absorption, metabolism, microbiota and associated markers of cardiometabolic health.DesignA double-blind, randomised controlled 4-week study involving 58 postmenopausal women was used to assess the chronic effects of milk PL consumption (0, 3 or 5 g-PL/day) on lipid metabolism and gut microbiota. The acute effects of milk PL on intestinal absorption and metabolism of cholesterol were assessed in a randomised controlled crossover study using tracers in ileostomy patients.ResultsOver 4 weeks, milk PL significantly reduced fasting and postprandial plasma concentrations of cholesterol and surrogate lipid markers of cardiovascular disease risk, including total/high-density lipoprotein-cholesterol and apolipoprotein (Apo)B/ApoA1 ratios. The highest PL dose preferentially induced a decreased number of intestine-derived chylomicron particles. Also, milk PL increased faecal loss of coprostanol, a gut-derived metabolite of cholesterol, but major bacterial populations and faecal short-chain fatty acids were not affected by milk PL, regardless of the dose. Acute ingestion of milk PL by ileostomy patients shows that milk PL decreased cholesterol absorption and increased cholesterol-ileal efflux, which can be explained by the observed co-excretion with milk sphingomyelin in the gut.ConclusionThe present data demonstrate for the first time in humans that milk PL can improve the cardiometabolic health by decreasing several lipid cardiovascular markers, notably through a reduced intestinal cholesterol absorption involving specific interactions in the gut, without disturbing the major bacterial phyla of gut microbiota.Trial registration number NCT02099032 and NCT02146339; Results.

A number of epidemiological and genetic studies have attempted to determine whether levels of circulating lipids are associated with risks of various cancers, including breast cancer (BC). However, it remains unclear whether a causal relationship exists between lipids and BC. If alteration of lipid levels also reduced risk of BC, this could present a target for disease prevention. This study aimed to assess a potential causal relationship between genetic variants associated with plasma lipid traits (high-density lipoprotein, HDL; low-density lipoprotein, LDL; triglycerides, TGs) with risk for BC using Mendelian randomization (MR). Data from genome-wide association studies in up to 215,551 participants from the Million Veteran Program (MVP) were used to construct genetic instruments for plasma lipid traits. The effect of these instruments on BC risk was evaluated using genetic data from the BCAC (Breast Cancer Association Consortium) based on 122,977 BC cases and 105,974 controls. Using MR, we observed that a 1-standard-deviation genetically determined increase in HDL levels is associated with an increased risk for all BCs (HDL: OR [odds ratio] = 1.08, 95% confidence interval [CI] = 1.04-1.13, P < 0.001). Multivariable MR analysis, which adjusted for the effects of LDL, TGs, body mass index (BMI), and age at menarche, corroborated this observation for HDL (OR = 1.06, 95% CI = 1.03-1.10, P = 4.9 × 10-4) and also found a relationship between LDL and BC risk (OR = 1.03, 95% CI = 1.01-1.07, P = 0.02). We did not observe a difference in these relationships when stratified by breast tumor estrogen receptor (ER) status. We repeated this analysis using genetic variants independent of the leading association at core HDL pathway genes and found that these variants were also associated with risk for BCs (OR = 1.11, 95% CI = 1.06-1.16, P = 1.5 × 10-6), including locus-specific associations at ABCA1 (ATP Binding Cassette Subfamily A Member 1), APOE-APOC1-APOC4-APOC2 (Apolipoproteins E, C1, C4, and C2), and CETP (Cholesteryl Ester Transfer Protein). In addition, we found evidence that genetic variation at the ABO locus is associated with both lipid levels and BC. Through multiple statistical approaches, we minimized and tested for the confounding effects of pleiotropy and population stratification on our analysis; however, the possible existence of residual pleiotropy and stratification remains a limitation of this study. We observed that genetically elevated plasma HDL and LDL levels appear to be associated with increased BC risk. Future studies are required to understand the mechanism underlying this putative causal relationship, with the goal of developing potential therapeutic strategies aimed at altering the cholesterol-mediated effect on BC risk.

Matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) can simultaneously record the lateral distribution of numerous biomolecules in tissue slices, but its sensitivity is restricted by limited ionization. We used a wavelength-tunable postionization laser to initiate secondary MALDI-like ionization processes in the gas phase. In this way, we could increase the ion yields for numerous lipid classes, liposoluble vitamins, and saccharides, imaged in animal and plant tissue with a 5-micrometer-wide laser spot, by up to two orders of magnitude. Critical parameters for initiation of the secondary ionization processes are pressure of the cooling gas in the ion source, laser wavelength, pulse energy, and delay between the two laser pulses. The technology could enable sensitive MALDI-MS imaging with a lateral resolution in the low micrometer range.

Saturated fatty acid (SFA) vs polyunsaturated fatty acid (PUFA) may promote nonalcoholic fatty liver disease by yet unclear mechanisms. To investigate if overeating SFA- and PUFA-enriched diets lead to differential liver fat accumulation in overweight and obese humans. Double-blind randomized trial (LIPOGAIN-2). Overfeeding SFA vs PUFA for 8 weeks, followed by 4 weeks of caloric restriction. General community. Men and women who are overweight or have obesity (n = 61). Muffins, high in either palm (SFA) or sunflower oil (PUFA), were added to the habitual diet. Lean tissue mass (not reported here). Secondary and exploratory outcomes included liver and ectopic fat depots. By design, body weight gain was similar in SFA (2.31 ± 1.38 kg) and PUFA (2.01 ± 1.90 kg) groups, P = 0.50. SFA markedly induced liver fat content (50% relative increase) along with liver enzymes and atherogenic serum lipids. In contrast, despite similar weight gain, PUFA did not increase liver fat or liver enzymes or cause any adverse effects on blood lipids. SFA had no differential effect on the accumulation of visceral fat, pancreas fat, or total body fat compared with PUFA. SFA consistently increased, whereas PUFA reduced circulating ceramides, changes that were moderately associated with liver fat changes and proposed markers of hepatic lipogenesis. The adverse metabolic effects of SFA were reversed by calorie restriction. SFA markedly induces liver fat and serum ceramides, whereas dietary PUFA prevents liver fat accumulation and reduces ceramides and hyperlipidemia during excess energy intake and weight gain in overweight individuals.

Lipids are important biomolecules in all biological systems and serve numerous essential cellular functions. The global analysis of complex lipids is very challenging due to the extreme diversity in lipid structures. Variation in linkages and positions of fatty acyl chain(s) on the lipid backbone, functional group modification, occurrence of the molecular species as isomers or isobars are among some of the greatest challenges to resolve in lipidomics. In this work, we describe a routine analytical approach combining two liquid chromatography platforms: hydrophilic interaction (HILIC) and C30 reversed-phase chromatography (C30RP) coupled to high resolution mass spectrometry (HRMS) as complementary high throughput platforms to analyze complex lipid mixtures. Vascular plants (kale leaves and corn roots), rat brain and soil microbes were used as proxies to evaluate the efficiency of the enhanced approach to resolve traditional, as well as, modified lipids during routine lipidomics analysis. We report for the first time, the observation of a modified class of acylphosphatidylglycerol (acylPG) in corn roots by HILIC, and further resolution of the isomers using C30RP chromatography. We also used this approach to demonstrate the presence of high levels of N -monomethyl phosphatidylethanolamine (MMPE) in soil microbes, as well as to determine the regioisomers of lysophospholipids in kale leaves. Additionally, neutral lipids were demonstrated using C30RP chromatography in positive ion mode to resolve triacylglycerol isomers in rat brain. The work presented here demonstrates how the enhanced approach can more routinely permit novel biomarker discovery, or lipid metabolism in a wide range of biological samples.

