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Exploration of Blood Lipoprotein and Lipid Fraction Profiles in Healthy Subjects Through Integrated Univariate, Multivariate, An H OH metabolites OH Article Exploration of Blood Lipoprotein and Lipid Fraction Profiles in Healthy Subjects through Integrated Univariate, Multivariate, and Network Analysis Reveals Association of Lipase Activity and Cholesterol Esterification with Sex and Age Yasmijn Balder 1 , Alessia Vignoli 2,3 , Leonardo Tenori 2,3 , Claudio Luchinat 2,3 and Edoardo Saccenti 1,* 1 Laboratory of Systems and Synthetic Biology, Wageningen University & Research, Stippeneng 4, 6708 WE Wageningen, The Netherlands; [email protected] 2 Magnetic Resonance Center (CERM) and Department of Chemistry “Ugo Schiff”, University of Florence, Via Luigi Sacconi 6, 50019 Sesto Fiorentino, Italy; [email protected]fi.it (A.V.); [email protected]fi.it (L.T.); [email protected]fi.it (C.L.) 3 Consorzio Interuniversitario Risonanze Magnetiche MetalloProteine (CIRMMP), Via Luigi Sacconi 6, 50019 Sesto Fiorentino, Italy * Correspondence: [email protected] Abstract: In this study, we investigated blood lipoprotein and lipid fraction profiles, quantified using nuclear magnetic resonance, in a cohort of 844 healthy blood donors, integrating standard univariate and multivariate analysis with predictive modeling and network analysis. We observed a strong association of lipoprotein and lipid main fraction profiles with sex and age. Our results suggest an Citation: Balder, Y.; Vignoli, A.; age-dependent remodulation of lipase lipoprotein activity in men and a change in the mechanisms Tenori, L.; Luchinat, C.; Saccenti, E. Exploration of Blood Lipoprotein and controlling the ratio between esterified and non-esterified cholesterol in both men and women. Lipid Fraction Profiles in Healthy Subjects through Integrated Keywords: analysis of biological networks; lipid metabolism; lipidomics; metabolomics; nuclear Univariate, Multivariate, and magnetic resonance Network Analysis Reveals Association of Lipase Activity and Cholesterol Esterification with Sex and Age. Metabolites 2021, 11, 326. 1. Introduction https://doi.org/10.3390/metabo11050326 Lipids are the most abundant biological molecules in human plasma [1]. This group of small molecular weight molecules shows large structural and functional variations: Academic Editor: Peter Meikle they are fundamental building blocks of the cell wall and are key components of the cell membrane and other cellular compartments, including the nuclear membrane, the Received: 29 April 2021 endoplasmic reticulum, and the Golgi apparatus, as well as trafficking vesicles such as Accepted: 14 May 2021 Published: 18 May 2021 endosomes and lysosomes [2]. Mammalian cells express tens of thousands of different lipid species and use hundreds Publisher’s Note: MDPI stays neutral of proteins to synthesize, metabolize, and transport them: the diversity of lipids is of the with regard to jurisdictional claims in same order of magnitude as that of proteins, but until recent years they were not studied published maps and institutional affil- as much as proteins [2]. iations. Lipids are transported in the blood by proteins; lipoproteins exist in different densi- ties: chylomicrons, very low-density lipoprotein (VLDL), low-density lipoprotein (LDL), intermediate-density lipoprotein (IDL), and high-density lipoprotein (HDL). These lipopro- teins determine where the lipid is transported to, which contributes to the wide functional variability of the lipidome. Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. It is widely recognized that variations in lipoprotein profiles and metabolism are This article is an open access article associated with metabolic diseases such as diabetes mellitus and cardiovascular diseases, distributed under the terms and and can thus be used to monitor and assess the risk of such diseases. For instance, elevated conditions of the Creative Commons levels of LDL cholesterol [1] and triglycerides [3,4] increase the risk of cardiovascular dis- Attribution (CC BY) license (https:// eases, while high levels of HDL cholesterol are correlated with a low risk of cardiovascular creativecommons.org/licenses/by/ diseases [1,3,5]. Moreover, alterations of lipoprotein profiles have been associated with 4.0/). different types of cancer [6–8] and autoimmune diseases [9–11]. Metabolites 2021, 11, 326. https://doi.org/10.3390/metabo11050326 https://www.mdpi.com/journal/metabolites Metabolites 2021, 11, x FOR PEER REVIEW 2 of 28 levels of LDL cholesterol [1] and triglycerides [3,4] increase the risk of cardiovascular diseases, while high levels of HDL cholesterol are correlated with a low risk of cardiovascular diseases [1,3,5]. Moreover, alterations of lipoprotein profiles have been associated with different types of cancer [6–8] and autoimmune diseases [9–11]. Variations