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Purpose By-products from farmed fish contain large amounts of proteins and may be used for human consumption. The purpose of this study was to investigate cardiometabolic effects and metabolic tolerance in mice consuming fishmeal from salmon by-products, salmon filet or beef. Methods Female C57BL/6J mice were fed chow, as a healthy reference group, or a high-fat diet for 10 weeks to induce obesity and glucose intolerance. Obese mice were subsequently given isocaloric diets containing 50% of the dietary protein from salmon fishmeal, salmon filet or beef for 10 weeks. Mice were subjected to metabolic phenotyping, which included measurements of body composition, energy metabolism in metabolic cages and glucose tolerance. Lipid content and markers of hepatic toxicity were determined in plasma and liver. Hepatic gene and protein expression was determined with RNA sequencing and immunoblotting. Results Mice fed fishmeal, salmon filet or beef had similar food intake, energy consumption, body weight gain, adiposity, glucose tolerance and circulating levels of lipids and hepatic toxicity markers, such as p-ALT and p-AST. Fishmeal increased hepatic cholesterol levels by 35–36% as compared to salmon filet (p = 0.0001) and beef (p = 0.005). This was accompanied by repressed expression of genes involved in steroid and cholesterol metabolism and reduced levels of circulating Pcsk9. Conclusion Salmon fishmeal was well tolerated, but increased hepatic cholesterol content. The high cholesterol content in fishmeal may be responsible for the effects on hepatic cholesterol metabolism. Before introducing fishmeal from salmon by-products as a dietary component, it may be advantageous to reduce the cholesterol content in fishmeal.

Background & aims: Intake assessment in multicenter trials is challenging, yet important for accurate outcome evaluation. The present study aimed to characterize a multicenter randomized controlled trial with a healthy Nordic diet (HND) compared to a Control diet (CD) by plasma and urine metabolic profilesand to associate them with cardiometabolic markers. Methods: During 18e24 weeks of intervention, 200 participants with metabolic syndrome were advised at six centres to eat either HND (e.g. whole-grain products, berries, rapeseed oil, fish and low-fat dairy) or CD while being weight stable. Of these 166/159 completers delivered blood/urine samples. Metabolicprofiles of fasting plasma and 24 h pooled urine were analysed to identify characteristic diet-related patterns. Principal components analysis (PCA) scores (i.e. PC1 and PC2 scores) were used to test their combined effect on blood glucose response (primary endpoint), serum lipoproteins, triglycerides, andinflammatory markers.Results: The profiles distinguished HND and CD with AUC of 0.96 ± 0.03 and 0.93 ± 0.02 for plasma and urine, respectively, with limited heterogeneity between centers, reflecting markers of key foods. Markers of fish, whole grain and polyunsaturated lipids characterized HND, while CD was reflected by lipidscontaining palmitoleic acid. The PC1 scores of plasma metabolites characterizing the intervention is associated with HDL (β = 0.05; 95% CI: 0.02, 0.08; P = 0.001) and triglycerides (β = 0.06; 95% CI: -0.09, -0.03; P < 0.001). PC2 scores were related with glucose metabolism (2 h Glucose, β = 0.1; 95% CI: 0.05, 0.15; P < 0.001), LDL (β = 0.06; 95% CI: 0.01, 0.1; P = 0.02) and triglycerides (β 0.11; 95% CI: 0.06, 0.15; P < 0.001). For urine, the scores were related with LDL cholesterol. Conclusions: Plasma and urine metabolite profiles from SYSDIET reflected good compliance with dietary recommendations across the region. The scores of metabolites characterizing the diets associated with outcomes related with cardio-metabolic risk. Our analysis therefore offers a novel way to approach a per protocol analysis with a balanced compliance assessment in larger multicentre dietary trials.The study was registered at clinicaltrials.gov with NCT00992641.

In this chapter, we will describe the molecular principles of glucose homeostasis and insulin signaling as well as their dysregulation leading to insulin resistance and β cell failure. Since our blood glucose levels need to stay within a physiological range of 4–6 mM, glucose intake, storage, mobilization and breakdown are tightly regulated. Insulin plays a key role in these regulatory processes. When normal concentrations of insulin cause an insufficient response of the major insulin target tissues, such as skeletal muscle, liver and adipose tissue, insulin resistance has developed. Ectopic overload of lipids, chronic inflammatory response and ER stress are the main processes that can lead to insulin resistance. Moreover, glucotoxic and lipotoxic stress to β cells of the pancreas are mediated via inflammatory response, oxidative stress and ER stress eventually resulting in the failure of the cells, i.e., in the inability to produce insulin. We will describe diabetes as a disease of dysregulation of glucose and lipid homeostasis that does not only affect the insulin production in pancreatic β cells but also the metabolism in organs, such as liver, muscle and fat. Worldwide, the prevalence of T2D is rapidly increasing, which, when not properly treated, ultimately leads to reduced life expectancy due to microvascular (retinopathy, nephropathy and neuropathy) and macrovascular (heart disease and stroke) complications. Both genetic and environmental factors contribute to the development of the disease. We will realize that despite large GWAS screening for risk genes less than 10% of the inheritance of T2D is understood. Therefore, epigenome-wide changes, both prenatal as well as in adult life, play an important role in the disease.

Obesity is associated with increased muscle mass and muscle strength. Methods taking into account the total body mass to reveal obese older individuals at increased risk of functional impairment are needed. Therefore, we aimed to detect methods to identify obese older adults at increased risk of functional impairment. Home-dwelling older adults (n 417, ≥ 70 years of age) were included in this cross-sectional study. Sex-specific cut-off points for two obesity phenotypes (waist circumference (WC) and body fat mass (FM %)) were used to divide women and men into obese and non-obese groups, and within-sex comparisons were performed. Obese women and men, classified by both phenotypes, had similar absolute handgrip strength (HGS) but lower relative HGS (HGS/total body mass) (P < 0·001) than non-obese women and men, respectively. Women with increased WC and FM %, and men with increased WC had higher appendicular skeletal muscle mass (P < 0·001), lower muscle quality (HGS/upper appendicular muscle mass) (P < 0·001), and spent longer time on the stair climb test and the repeated sit-to-stand test (P < 0·05) than non-obese women and men, respectively. Absolute muscle strength was not able to discriminate between obese and non-obese older adults. However, relative muscle strength in particular, but also muscle quality and physical performance tests, where the total body mass was taken into account or served as an extra load, identified obese older adults at increased risk of functional impairment. Prospective studies are needed to determine clinically relevant cut-off points for relative HGS in particular. The present study was supported by the Research Council of Norway (Grant number 225258/E40), Oslo and Akershus University College of Applied Sciences, University of Oslo, Throne Holst Foundation for Nutrition Research and TINE SA.

