Comprehensive lipid and metabolite profiling of children with and without familial hypercholesterolemia: A cross-sectional study

Christensen, Jacob J.; Ulven, Stine Marie; Retterstøl, Kjetil; Narverud, Ingunn; Bogsrud, Martin P.; Henriksen, Tore; Bollerslev, Jens; Halvorsen, Bente; Aukrust, Pål; Holven, Kirsten B.

doi:10.1016/j.atherosclerosis.2017.09.021

Cited by 32 publications

(35 citation statements)

References 46 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We observed an increase in fasting plasma concentrations of acetoacetate and acetate in the Ex-diet group, which are metabolites involved in ketogenesis and intermediary metabolism. We recently showed that children with familial hypercholesterolemia with higher plasma concentrations of total and LDL cholesterol had significantly lower plasma concentrations of acetoacetate and acetate (37). This may be due to reduced uptake of LDL in the liver (as in familial hypercholesterolemia), creating a temporary cellular cholesterol deficiency in the hepatocytes, potentially leading to the utilization of acetate and other carbon sources for cholesterol synthesis rather than production of acetoacetate.…”

Section: Discussionmentioning

confidence: 99%

Using metabolic profiling and gene expression analyses to explore molecular effects of replacing saturated fat with polyunsaturated fat—a randomized controlled dietary intervention study

Ulven

Christensen

Nygård

et al. 2019

The American Journal of Clinical Nutrition

View full text Add to dashboard Cite

Background 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. Objectives The aim of this study was to gain knowledge of metabolic alterations paralleling improvements in the fat quality of the diet. Methods 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. Results 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. Conclusions 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.

show abstract

Section: Discussionmentioning

confidence: 99%

Using metabolic profiling and gene expression analyses to explore molecular effects of replacing saturated fat with polyunsaturated fat—a randomized controlled dietary intervention study

Ulven

Christensen

Nygård

et al. 2019

The American Journal of Clinical Nutrition

View full text Add to dashboard Cite

show abstract

“…These particles contain more TAG than the smaller particles. Christensen et al (57) also found higher level of the largest HDL sub-class in children with FH compared with controls, particularly in nonstatin-treated subjects. This may be related to an enhanced cholesteryl ester transfer protein activity in subjects with FH (58) .…”

Section: Differences Between the Groupsmentioning

confidence: 86%

Delayed postprandial TAG peak after intake of SFA compared with PUFA in subjects with and without familial hypercholesterolaemia: a randomised controlled trial

et al. 2018

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…All children had a definite FH diagnosis, verified by genetic or clinical diagnosis, the latter based on the Simon Broome criteria (10). Eighteen children (38 %) were currently on statins, and 20 (43 %) had LDL receptor (LDLR) negative mutations ( Supplementary Material ) (9,11). Furthermore, we included 56 non-FH, healthy children that were part of the Stork children follow-up study at Department of Nutrition, University of Oslo (UoO) in Oslo, Norway (8,12).…”

Section: Methodsmentioning

confidence: 99%

“…Briefly, the biomarkers covered particle concentration and lipid content of 14 subclasses of lipoproteins, and plasma fatty acids, amino acids, glucose metabolites, ketone bodies and other biomarkers, including certain protein biomarkers. In contrast to our previous work which was based on the original 2016 algorithm (9), the data values for the present analysis were estimated using the 2020 algorithm (Nightingale Health, Finland). Note also that previous metabolomics analyses regarding LDL aggregation was based on LC-MS, not NMR (3).…”

Section: Methodsmentioning

confidence: 99%

Children with familial hypercholesterolemia display changes in LDL and HDL function: a cross-sectional study

Christensen

Narverud

Ruuth

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Comprehensive lipid and metabolite profiling of children with and without familial hypercholesterolemia: A cross-sectional study

Cited by 32 publications

References 46 publications

Using metabolic profiling and gene expression analyses to explore molecular effects of replacing saturated fat with polyunsaturated fat—a randomized controlled dietary intervention study

Using metabolic profiling and gene expression analyses to explore molecular effects of replacing saturated fat with polyunsaturated fat—a randomized controlled dietary intervention study

Delayed postprandial TAG peak after intake of SFA compared with PUFA in subjects with and without familial hypercholesterolaemia: a randomised controlled trial

Children with familial hypercholesterolemia display changes in LDL and HDL function: a cross-sectional study

Contact Info

Product

Resources

About