The transition from an aquatic ancestral condition to a terrestrial environment exposed the first land plants to the desiccating effects of air and potentially large fluctuations in temperature and light intensity. To be successful, this transition necessitated metabolic, physiological, and morphological modifications, among which one of the most important was the capacity to synthesize hydrophobic extracellular biopolymers such as those found in the cuticular membrane, suberin, lignin, and sporopollenin, which collectively reduce the loss of water, provide barriers to pathogens, protect against harmful levels of UV radiation, and rigidify targeted cell walls. Here, we review phylogenetic and molecular data from extant members of the green plant clade (Chlorobionta) and show that the capacity to synthesize the monomeric precursors of all four biopolymers is ancestral and extends in some cases to unicellular plants (e.g. Chlamydomonas). We also review evidence from extant algae, bryophytes, and early-divergent tracheophytes and show that gene duplication, subsequent neo-functionalization, and the co-option of fundamental and ancestral metabolic pathways contributed to the early evolutionary success of the land plants.

Background Critically ill adults typically develop hypocholesterolemia, associated with poor outcome. Whether similar alterations occur in critically ill children is less clear. Methods In secondary analyses of the PEPaNIC RCT (n = 1440), we first documented the time course of plasma cholesterol and triglyceride concentrations, and the effect of randomization to early-parenteral-nutrition (early-PN) or late-PN hereon, for 96 matched critically ill children staying ≥ 5 days in PICU. Second, for 1165 children with available admission plasma samples, lipid profiles were determined and their independent associations with outcome (time to live PICU discharge, new infection and 90-day mortality) were assessed with Multivariable Cox proportional hazard and logistic regression, adjusting for baseline risk factors. Results Plasma HDL-cholesterol, LDL-cholesterol, total-cholesterol and triglycerides were low throughout the 5 PICU days, with only HDL-cholesterol further decreasing over time ( P  < 0.0001) and without effect of randomization to early-PN or late-PN, and with admission values lower in infants than older children and in patients with infection ( P  < 0.05). Lower admission HDL- and total-cholesterol concentrations were independently associated with a lower likelihood of an earlier live PICU discharge ( P  < 0.001) and with a higher risk of 90-day mortality ( P  ≤ 0.01), whereas higher plasma triglycerides were independently associated with higher risk of 90-day mortality ( P  = 0.004). Low admission plasma HDL-cholesterol was independently associated with a higher risk of acquiring a new infection ( P  = 0.05). Conclusion Critically ill children presented with low circulating levels of lipids. Low plasma cholesterol concentrations were associated with poor outcomes, most robustly for HDL-cholesterol. Whether these associations are causal or casual requires further investigation.

Homozygous familial hypercholesterolaemia is a rare genetic disorder in which both LDL-receptor alleles are defective, resulting in very high concentrations of LDL cholesterol in plasma and premature coronary artery disease. This study investigated whether an antisense inhibitor of apolipoprotein B synthesis, mipomersen, is effective and safe as an adjunctive agent to lower LDL cholesterol concentrations in patients with this disease. This randomised, double-blind, placebo-controlled, phase 3 study was undertaken in nine lipid clinics in seven countries. Patients aged 12 years and older with clinical diagnosis or genetic confirmation of homozygous familial hypercholesterolaemia, who were already receiving the maximum tolerated dose of a lipid-lowering drug, were randomly assigned to mipomersen 200 mg subcutaneously every week or placebo for 26 weeks. Randomisation was computer generated and stratified by weight (<50 kg vs ≥50 kg) in a centralised blocked randomisation, implemented with a computerised interactive voice response system. All clinical, medical, and pharmacy personnel, and patients were masked to treatment allocation. The primary endpoint was percentage change in LDL cholesterol concentration from baseline. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00607373. 34 patients were assigned to mipomersen and 17 to placebo; data for all patients were analysed. 45 patients completed the 26-week treatment period (28 mipomersen, 17 placebo). Mean concentrations of LDL cholesterol at baseline were 11·4 mmol/L (SD 3·6) in the mipomersen group and 10·4 mmol/L (3·7) in the placebo group. The mean percentage change in LDL cholesterol concentration was significantly greater with mipomersen (−24·7%, 95% CI −31·6 to −17·7) than with placebo (−3·3%, −12·1 to 5·5; p=0·0003). The most common adverse events were injection-site reactions (26 [76%] patients in mipomersen group vs four [24%] in placebo group). Four (12%) patients in the mipomersen group but none in the placebo group had increases in concentrations of alanine aminotransferase of three times or more the upper limit of normal. Inhibition of apolipoprotein B synthesis by mipomersen represents a novel, effective therapy to reduce LDL cholesterol concentrations in patients with homozygous familial hypercholesterolaemia who are already receiving lipid-lowering drugs, including high-dose statins. ISIS Pharmaceuticals and Genzyme Corporation.