Background More than one third of Norwegian women and men between 20 and 40 years of age have elevated cholesterol concentration. Parental metabolic health around conception or during pregnancy may affect the offspring’s cardiovascular disease risk. Lipids are important for fetal development, but the determinants of cord blood lipids have scarcely been studied. We therefore aimed to describe the associations between maternal and paternal peri-pregnancy lipid and metabolic profile and newborn cord blood lipid and metabolic profile. Methods This study is based on 710 mother–father–newborn trios from the Norwegian Mother, Father and Child Cohort Study (MoBa) and uses data from the Medical Birth Registry of Norway (MBRN). The sample included in this study consisted of parents with and without self-reported hypercholesterolemia the last 6 months before pregnancy and their partners and newborns. Sixty-four cord blood metabolites detected by nuclear magnetic resonance spectroscopy were analyzed by linear mixed model analyses. The false discovery rate procedure was used to correct for multiple testing. Results Among mothers with hypercholesterolemia, maternal and newborn plasma high-density lipoprotein cholesterol, apolipoprotein A1, linoleic acid, docosahexaenoic acid, alanine, glutamine, isoleucine, leucine, valine, creatinine, and particle concentration of medium high-density lipoprotein were significantly positively associated (0.001 ≤ q ≤ 0.09). Among mothers without hypercholesterolemia, maternal and newborn linoleic acid, valine, tyrosine, citrate, creatinine, high-density lipoprotein size, and particle concentration of small high-density lipoprotein were significantly positively associated (0.02 ≤ q ≤ 0.08). Among fathers with hypercholesterolemia, paternal and newborn ratio of apolipoprotein B to apolipoprotein A1 were significantly positively associated (q = 0.04). Among fathers without hypercholesterolemia, no significant associations were found between paternal and newborn metabolites. Sex differences were found for many cord blood lipids. Conclusions Maternal and paternal metabolites and newborn sex were associated with several cord blood metabolites. This may potentially affect the offspring’s long-term cardiovascular disease risk.

The association between fish consumption and decreased risk of CVD is well documented. However, studies on health effects of fish consumption suggest that other components than n-3 PUFA have beneficial cardiometabolic effects, including effects on glucose metabolism. The aim of the present study was to investigate effects of salmon fish protein on cardiometabolic risk markers in a double-blind, randomised controlled parallel trial. We hypothesised that daily intake of a salmon fish protein supplement for 8 weeks would improve glucose tolerance in persons with increased risk of type 2 diabetes mellitus (T2DM). Our primary outcome measure was serum glucose (s-glucose) 2 h after a standardised oral glucose tolerance test. In total, eighty-eight adults with elevated s-glucose levels were randomised to 7·5 g of salmon fish protein/d or placebo, and seventy-four participants were included in the analysis. We found no significant effect of salmon fish protein supplementation on our primary outcome or other markers related to glucose tolerance, serum lipids, weight or blood pressure compared with placebo. The present study does not support the hypothesis that daily intake of a salmon fish protein supplement for 8 weeks improves glucose tolerance in persons with increased risk of T2DM.

Replacing intake of SFA with PUFA reduces serum cholesterol levels and CVD risk. The effect on glycaemic regulation is, however, less clear. The main objective of the present study was to investigate the short-term effect of replacing dietary SFA with PUFA on glycaemic regulation. Seventeen healthy, normal-weight participants completed a 25-d double-blind, randomised and controlled two-period crossover study. Participants were allocated to either interventions with PUFA products or SFA products (control) in a random order for three consecutive days, separated by a 1·5-week washout period between the intervention periods. Glucose, insulin and TAG were measured before and after an oral glucose tolerance test. In addition, fasting total cholesterol, NEFA and plasma total fatty acid profile were measured before and after the 3-d interventions. Fasting and postprandial glucose, insulin, and TAG levels and fasting levels of NEFA and plasma fatty acid profile did not differ between the groups. However, replacing dietary SFA with PUFA significantly reduced total cholesterol levels by 8 % after 3 d (P = 0·002). Replacing dietary SFA with PUFA for only 3 d has beneficial cardio-metabolic effects by reducing cholesterol levels in healthy individuals.

Background Dyslipidemia and insulin resistance (HOMA-IR) are cardiovascular risk factors prevalent in patients with psychosis. Whether these factors are intrinsic or affected by lifestyle or antipsychotic medication (AP) is unclear. Therefore, we investigated lipid profiles, HOMA-IR, and psychotic phenotypes in patients aged 12–18 years with early-onset psychosis (EOP) with and without AP exposure. Method We measured fasting total cholesterol (TC), high-density lipoprotein cholesterol (HDLC), triglycerides (TG), insulin, and glucose in patients with EOP (n = 39) and healthy controls (HC) (n = 66). Diet information was not available. Negative symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). We used univariate analysis of variance to compare TC/HDL-C ratios and TG and HOMA-IR values, controlling for body mass index (BMI) and AP exposure. We assessed the explained variance of having EOP using multiple regression analysis. Results Patients with and without AP exposure had significantly higher TC/HDL-C (p = 0.003, p = 0.029) and TG values (p 21 had significantly higher levels of TG than those with low scores (p = 0.032). Conclusion Our results suggest that lipid alterations predate AP treatment in adolescents with EOP. Higher levels of negative symptoms and AP further increase metabolic risk. The preliminary findings propose that subclinical dyslipidemia may be intrinsic to EOP.

Childbearing decreases HDL-cholesterol, potentially contributing to the increased risk of CVD in parous women. Large HDL particles (HDL-P) are associated with lower risk of CVD. In this secondary analysis of a randomised controlled trial, we investigated the effects of 12-week dietary and exercise treatments on HDL-P subclass concentration, size and apoA1 in lactating women with overweight/obesity. At 10–14 weeks postpartum, 68 women with pre-pregnant BMI 25–35 kg/m2 were randomised to four groups using 2 × 2 factorial design: (1) dietary treatment for weight loss; (2) exercise treatment; (3) both treatments and (4) no treatment. Lipoprotein subclass profiling by NMR spectroscopy was performed in serum at randomisation and after 3 and 12 months, and the results analysed with two-way ANCOVA. Lipid concentrations decline naturally postpartum. At 3 months (5–6 months postpartum), both diet (P = 0·003) and exercise (P = 0·008) reduced small HDL-P concentration. Concurrently, exercise limited the decline in very large HDL-P (P = 0·002) and the effect was still significant at 12 months (15 months postpartum) (P = 0·041). At 12 months, diet limited the decline in very large HDL-P (P = 0·005), large HDL-P (P = 0·001) and apoA1 (P = 0·002) as well as HDL size (P = 0·002). The dietary treatment for weight loss and the exercise treatment both showed effects on HDL-P subclasses in lactating women with overweight and obesity possibly associated with lower CVD risk. The dietary treatment had more effects than the exercise treatment at 12 months, likely associated with a 10 % weight loss.

BackgroundThe functional status of lipoprotein particles contributes to atherogenesis. The tendency of plasma LDL particles to aggregate and the ability of HDL particles to induce and mediate reverse cholesterol transport associate with high and low risk for cardiovascular disease in adult patients, respectively. However, it is unknown whether children with familial hypercholesterolemia (FH) display lipoprotein function alterations.HypothesisWe hypothesized that FH children had disrupted lipoprotein function.MethodsWe analyzed LDL aggregation susceptibility and HDL-apoA-I exchange to apoA-I ratio (HAE/apoA-I ratio), and activity of four proteins that regulate lipoprotein metabolism (CETP, LCAT, PLTP and PON1) in plasma samples derived from children with FH (n = 47) and from healthy children (n = 56). Potential biological mechanisms behind any variation in lipoprotein functionalities were explored using an NMR-based metabolomics profiling approach.ResultsLDL aggregation was higher and HAE/apoA-I ratio was lower in FH children than in healthy children. LDL aggregation associated positively with LDL-C and negatively with triglycerides, and HAE/apoA-I ratio associated negatively with LDL-C. Generally, the metabolomic profile for LDL aggregation was a mirror image of that for HAE/apoA-I ratio.ConclusionsFH children displayed increased atherogenicity of LDL and disrupted HDL function. These newly observed functional alterations in LDL and HDL may increase the risk for atherosclerotic cardiovascular disease in FH children.

