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

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

doi:10.1016/j.atherosclerosis.2017.09.021

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

Atherosclerosis. 2017 Nov:266:48-57. doi: 10.1016/j.atherosclerosis.2017.09.021. Epub 2017 Sep 21.

Authors

Affiliations

¹ Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, P.O box 1046 Blindern, 0317 Oslo, Oslo, Norway; The Lipid Clinic, Oslo University Hospital Rikshospitalet, P.O box 4950 Nydalen, 0424 Oslo, Oslo, Norway.
² Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, P.O box 1046 Blindern, 0317 Oslo, Oslo, Norway.
³ Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, P.O box 1046 Blindern, 0317 Oslo, Oslo, Norway; Norwegian National Advisory Unit on Familial Hypercholesterolemia, Oslo University, Hospital Rikshospitalet, P.O box 4950 Nydalen, 0424 Oslo, Oslo, Norway.
⁴ The Lipid Clinic, Oslo University Hospital Rikshospitalet, P.O box 4950 Nydalen, 0424 Oslo, Oslo, Norway; Norwegian National Advisory Unit on Familial Hypercholesterolemia, Oslo University, Hospital Rikshospitalet, P.O box 4950 Nydalen, 0424 Oslo, Oslo, Norway.
⁵ Department of Obstetrics, Oslo University Hospital Rikshospitalet, P.O box 4950 Nydalen, 0424 Oslo, Oslo, Norway; Faculty of Medicine, University of Oslo, P.O box 1046 Blindern, 0317 Oslo, Oslo, Norway.
⁶ Faculty of Medicine, University of Oslo, P.O box 1046 Blindern, 0317 Oslo, Oslo, Norway; Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital Rikshospitalet, P.O box 4950 Nydalen, 0424 Oslo, Oslo, Norway.
⁷ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, P.O box 4950 Nydalen, 0424 Oslo, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, P.O box 1171 Blindern 0318 Oslo, Oslo, Norway; K.G. Jebsen Inflammatory Research Center, P.O box 1171 Blindern 0318 Oslo, Oslo, Norway.
⁸ Research Institute of Internal Medicine, Oslo University Hospital Rikshospitalet, P.O box 4950 Nydalen, 0424 Oslo, Oslo, Norway; Institute of Clinical Medicine, University of Oslo, P.O box 1171 Blindern 0318 Oslo, Oslo, Norway; K.G. Jebsen Inflammatory Research Center, P.O box 1171 Blindern 0318 Oslo, Oslo, Norway; Section of Clinical Immunology and Infectious Diseases, Oslo University Hospital Rikshospitalet, P.O box 4950 Nydalen, 0424 Oslo, Oslo, Norway.
⁹ Department of Nutrition, Institute of Basic Medical Sciences, University of Oslo, P.O box 1046 Blindern, 0317 Oslo, Oslo, Norway; Norwegian National Advisory Unit on Familial Hypercholesterolemia, Oslo University, Hospital Rikshospitalet, P.O box 4950 Nydalen, 0424 Oslo, Oslo, Norway. Electronic address: k.b.holven@medisin.uio.no.

PMID: 28963918
DOI: 10.1016/j.atherosclerosis.2017.09.021

Abstract

Background and aims: Individuals with familial hypercholesterolemia (FH) have elevated low-density lipoprotein cholesterol (LDL-C), accelerated atherosclerosis, and premature cardiovascular disease. Whereas children with lifestyle-induced dyslipidemias often present with complex lipid abnormalities, children with FH have isolated hypercholesterolemia. However, to the best of our knowledge, a comprehensive profiling of FH children is lacking. Therefore, we aimed to characterize the lipid-related and metabolic alterations associated with elevated LDL-C in children with FH and healthy children.

Methods: We measured plasma metabolites in children with FH (n = 47) and in healthy children (n = 57) using a high-throughput nuclear magnetic resonance (NMR) spectroscopy platform, and compared the differences between FH and healthy children.

Results: Both statin treated (n = 17) and non-statin treated FH children (n = 30) had higher levels of atherogenic ApoB-containing lipoproteins and lipids, and lipid fractions in lipoprotein subclasses, compared to healthy children (n = 57). FH children displayed alterations in HDL particle concentration and lipid content, compared with healthy children. Interestingly, the small HDL particles were characterized by higher content of cholesteryl esters, and lower levels of free cholesterol and phospholipids. Furthermore, plasma fatty acids were higher in non-statin treated FH children, particularly linoleic acid. Finally, acetoacetate and acetate were lower in FH children compared with healthy children.

Conclusions: Hypercholesterolemia in children associates with diverse metabolic repercussions and is more complex than previously believed. In particular, we found that hypercholesterolemia in FH children was paralleled not only by increased atherogenic ApoB-containing lipoproteins and lipid fractions, but also alterations in HDL subfractions that suggest impaired reverse cholesterol transport.

Keywords: Children; Familial hypercholesterolemia; LDL cholesterol; Lipids; Metabolic profiling; Metabolomics.

MeSH terms

Adolescent
Age Factors
Biomarkers / blood
Case-Control Studies
Child
Cross-Sectional Studies
Female
High-Throughput Screening Assays
Humans
Hydroxymethylglutaryl-CoA Reductase Inhibitors / therapeutic use
Hyperlipoproteinemia Type II / blood*
Hyperlipoproteinemia Type II / diagnosis
Hyperlipoproteinemia Type II / drug therapy
Hyperlipoproteinemia Type II / genetics
Lipids / blood*
Magnetic Resonance Spectroscopy
Male
Metabolomics / methods*
Predictive Value of Tests

Substances

Biomarkers
Hydroxymethylglutaryl-CoA Reductase Inhibitors
Lipids