Background While electronic cigarettes (ECIG) may have lower toxicant delivery than cigarettes, ECIG-liquids and aerosols still contain toxicants that can potentially disrupt lung lipid homeostasis. Methods Participants from two studies underwent bronchoscopy and bronchoalveolar lavage (BAL). Ninety-eight participants (21-44 years old) were included in a cross-sectional study, with 17 ECIG users, 52 non-smokers, and 29 smokers. In the four-week clinical trial, 30 non-smokers were randomly assigned to use nicotine-free, flavorless ECIG or no use. A panel of 75 quantifiable lipid species and 7 lipid classes were assessed in the BAL using two tandem mass spectrometry (MS/MS) platforms. Ten cytokines and lipid-laden macrophages (LLM) were analyzed using the V-PLEX Plus Proinflam Combo 10 panel and Oil Red O staining, respectively. Results In the cross-sectional study, 43 lipids were associated with smoking status at FDR<0.1, including two between ECIG and non-smokers (PC(14:0/18:1) and PC(18:0/14:0)) in pairwise follow-up analyses (Bonferroni-adjusted p<0.017). Associations between lipid species and cotinine, inflammatory markers, including IL-1β and IL-8, and LLM were also identified, as well as differences in lipid classes between smokers and the other groups. Smokers had higher saturated lipids, including ceramide (CER), sphingomyelin (SM), and diacylglycerol (DAG) than that of non-smokers and ECIG users. No significant associations were identified in the 4-week clinical trial. Conclusions Smoking was associated with altered lipid levels, as compared to both non-smokers and ECIG users; the majority were downregulated and ECIG effects tend to be smaller in magnitude than smoking effects, although some were different than those in the smokers group. This is a novel study of healthy individuals examining lipidomic differences between smokers, ECIG users, and non-smokers, indicating potential roles of smoking and ECIG-related lipid alterations in pulmonary disease. Trial registration The study was approved by The OSU Institutional Review Board (OSU-2015C0088) in accordance with its ethical standards, the Helsinki declaration, and the Belmont Report, and is registered on Clinicaltrials.gov (NCT02596685; 2015-11-04).

We describe a method for direct, quantitative, in vivo lipid profiling of oil-producing microalgae using single-cell laser-trapping Raman spectroscopy. This approach is demonstrated in the quantitative determination of the degree of unsaturation and transition temperatures of constituent lipids within microalgae. These properties are important markers for determining engine compatibility and performance metrics of algal biodiesel. We show that these factors can be directly measured from a single living microalgal cell held in place with an optical trap while simultaneously collecting Raman data. Cellular response to different growth conditions is monitored in real time. Our approach circumvents the need for lipid extraction and analysis that is both slow and invasive. Furthermore, this technique yields real-time chemical information in a label-free manner, thus eliminating the limitations of impermeability, toxicity, and specificity of the fluorescent probes common in currently used protocols. Although the single-cell Raman spectroscopy demonstrated here is focused on the study of the microalgal lipids with biofuel applications, the analytical capability and quantitation algorithms demonstrated are applicable to many different organisms and should prove useful for a diverse range of applications in lipidomics.