Replacing dietary saturated fatty acids (SFAs) with polyunsaturated fatty acids (PUFA) reduces the plasma low-density lipoprotein (LDL) cholesterol and subsequently the risk of cardiovascular disease. However, beyond changes in LDL cholesterol, we lack a complete understanding of the physiologic alterations that occur when improving dietary fat quality. The aim of this study was to gain knowledge of metabolic alterations paralleling improvements in the fat quality of the diet. We recently conducted an 8-wk, double-blind, randomized controlled trial replacing SFAs with PUFAs in healthy subjects with moderate hypercholesterolemia (n = 99). In the present substudy, we performed comprehensive metabolic profiling with multiple platforms (both nuclear magnetic resonance- and mass spectrometry-based technology) (n = 99), and analyzed peripheral blood mononuclear cell gene expression (n = 95) by quantitative real-time polymerase chain reaction. A large number of lipoprotein subclasses, myristoylcarnitine and palmitoylcarnitine, and kynurenine were reduced when SFAs were replaced with PUFAs. In contrast, bile acids, proprotein convertase subtilisin/kexin type 9, acetate, and acetoacetate were increased by the intervention. Some amino acids were also altered by the intervention. The mRNA levels of LXRA and LDLR were increased, in addition to several liver X receptor α target genes and genes involved in inflammation, whereas the mRNA levels of UCP2 and PPARD were decreased in peripheral blood mononuclear cells after replacing SFAs with PUFAs. Partial least squares-discriminant analysis showed that the 30 most important variables that contributed to class separation spanned all classes of biomarkers, and was in accordance with the univariate analysis. Applying metabolomics in randomized controlled dietary intervention trials has the potential to extend our knowledge of the biological and molecular effects of dietary fat quality. This study was registered at clinicaltrials.gov as NCT 01679496.

Postprandial lipemia is a risk factor for cardiovascular disease. Dairy products differ in nutrient content and food matrix, and little is known about how different dairy products affect postprandial triglyceride (TG) concentrations. We investigated the effect of meals with similar amounts of fat from different dairy products on postprandial TG concentrations over 6 h in healthy adults. A randomized controlled cross-over study was performed on 47 subjects (30% men), with median (25th–75th percentile) age of 32 (25–46) y and body mass index of 23.6 (21.0–25.8) kg/m2. Meals included 1 of butter, cheese, whipped cream, or sour cream, corresponding to 45 g of fat (approximately 60 energy%). Serum concentrations of TGs (primary outcome), and total cholesterol (TC), low density lipoprotein cholesterol (LDL cholesterol), high density lipoprotein cholesterol (HDL cholesterol), insulin, glucose, non-esterified fatty acids, and plasma glucose-dependent insulinotropic polypeptide (secondary outcomes) were measured before the meal and 2, 4, and 6 h postprandially. Incremental AUC (iAUC) was calculated for the responses, and data were analyzed using a linear mixed model. Sour cream induced a 61% larger TG-iAUC0–6 h compared to whipped cream (P

Elevated lipoprotein(a) (Lp(a)) is associated with CVD and is mainly genetically determined. Studies suggest a role of dietary fatty acids (FA) in the regulation of Lp(a); however, no studies have investigated the association between plasma Lp(a) concentration and n-6 FA. We aimed to investigate whether plasma Lp(a) concentration was associated with dietary n-6 FA intake and plasma levels of arachidonic acid (AA) in subjects with familial hypercholesterolaemia (FH). We included FH subjects with (n 68) and without (n 77) elevated Lp(a) defined as ≥75 nmol/l and healthy subjects (n 14). Total FA profile was analysed by GC–flame ionisation detector analysis, and the daily intake of macronutrients (including the sum of n-6 FA: 18 : 2n-6, 20 : 2n-6, 20 : 3n-6 and 20 : 4n-6) were computed from completed FFQ. FH subjects with elevated Lp(a) had higher plasma levels of AA compared with FH subjects without elevated Lp(a) (P = 0·03). Furthermore, both FH subjects with and without elevated Lp(a) had higher plasma levels of AA compared with controls (P < 0·001). The multivariable analyses showed associations between dietary n-6 FA intake and plasma levels of AA (P = 0·02) and between plasma levels of Lp(a) and AA (P = 0·006). Our data suggest a novel link between plasma Lp(a) concentration, dietary n-6 FA and plasma AA concentration, which may explain the small diet-induced increase in Lp(a) levels associated with lifestyle changes. Although the increase may not be clinically relevant, this association may be mechanistically interesting in understanding more of the role and regulation of Lp(a).