in the blood lipid profiles are associated not only with particular Metabolites 2021, 11, 326 pathophysiological statuses but also with sex and age: women tend to have higher2 of 28 levels of triglyceride VLDL than men [12], whereas men have higher total triglycerides and cholesterol levels [13], and the overall concentration of VLDL in men increases with age, while itVariations decreases in in the women blood lipid[5]. profiles are associated not only with particular patho- physiologicalMany more statuses sex- and but age also- lipoprotein with sex and associations age: women are tend being to have discovered higher levels [5,14 of–16]: in thetriglyceride era of precision VLDL medicine, than men [understanding12], whereas men how have sex higher and totalage shape triglycerides the lipidome and choles- can lead to bteroletter levels diagnosis [13], and and the treatment overall concentration of conditions of VLDL that inoccur men more increases frequently with age, in while one it of the twodecreases sexes, present in women sex [-5specific]. symptoms and outcomes, or are characteristic of a specific age groupMany [17] more. sex- and age- lipoprotein associations are being discovered [5,14–16]: in theIn era this of precisionstudy, we medicine, investigate understanding sex- and age how-specific sex and differences age shape the in lipidome the plasma can leadlipidome of 844to better young diagnosis and middle and treatment-aged healthy of conditions blood donors that occur of both more sexes frequently who were in one analyzed of the for two sexes, present sex-specific symptoms and outcomes, or are characteristic of a specific their lipoprotein blood profiles via nuclear magnetic resonance (NMR) spectroscopy age group [17]. [18,19].In this study, we investigate sex- and age-specific differences in the plasma lipidome ofWe 844 youngintegrated and middle-aged standard univariate healthy blood analysis, donors multivariat of both sexese whoexploratory were analyzed analysis, for and predictivetheir lipoprotein modeling blood with profiles systems via nuclear biology magnetic tools resonance to explore (NMR) the spectroscopy relationships [18,19 among]. lipoproteinWe integrated fractions standard using association univariate analysis, networks multivariate and differential exploratory network analysis, analysis and pre-. Since lipoproteindictive modeling concentrations with systems change biology in an tools orchestrated to explore the fashion, relationships the patterns among lipoprotein of associations betweenfractions lipoprotein using association fraction networkss can be andconsidered, differential to networksome extent, analysis. related Since to lipoprotein the underlying structureconcentrations of the biological change in networks an orchestrated [20]. Differences fashion, the in patterns lipoprotein of associations associations between which are lipoprotein fractions can be considered, to some extent, related to the underlying struc- sex- and age-related can indeed point to affected molecular mechanisms since changes ture of the biological networks [20]. Differences in lipoprotein associations which are sex- canand be age-relatedmore significant can indeed than point levels to affectedalone [21,22] molecular, as shown mechanisms in applications since changes to canhealth be , sex, andmore age significantphenotyping than [17,23] levels alone, cardiovascular [21,22], as shown risk [24 in applications–26], and bacterial to health, infections sex, and age [27,28]. phenotypingHere, we report [17,23], the cardiovascular findings of risk this [24 integrated–26], and bacterial analysis infections describing [27 ,28how]. sex and age affect bothHere, the we concentration report the findings and the of correlation this integrated patterns analysis of lipoprotein describing profiles how sex in and healthy subjectage affects, and both we suggest the concentration that lipids and may the be correlation used as an patterns early biomarker of lipoprotein to monitor profiles healthy in aging.healthy subjects, and we suggest that lipids may be used as an early biomarker to monitor healthy aging. 2. Results2. Results AnAn overview overview of of the the lipid lipid fractionsfractions and and lipoprotein lipoprotein distribution distribution in the in overallthe overall study study groupgroup (m (menen and and women) women) is is shown inin Figure Figure1. 1. Age Age characteristics characteristics are givenare given in Table in 1Table. 1. FigureFigure 1. Relative 1. Relative concentration concentration (%) ofof lipoproteins lipoproteins and and lipids lipid (A) ands (A lipid) and main lipid fractions main (B fractions) in the study (B) cohort in the comprising study cohort comprising844 heathy 844 bloodheathy donors blood (661 donors men + 183(661 women). men + Very 183 low-density women).
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