[Abstract] The alkaline comet assay, or single cell gel electrophoresis, is one of the most popular methods for assessing DNA damage in human population. One of the open issues concerning this assay is the identification of those factors that can explain the large inter-individual and inter-laboratory variation. International collaborative initiatives such as the hCOMET project - a COST Action launched in 2016 - represent a valuable tool to meet this challenge. The aims of hCOMET were to establish reference values for the level of DNA damage in humans, to investigate the effect of host factors, lifestyle and exposure to genotoxic agents, and to compare different sources of assay variability. A database of 19,320 subjects was generated, pooling data from 105 studies run by 44 laboratories in 26 countries between 1999 and 2019. A mixed random effect log-linear model, in parallel with a classic meta-analysis, was applied to take into account the extensive heterogeneity of data, due to descriptor, specimen and protocol variability. As a result of this analysis interquartile intervals of DNA strand breaks (which includes alkali-labile sites) were reported for tail intensity, tail length, and tail moment (comet assay descriptors). A small variation by age was reported in some datasets, suggesting higher DNA damage in oldest age-classes, while no effect could be shown for sex or smoking habit, although the lack of data on heavy smokers has still to be considered. Finally, highly significant differences in DNA damage were found for most exposures investigated in specific studies. In conclusion, these data, which confirm that DNA damage measured by the comet assay is an excellent biomarker of exposure in several conditions, may contribute to improving the quality of study design and to the standardization of results of the comet assay in human populations. This article is based upon work from COST Action hCOMET CA15132, supported by COST (European Cooperation in Science and Technology www.cost.eu) - STSM fellowships for Mirta Milić (IMROH, EU 19); IMROH, Zagreb, Croatia, Institute for Medical Research and Occupational Health (IMROH), Zagreb, Croatia, and the Ministry of Science, Education and Sports of the Republic of Croatia (Grant No. 022-0222148-2125) (EU4); Cancer Plan for PestiBG; Grant number: no ENV201401(EU 8, EU9); Italian Ministry of Education, University and Research PRIN 2005, prot. 2005058197 and Cariplo Foundation (Milan, Italy), Rif. Pratica 2007-5810 and Rif. Pratica 2010.2303 (EU 18); Associazione Italiana per la Ricerca sul Cancro (AIRC) (IG 2015/17564). (EU19); European Union Integrated Projects New Generis, 6th Framework Programme, Priority 5: Food Quality and Safety; Newborns and Genotoxic Exposure Risks, FOOD-CT-2005-016320 (EU22); ACT project No. 036APy/09 and No. 005DBB/12 (EU 24); FCT-SFRH/BPD/96196/2013, SFRH/BPD/100948/2014, Portugal (EU 26); MZ 2012/8-UKBA-8; VEGA 1/0703/13, APVV 15-0063 (EU30); Xunta de Galicia (XUGA 10605B98; INCITE08PXIB106155PR; ED481B2016/190-0; Grants ED431B2019/02), Spain (EU 32); Grant 01 173034, Ministry of Education, Science and Technological Development of the Republic of Serbia (EU 42); The Centre for Industrial and Technological Development within National Strategic Consortia for Techical Research (Industrial Research diets and food with specific characteristics for elderly, SENIFOOD); University of Navarra LE/97; Physiopathology of Obesity and Nutrition (CIBER Obn); Carlos III Health Research Institute (CB12/03/30002); Ministerio de Economia y Compatitividad (‘Ramón y Cajal’ Programme, RYC-2013-14370) of the Spanish Government for personal support (EU 45); the Ministry of Education, Youth and Sports of the Czech Republic project Healthy Aging in Industrial Environment HAIE (CZ.02.1.01/0.0/0.0/16_019/0000798) which is co-financed by the European Union (European Structural and Investment funds; Operation Programme Research, Development and Education); MYES LO 1508 (EU 46); MICRODIAB Study; ClinicalTrials.org (#NCT02231736) (EU 52); The study was funded by the Italian Ministry for Education, University and Scientific Research (MIUR) - Research No. 2005-062547 (EU14, EU53); Projects financed from Serbian Ministry of Education, Science and Technological Development #11146002, #175035, #173034 (EU 54); Mehr foundation organisation, UK (EU 55); MCTI/CNPQ No. 01/2016-Universal; FAPESC No. 09/2015; MEC/MCTI/CAPES/CNPQ/FAPS/ No. 09/2014, Brazil (CSA 6); the National Nuclear Energy Agency of Indonesia (Badan Tenaga Nuklir Nasional) with contract number 080.01.06 3447.001 001.052.A (AS4); Slovak Grant Agency (APVT-21 013202, APVT-21- 017704); Ministry of Health, Slovak Republic (2005/43-SZU-21, 2006/07- SZU-02 MZ SR, 2005/42-SZU-20

Scope The aim of this study is to explore the molecular mechanisms underlying the effect of replacing dietary saturated fat (SFA) with polyunsaturated fat (PUFA) on cardiovascular disease (CVD) risk using a whole transcriptome approach. Methods and Results Healthy subjects with moderate hypercholesterolemia (n = 115) are randomly assigned to a control diet (C-diet) group or an experimental diet (Ex-diet) group receiving comparable food items with different fatty acid composition for 8 weeks. RNA isolated from peripheral blood mononuclear cells (PBMCs) at baseline and after 8 weeks of intervention is analyzed by microarray technology (n = 95). By use of a linear regression model (n = 92), 14 gene transcripts are differentially altered in the Ex-diet group compared to the C-diet group. These include transcripts related to vascular smooth muscle cell proliferation, low-density lipoprotein receptor folding, and regulation of blood pressure. Furthermore, pathways mainly related to immune response and inflammation, signal transduction, development, and cytoskeleton remodeling, gene expression and protein function, are differentially enriched between the groups. Conclusion Replacing dietary SFA with PUFA for 8 weeks modulates PBMC gene expression and pathways related to CVD risk in healthy subjects with moderate hypercholesterolemia.

Background and aims Both the Nordic and Mediterranean diets claim to have a beneficial effect on lipid metabolism and cardiovascular prevention. The objective of this study was to compare diets consumed by children with FH at the time of diagnosis in Norway and Spain and to study their relationship with the lipid profile. Methods and results In this cross-sectional study, we appraised the dietary intake in children (4–18 years old) with (n = 114) and without FH (n = 145) from Norway and Spain. We compared Nordic and Mediterranean diet composition differences and determined the association between food groups and lipid profiles. Results The Spanish FH group had a higher intake of total fats (mainly monounsaturated fatty acids (MUFAs)), cholesterol and fibre, but a lower intake of polyunsaturated fatty acids (PUFAs) compared to the Norwegian FH group. The Norwegian children consumed more rapeseed oil, low-fat margarine and whole grains and less olive oil, eggs, fatty fish, meat, legumes and nuts. In the Norwegian FH group, fat and MUFAs were directly correlated with total cholesterol, low-density lipoprotein cholesterol and apolipoprotein B and inversely correlated with high-density lipoprotein (HDL-C). In Spanish children with FH, the intake of fats (mainly MUFAs) was directly associated with HDL-C and apolipoprotein A1. Conclusions Despite a similar lipid phenotype, diets consumed by children with FH in Norway and Spain have significant differences at time of diagnosis. Nutrition advice should be more adapted to local intake patterns than on specific nutrient composition.

Background The aim was to investigate if fatty acid profile and estimated desaturase activities; stearoyl CoA-desaturase (SCD), delta-5-desaturase and delta-6-desaturase (D5D; D6D), differ between individuals with metabolically healthy (MH) and unhealthy (MU) phenotypes. We also explored these associations according to BMI categories. Methods Men and women at moderately elevated risk of cardiovascular disease were included in this cross-sectional study (n = 321). If subjects met ≥4 out of 5 criteria (elevated triglycerides, total and LDL-cholesterol, HbA1c and low HDL-cholesterol), they were classified as MU (n = 52). If levels were within reference ranges for ≥3 of the same criteria, subjects were classified as MH (n = 150). Utilizing the entire population, a score ranging from 0 to 5 denoting the number of MU criteria met was computed. Estimated desaturase activities were calculated as product-to-precursor ratio of fatty acids in whole blood (SCD16 [16:1n7/16:0], SCD18 [18:1n9/18:0], D5D [18:3n6/18:2n6], D6D [20:4n6/20:3n6]). Results Individuals with MH had lower estimated SCD16 and SCD18 activities, whereas estimated D6D activity was higher compared to MU. Similar, SCD16 and SCD18 increased, whereas D6D decreased with increasing criteria of MU. Trends were similar across BMI categories. Conclusions This study supports the notion of estimated desaturase activities as possible novel biomarkers of metabolic health irrespectively of BMI.

The cholesterol-sensing nuclear receptor liver X receptor (LXR) and the glucose-sensing transcription factor carbohydrate responsive element-binding protein (ChREBP) are central players in regulating glucose and lipid metabolism in the liver. More knowledge of their mechanistic interplay is needed to understand their role in pathological conditions like fatty liver disease and insulin resistance. In the current study, LXR and ChREBP co-occupancy was examined by analyzing ChIP-seq datasets from mice livers. LXR and ChREBP interaction was determined by Co-immunoprecipitation (CoIP) and their transactivity was assessed by real-time quantitative polymerase chain reaction (qPCR) of target genes and gene reporter assays. Chromatin binding capacity was determined by ChIP-qPCR assays. Our data show that LXR&alpha, and ChREBP&alpha, interact physically and show a high co-occupancy at regulatory regions in the mouse genome. LXR&alpha, co-activates ChREBP&alpha, and regulates ChREBP-specific target genes in vitro and in vivo. This co-activation is dependent on functional recognition elements for ChREBP but not for LXR, indicating that ChREBP&alpha, recruits LXR&alpha, to chromatin in trans. The two factors interact via their key activation domains, the low glucose inhibitory domain (LID) of ChREBP&alpha, and the ligand-binding domain (LBD) of LXR&alpha, While unliganded LXR&alpha, ligand-bound LXR&alpha, surprisingly represses ChREBP&alpha, activity on ChREBP-specific target genes. Mechanistically, this is due to a destabilized LXR&alpha, ChREBP&alpha, interaction, leading to reduced ChREBP-binding to chromatin and restricted activation of glycolytic and lipogenic target genes. This ligand-driven molecular switch highlights an unappreciated role of LXR&alpha, in responding to nutritional cues that was overlooked due to LXR lipogenesis-promoting function.

Background and aims Diet may alter gene expression in immune cells involved in atherosclerotic cardiovascular disease susceptibility. However, we still lack a robust understanding of the association between diet and immune cell-related gene expression in humans. Therefore, we examined associations between dietary patterns (DPs) and gene expression profiles in peripheral blood mononuclear cells (PBMCs) in a population of healthy, Norwegian adults (n = 130 women and 105 men). Methods and results We used factor analysis to define a posteriori DPs from food frequency questionnaire-based dietary assessment data. In addition, we derived interpretable features from microarray-based gene expression data (13 967 transcripts) using two algorithms: CIBERSORT for estimation of cell subtype proportions, and weighted gene co-expression network analysis (WGCNA) for cluster discovery. Finally, we associated DPs with either CIBERSORT-predicted PBMC leukocyte distribution or WGCNA gene clusters using linear regression models. We detected three DPs that broadly reflected Western, Vegetarian, and Low carbohydrate diets. CIBERSORT-predicted percentage of monocytes associated negatively with the Vegetarian DP. For women, the Vegetarian DP associated with a large gene cluster consisting of 600 genes mainly involved in regulation of DNA transcription, whereas for men, the Western DP inversely associated with a smaller cluster of 36 genes mainly involved in regulation of metabolic and inflammatory processes. A subsequent protein–protein interaction network analysis suggested that genes within these clusters might physically interact in biological networks. Conclusions Although the present findings are exploratory, our analysis pipeline serves as a useful framework for studying the association between diet and gene expression.

Purpose of review Give an update on recent dietary intervention studies that have used peripheral blood mononuclear cell gene expression analysis and/or metabolic profiling to understand how intake of polyunsaturated and saturated fat affects and biological pathways linked to cardiovascular disease. Recent findings Several studies showed that intake of fish oil and vegetable oil, high in omega-3 fatty acids, reduced expression level of genes involved in inflammation. One intervention study showed that gene transcripts encoding genes involved inflammation and lipid metabolism increased after intake of polyunsaturated fat (mainly omega-6 fatty acids) compared to saturated fat. Additionally, using targeted metabolomics, the concentrations of atherogenic lipoprotein particles and several metabolites including palmitoylcarnitine, myristoylcarnitine, and kynurenine were reduced after intake of polyunsaturated fat compared to saturated fat, whereas acetate and acetoacetate were increased. The use of targeted metabolomics showed that overfeeding with polyunsaturated fat reduced the serum concentration of ceramides, dihydroceramides, glucosylceramides, and lactosylceramides, whereas overfeeding with saturated fat increased serum concentration of these metabolites. Summary The use of gene expression profiling and metabolomics are promising tools to identify possible new biomarkers linking fat quality to cardiovascular disease risk.

Under conditions of calorie restriction, i.e. at reduced food intake, the lifespan of model organisms, such as yeast, worms or flies, is increased. Similarly, when the activity of nutrient-sensing pathways is reduced by the knockdown of one or several of their key genes, these species live longer. Even in rodents and rhesus monkeys decreased nutrient-sensing pathway activity or calorie restriction protects them against T2D, CVD and cancer. The molecular basis of these processes are sensing of glucose and amino acids via the insulin/IGF and the TOR pathways, respectively, and the integration of the nutritional and energetic status of cells and tissues via HDACs of the sirtuin family and AMPK. Since these signal transduction pathways are evolutionary conserved, also humans may be protected against age-related pathologies. Humans may slow down their aging process, when their nutrient signaling pathways are modulated by moderate intake of a diet that was personalized for them.

Fish consumption is associated with reduced risk of CVD, which may be partly mediated by alterations in plasma lipids, such as HDL-cholesterol. However, comprehensive analyses of associations between fatty fish consumption and lipoprotein subclass profile are limited and show inconsistent results. Therefore, the aim of the present exploratory study was to investigate the association between fatty fish consumption and lipoprotein subclass particle concentrations and composition, with an emphasis on HDL. We performed a comprehensive plasma metabolite profiling in 517 healthy adults, using a targeted high-throughput NMR spectroscopy platform. The participants were divided into tertiles based on consumption of fatty fish, reported through a validated FFQ. We compared the concentration of metabolites between the participants in the lowest and highest tertiles of fatty fish consumption. We show that high consumers of fatty fish (>223 g/week, median intake 294 g/week) had higher particle concentrations and content of total lipids, free cholesterol and phospholipids in large and extra-large HDL particles and higher content of total cholesterol, cholesteryl esters and TAG in large HDL particles than low consumers (

Background The ever-increasing prevalence of obesity constitutes a major health problem worldwide. A subgroup of obese individuals has been described as “metabolically healthy obese” (MHO). In contrast to metabolically unhealthy obese (MUO), the MHO phenotype has a favorable risk profile. Despite this, the MHO phenotype is still sub-optimally characterized with respect to a comprehensive risk assessment. Our aim was to increase the understanding of metabolic alterations associated with healthy and unhealthy obesity. Methods In this cross-sectional study, men and women (18–70 years) with obesity (body mass index (BMI) ≥ 30 kg/m2) or normal weight (NW) (BMI ≤ 25 kg/m2) were classified with MHO (n = 9), MUO (n = 10) or NW (n = 11) according to weight, lipid profile and glycemic regulation. We characterized individuals by comprehensive metabolic profiling using a commercial available high-throughput proton NMR metabolomics platform. Plasma fatty acid profile, including short chain fatty acids, was measured using gas chromatography. Results The concentrations of very low density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and low density lipoprotein (LDL) subclasses were overall significantly higher, and high density lipoprotein (HDL) subclasses lower in MUO compared with MHO. VLDL and IDL subclasses were significantly lower and HDL subclasses were higher in NW compared with MHO. The concentration of isoleucine, leucine and valine was significantly higher in MUO compared with MHO, and the concentration phenylalanine was lower in NW subjects compared with MHO. The fatty acid profile in MHO was overall more favorable compared with MUO. Conclusions Comprehensive metabolic profiling supports that MHO subjects have intermediate-stage cardiovascular disease risk marker profile compared with NW and MUO subjects. Clinical trial registration number NCT01034436, Fatty acid quality and overweight (FO-study). Graphical abstract

Macrophages are associated with various tissues and either derive from monocytes circulating in the blood or from self-renewing embryonal cell populations. They show a large variety of stimulus- and tissue-specific functions, of which the extremes are pro-inflammatory M1-type and anti-inflammatory M2-type macrophages. M1 macrophages are key cells in the initiation of the acute inflammatory response, while M2 macrophages are resolving inflammation and coordinate tissue repair. However, tissue inflammation is not only caused by bacterial infection or tissue injury but may also derive from changes in the concentration of nutrients and metabolites. In this case, the immune system cannot cope the primary stimulus, so that chronic inflammation develops. This metabolic stress, in contrast to infectious or traumatic stress, is often caused by lipid overload in the blood and in adipose tissue. This again is a hallmark of age-related metabolic diseases, such as obesity, insulin resistance and atherosclerosis. For example, hypercholesterolemia (Sect. 11.3) causes stress to macrophages and their associated cells. Moreover, perturbations of the homeostasis of nutrient metabolism dys-regulate functions of the liver.

The cholesterol-sensing nuclear receptor liver X receptor (LXR) and the glucose-sensing transcription factor carbohydrate responsive element-binding protein (ChREBP) are central players in regulating glucose and lipid metabolism in liver. We have previously shown that LXR regulates ChREBP transcription and activity; however, the underlying mechanisms are unclear. In the current study, we demonstrate that LXRα and ChREBPα interact physically, and show a high co-occupancy at regulatory regions in the mouse genome. LXRα co-activates ChREBPα, and regulates ChREBP-specific target genesin vitroandin vivo. This co-activation is dependent on functional recognition elements for ChREBP, but not for LXR, indicating that ChREBPα recruits LXRα to chromatin intrans. The two factors interact via their key activation domains; ChREBPα’s low glucose inhibitory domain (LID) and the ligand-binding domain (LBD) of LXRα. While unliganded LXRα co-activates ChREBPα, ligand-bound LXRα surprisingly represses ChREBPα activity on ChREBP-specific target genes. Mechanistically, this is due to a destabilized LXRα:ChREBPα interaction, leading to reduced ChREBP-binding to chromatin and restricted activation of glycolytic and lipogenic target genes. This ligand-driven molecular switch highlights an unappreciated role of LXRα that was overlooked due to LXR lipogenesis-promoting function.

Branched-chain amino acids (BCAA) are essential amino acids that are necessary for muscle mass maintenance. Little is known about the plasma concentrations of BCAA and the protein intake in relation to sarcopenia. We aimed to compare the non-fasting plasma concentrations of the BCAA and the dietary protein intake between sarcopenic and non-sarcopenic older adults. Norwegian older home-dwelling adults (≥70 years) were invited to a cross-sectional study with no other exclusion criteria than age. Sarcopenic subjects were defined by the diagnostic criteria by the European Working Group on Sarcopenia in Older People. Non-fasting plasma concentrations of eight amino acids were quantified using NMR spectroscopy. Protein intake was assessed using 2×24-h dietary recalls. In this study, ninety out of 417 subjects (22 %) were sarcopenic, and more women (32 %) than men (11 %) were sarcopenic (PP=0·003, P=0·026 and P=0·003, respectively). A similar protein intake was observed in the two groups when adjusted for body weight (BW) and sex (1·1 g protein/kg BW per d; P=0·50). We show that sarcopenia is associated with reduced non-fasting plasma concentration of the BCAA leucine and isoleucine, and lower absolute intake of protein. More studies are needed to clarify the clinical relevance of these findings, related to maintenance of muscle mass and prevention of sarcopenia.

Postprandial hypertriacylglycerolaemia is associated with an increased risk of developing CVD. How fat quality influences postprandial lipid response is scarcely explored in subjects with familial hypercholesterolaemia (FH). The aim of this study was to investigate the postprandial response of TAG and lipid sub-classes after consumption of high-fat meals with different fat quality in subjects with FH compared with normolipidaemic controls. A randomised controlled double-blind cross-over study with two meals and two groups was performed. A total of thirteen hypercholesterolaemic subjects with FH who discontinued lipid-lowering treatment 4 weeks before and during the study, and fourteen normolipidaemic controls, were included. Subjects were aged 18–30 years and had a BMI of 18·5–30·0 kg/m2. Each meal consisted of a muffin containing 60 g (70 E%) of fat, either mainly SFA (40 E%) or PUFA (40 E%), eaten in a random order with a wash-out period of 3–5 weeks between the meals. Blood samples were collected at baseline (fasting) and 2, 4 and 6 h after intake of the meals. In both FH and control subjects, the level of TAG and the largest VLDL sub-classes peaked at 2 h after intake of PUFA and at 4 h after intake of SFA. No significant differences were found in TAG levels between meals or between groups (0·25≤P≤0·72). The distinct TAG peaks may reflect differences in the postprandial lipid metabolism after intake of fatty acids with different chain lengths and degrees of saturation. The clinical impact of these findings remains to be determined.

Background Cardiovascular diseases are among the main causes of morbidity and mortality in Norway. The objective of this article is to provide an overview of literature that describes the effect of a Nordic diet in line with the authorities’ dietary advice on risk factors for cardiovascular disease. Method Electronic literature searches were undertaken in the PubMed, Cochrane and Embase databases. Randomised, controlled studies that described the Nordic diet and cardiovascular disease were included. A total of 15 articles were included. These are based on four dietary intervention studies conducted in the Nordic countries. Results All of the dietary intervention studies indicated effects on blood lipids. In one of the studies, a Nordic diet caused a 21 % reduction in LDL cholesterol levels. Three of the studies showed that a Nordic diet reduces blood pressure. Results from two of the studies showed that it also improved glucose and insulin sensitivity, but after adjustment for weight loss, this effect disappeared. Three of the studies showed that a Nordic diet may positively affect inflammation. Interpretation A diet based on the authorities’ dietary recommendation and consisting of Nordic ingredients improves the risk profile in those who are predisposed to developing cardiovascular disease.

Background Adequate protein intake among older adults is associated with better health outcomes such as immune function and metabolic regulation of skeletal muscle, but conflicting results make it difficult to define the optimal intake. To further understand the impact of protein intake on metabolic processes, the aim of the study was to explore genome-wide gene expression changes in peripheral blood mononuclear cells (PBMCs) in home-dwelling old subjects after increased protein intake for 12 weeks. Method In a parallel double-blind randomized controlled intervention study, subjects (≥ 70 years) received a protein-enriched milk (2 × 20 g protein/day, n = 14, mean (±SD) age 76.9 ± 4.9 years) or an isocaloric carbohydrate drink (n = 17, mean (±SD) age 77.7 ± 4.8 years) for breakfast and evening meal for 12 weeks. PBMCs were isolated before and after the intervention. Microarray analysis was performed using Illumina technology. Serum levels of gut peptides and insulin growth factor (IGF)-1 were also measured. Results In total 758 gene transcripts were regulated after increased protein intake, and 649 gene transcripts were regulated after intake of carbohydrates (p < 0.05). Forty-two of these genes were overlapping. After adjusting for multiple testing, 27 of the 758 gene transcripts were regulated (FDR, q-value < 0.25) after protein intake. Of these 25 were upregulated and two downregulated. In particular, genes and signaling pathways involved in pro-opiomelanocortin (POMC) processing, immune function, and IGF signaling were significantly altered. Conclusions PBMCs can be used to study gene expression changes after long-term protein intake, as many signaling pathways were regulated after increased protein intake. The functional significance of these findings needs to be further investigated. Trial registration ClinicalTrials.gov, ID no. NCT02218333. The study was registered on August 18, 2014.

Little is known about how dairy products with different nutrient contents and food matrices affect appetite sensation and gut hormone secretion. The objective of this study was to investigate how appetite sensation and gut hormone secretion in healthy adults are affected by meals with the same amount of fat but from different dairy products. Forty-seven healthy adults (70% women) were recruited to a randomized controlled crossover study with 4 dairy meals consisting of butter, cheese, whipped cream, or sour cream, corresponding to 45 g (approximately 60 energy percent) of fat. Plasma samples were collected for analysis of cholecystokinin (CCK), pancreatic polypeptide (PP), peptide YY (PYY), and ghrelin concentrations at 0, 2, 4, and 6 h after the meals and analyzed as the incremental area under the curve (iAUC0–6h) in a mixed model. Hunger, satiety, and appetite sensations were measured with a visual analog scale (VAS) immediately after finishing the meals and at 4 and 6 h postprandially. Intake of cheese induced a higher level of plasma PP-iAUC0–6h compared with butter or whipped cream, and a higher level of plasma CCK-iAUC0–6h compared with whipped cream. Intake of whipped cream increased VAS appetite at 4 h compared with cheese or sour cream, and at 6 h compared with cheese or butter. No significant meal effect was found for hunger, satiety, plasma PYY, or plasma ghrelin concentration. Intake of cheese increased postprandial plasma PP and CCK concentrations and decreased appetite compared with whipped cream but not with sour cream. These findings encourage further investigations of how different dairy products affect gut hormone secretion and appetite sensation.

Background Intake of the marine omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) reduces fasting triglyceride (TG) levels and may thereby lower cardiovascular disease risk. However, there are large inter-individual differences in the TG-lowering effect of omega-3 supplementation. Genotype differences partly explain this variation, but gene-environment interactions leading to gene expression differences may also be important. In this study, we aimed to investigate baseline differences and differences in the change in peripheral blood mononuclear cell (PBMC) gene expression and lipoprotein subclass TG levels between TG responders and non-responders to omega-3 fatty acid supplementation. Methods In a previous randomized controlled trial, healthy normotriglyceridemic subjects (n = 35, 71% women) received 1.6 g EPA + DHA/day for 7 weeks. In this exploratory sub-study, we defined TG responders as subjects having a TG reduction beyond the 20% day-to-day variation and non-responders as having a TG change between − 20% and + 20% after omega-3 supplementation. PBMC gene expression was measured using microarray, and lipoprotein subclasses were measured using nuclear magnetic resonance spectroscopy. Results Eight subjects were defined as responders with a median TG reduction of 37%, and 16 subjects were defined as non-responders with a median TG change of 0%. At baseline, responders had higher TG levels in two of four high-density lipoprotein (HDL) subclasses and 909 gene transcripts (p ≤ 0.05) were differentially expressed compared to non-responders. During the intervention, the plasma TG reduction among responders was reflected in TG reductions in four of six different very low-density lipoprotein subclasses and three of four different HDL subclasses. Compared to non-responders, the expression of 454 transcripts was differentially altered in responders (p ≤ 0.05). Pathway analyses revealed that responders had altered signaling pathways related to development and immune function. In addition, two of the top 10 enriched pathways in responders compared to non-responders were related to lysophosphatidic acid signaling. Conclusion TG responders and non-responders to omega-3 supplementation have different lipoprotein subclass and PBMC gene expression profiles at baseline and different lipoprotein subclass and PBMC gene expression responses to omega-3 supplementation. These gene expression differences may partially explain the variability in TG response observed after omega-3 supplementation. Graphical abstract Based on free images from Servier Medical Art (Creative Commons Attribution License) and image from www.colourbox.com .

Scope. To explore the effect of a healthy Nordic diet on the global transcriptome profile in peripheral blood mononuclear cells (PBMCs) of subjects with metabolic syndrome. Methods and results. Subjects with metabolic syndrome undergo a 18/24 week randomized intervention study comparing an isocaloric healthy Nordic diet with an average habitual Nordic diet served as control (SYSDIET study). Altogether, 68 participants are included. PBMCs are obtained before and after intervention and total RNA is subjected to global transcriptome analysis. 1302 probe sets are differentially expressed between the diet groups (p‐value < 0.05). Twenty‐five of these are significantly regulated (FDR q‐value < 0.25) and are mainly involved in mitochondrial function, cell growth, and cell adhesion. The list of 1302 regulated probe sets is subjected to functional analyses. Pathways and processes involved in the mitochondrial electron transport chain, immune response, and cell cycle are downregulated in the healthy Nordic diet group. In addition, gene transcripts with common motifs for 42 transcription factors, including NFR1, NFR2, and NF‐κB, are downregulated in the healthy Nordic diet group. Conclusion. These results suggest that benefits of a healthy diet may be mediated by improved mitochondrial function and reduced inflammation. The project was funded by NordForsk Nordic Centre of Excellencein Food, Nutrition and Health project 070014 (SYSDIET [Systems Biologyin Controlled Dietary Interventions and Cohort Studies]) and further, OsloMetropolitan University-OsloMet (Norway), University of Oslo (Norway),Throne Holst Foundation (Norway), Academy of Finland, SwedishResearch Council, Svenska Diabetesf ̈orbundet, SRP Diabetes, FinnishDiabetes Research Foundation, Finnish Foundation for CardiovascularResearch, the Sigrid Juselius Foundation, EVO funding from KuopioUniversity Hospital (Finland), the Druvan Foundation, Sk ̊ane UniversityHospital, the Heart-Lung Foundation, Diabetesfonden and FoundationCerealia (Sweden), the Danish Obesity Research Centre (DanORC,www.danorc.dk), the Danish Council for Strategic Research (DairyHealth,BioFunCarb) (Denmark), the Agricultural Productivity Fund, and theResearch Fund of the University of Iceland (Iceland).

Milk and dairy products contribute ≤14% of the caloric intake in developed countries. Recent evidence has shown controversial results with regard to the role of dairy products in deleterious processes such as inflammation. The increasing number of studies on the anti- and proinflammatory effects of milk and dairy products in the past 5 y reflects the growing interest in this area of research. The aim of this systematic review was to evaluate the scientific evidence provided in the past 5 y on the effects of milk and dairy products on inflammatory biomarkers provided by randomized clinical trials. The search strategy was conducted in Medline (via PubMed) and Scopus (which includes EMBASE and the Web of Science) databases and included articles from 1 January 2012 to 30 April 2018. The risk of bias was assessed using the Cochrane methodology. The number of study participants, type of study, doses, and the key results are reported. The following primary outcomes were considered for inclusion: circulating concentrations of C-reactive protein, interleukins, cytokines, and vascular adhesion molecules or expression of proinflammatory genes in peripheral blood mononuclear cells; however, the primary outcomes considered were not limited to these. Sixteen studies (15 articles) included in this systematic review reported on healthy individuals and subjects who were overweight or obese and who had metabolic syndrome or type 2 diabetes. The consumption of milk or dairy products did not show a proinflammatory effect in healthy subjects or individuals with metabolic abnormalities. The majority of studies documented a significant anti-inflammatory effect in both healthy and metabolically abnormal subjects, although not all the articles were of high quality. This review was registered on PROSPERO (International Prospective Register of Systematic Reviews) at https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=94535 as CRD42018094535.

Publisher's version (útgefin grein)., A healthy dietary pattern is associated with a lower risk of metabolic syndrome (MetS) and reduced inflammation. To explore this at the molecular level, we investigated the effect of a Nordic diet (ND) on changes in the gene expression profiles of inflammatory and lipid-related genes in peripheral blood mononuclear cells (PBMCs) of individuals with MetS. We hypothesized that the intake of an ND compared to a control diet (CD) would alter the expression of inflammatory genes and genes involved in lipid metabolism. The individuals with MetS underwent an 18/24-week randomized intervention to compare a ND with a CD. Eighty-eight participants (66% women) were included in this sub-study of the larger SYSDIET study. Fasting PBMCs were collected before and after the intervention and changes in gene expression levels were measured using TaqMan Array Micro Fluidic Cards. Forty-eight pre-determined inflammatory and lipid related gene transcripts were analyzed. The expression level of the gene tumor necrosis factor (TNF) receptor superfamily member 1A (TNFRSF1A) was down-regulated (p = 0.004), whereas the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) subunit, RELA proto-oncogene, was up-regulated (p = 0.016) in the ND group compared to the CD group. In conclusion, intake of an ND in individuals with the MetS may affect immune function., Funding: This research was funded by the NordForsk Nordic Centre of Excellence in Food, Nutrition and Health project 070014 [SYSDIET (Systems Biology in Controlled Dietary Interventions and Cohort Studies)] and further, the University of Oslo (Norway), Throne Holst Foundation (Norway), Academy of Finland, Swedish Research council, Svenska Diabetesförbundet, SRP Diabetes, Finnish Diabetes Research Foundation, Finnish Foundation for Cardiovascular Research, the Sigrid Juselius Foundation, EVO funding from Kuopio University Hospital (Finland), the Druvan Foundation, Skåne University Hospital, the Heart-Lung Foundation, Diabetesfonden and Foundation Cerealia (Sweden), the Agricultural Productivity Fund, and the Research Fund of the University of Iceland (Iceland). Acknowledgments: We thank Maritta Siloaho for their excellent expertise and advice for biochemical measurements and Marika Rönnholm for their excellent technical assistance.

Men have earlier first-time event of CHD and higher postprandial TAG response compared with women. The aim of this exploratory sub-study was to investigate if intake of meals with the same amount of fat from different dairy products affects postprandial lipoprotein subclasses differently in healthy women and men. A total of thirty-three women and fourteen men were recruited to a randomised controlled cross-over study with four dairy meals consisting of butter, cheese, whipped cream or sour cream, corresponding to 45 g of fat (approximately 60 energy percent). Blood samples were taken at 0, 2, 4 and 6 h postprandially. Lipoprotein subclasses were measured using NMR and analysed using a linear mixed model. Sex had a significant impact on the response in M-VLDL (P=0·04), S-LDL (P=0·05), XL-HDL (P=0·009) and L-HDL (P=0·001) particle concentration (P), with women having an overall smaller increase in M-VLDL-P, a larger decrease in S-LDL-P and a larger increase in XL- and L-HDL-P compared with men, independent of meal. Men showed a decrease in XS-VLDL-P compared with women after intake of sour cream (Pv. butter:P=0·001;v. cheese:P=0·04;v. whipped cream:P=0·006). Meals with the same amount of fat from different dairy products induce different postprandial effects on lipoprotein subclass concentrations in men and women.

Source at https://doi.org/10.1017/jns.2019.25. The long-term cholesterol-lowering effect of replacing intake of SFA with PUFA is well established, but has not been fully explained mechanistically. We examined the postprandial response of meals with different fat quality on expression of lipid genes in peripheral blood mononuclear cells (PBMC) in subjects with and without familial hypercholesterolaemia (FH). Thirteen subjects with FH (who had discontinued lipid-lowering treatment ≥4 weeks prior to both test days) and fourteen normolipidaemic controls were included in a randomised controlled double-blind crossover study with two meals, each with 60 g of fat either mainly SFA (about 40% energy) or n-6 PUFA (about 40% energy). PBMC were isolated in fasting, and 4 and 6 h postprandial blood samples. Expression of thirty-three lipid genes was analysed by reverse transcription quantitative PCR. A linear mixed model was used to assess postprandial effects between meals and groups. There was a significant interaction between meal and group for MSR1 (P = 0·03), where intake of SFA compared with n-6 PUFA induced a larger reduction in gene expression in controls only (P = 0·01). Intake of SFA compared with n-6 PUFA induced larger reductions in gene expression levels of LDLR and FADS1/2, smaller increases of INSIG1 and FASN, and larger increases of ABCA1 and ABCG1 (P = 0·01 for all, no group interaction). Intake of SFA compared with n-6 PUFA induced changes in gene expression of cholesterol influx and efflux mediators in PBMC including lower LDLR and higher ABCA1/G1, potentially explaining the long-term cholesterol-raising effect of a high SFA intake.

Background Innate and adaptive immune responses are pivotal in atherosclerosis, but their association with early‐stage atherosclerosis in humans is incompletely understood. In this regard, untreated children with familial hypercholesterolaemia may serve as a human model to investigate the effect of elevated low‐density lipoprotein (LDL)‐cholesterol. Objectives We aimed to study the immunological and inflammatory pathways involved in early atherosclerosis by examining mRNA molecules in peripheral blood mononuclear cells (PBMCs) from children with FH. Methods We analysed the level of 587 immune‐related mRNA molecules using state‐of‐the‐art Nanostring technology in PBMCs from children with (n = 30) and without (n = 21) FH, and from FH children before and after statin therapy (n = 10). Results 176 genes (30%) were differentially expressed between the FH and healthy children at P < 0.05. Compared to healthy children, the dysregulated pathways in FH children included the following: T cells (18/19); B cells (5/6); tumour necrosis factor super family (TNFSF) (6/8); cell growth, proliferation and differentiation (5/7); interleukins (5/9); toll‐like receptors (2/5); apoptosis (3/7) and antigen presentation (1/7), where the ratio denotes higher expressed genes to total number of genes. Statin therapy reversed expression of thirteen of these mRNAs in FH children. Conclusion FH children display higher PBMC expression of immune‐related genes mapped to several pathways, including T and B cells, and TNFSF than healthy children. Our results suggest that LDL‐C plays an important role in modulating expression of different immune‐related genes, and novel data on the involvement of these pathways in the early atherosclerosis may represent future therapeutic targets for prevention of atherosclerotic progression. ª 2019 The Authors. Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication 1 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited