Metabolomic Signature of Angiopoietin-Like Protein 3 Deficiency in Fasting and Postprandial State

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dc.contributor.author Tikkanen, Emmi
dc.contributor.author Minicocci, Ilenia
dc.contributor.author Hällfors, Jenni
dc.contributor.author Di Costanzo, Alessia
dc.contributor.author D'Erasmo, Laura
dc.contributor.author Poggiogalle, Eleonora
dc.contributor.author Donini, Lorenzo Maria
dc.contributor.author Wurtz, Peter
dc.contributor.author Jauhiainen, Matti
dc.contributor.author Olkkonen, Vesa M.
dc.contributor.author Arca, Marcello
dc.date.accessioned 2019-10-24T11:01:01Z
dc.date.available 2019-10-24T11:01:01Z
dc.date.issued 2019-04
dc.identifier.citation Tikkanen , E , Minicocci , I , Hällfors , J , Di Costanzo , A , D'Erasmo , L , Poggiogalle , E , Donini , L M , Wurtz , P , Jauhiainen , M , Olkkonen , V M & Arca , M 2019 , ' Metabolomic Signature of Angiopoietin-Like Protein 3 Deficiency in Fasting and Postprandial State ' , Arteriosclerosis, Thrombosis, and Vascular Biology , vol. 39 , no. 4 , pp. 665-674 . https://doi.org/10.1161/ATVBAHA.118.312021
dc.identifier.other PURE: 127621855
dc.identifier.other PURE UUID: 436f59fe-86b8-497b-a50d-eccef7039891
dc.identifier.other WOS: 000478872000019
dc.identifier.uri http://hdl.handle.net/10138/306354
dc.description.abstract Objective- Loss-of-function (LOF) variants in the ANGPTL3 (angiopoietin-like protein 3) have been associated with low levels of plasma lipoproteins and decreased coronary artery disease risk. We aimed to determine detailed metabolic effects of genetically induced ANGPTL3 deficiency in fasting and postprandial state. Approach and Results- We studied individuals carrying S17X LOF mutation in ANGPTL3 (6 homozygous and 32 heterozygous carriers) and 38 noncarriers. Nuclear magnetic resonance metabolomics was used to quantify 225 circulating metabolic measures. We compared metabolic differences between LOF carriers and noncarriers in fasting state and after a high-fat meal. In fasting, ANGPTL3 deficiency was characterized by similar extent of reductions in LDL (low-density lipoprotein) cholesterol (0.74 SD units lower concentration per LOF allele [95% CI, 0.42-1.06]) as observed for many TRL (triglyceride-rich lipoprotein) measures, including VLDL (very-low-density lipoprotein) cholesterol (0.75 [95% CI, 0.45-1.05]). Within most lipoprotein subclasses, absolute levels of cholesterol were decreased more than triglycerides, resulting in the relative proportion of cholesterol being reduced within TRLs and their remnants. Further, beta-hydroxybutyrate was elevated (0.55 [95% CI, 0.21-0.89]). Homozygous ANGPTL3 LOF carriers showed essentially no postprandial increase in TRLs and fatty acids, without evidence for adverse compensatory metabolic effects. Conclusions- In addition to overall triglyceride- and LDL cholesterol-lowering effects, ANGPTL3 deficiency results in reduction of cholesterol proportion within TRLs and their remnants. Further, ANGPTL3 LOF carriers had elevated ketone body production, suggesting enhanced hepatic fatty acid beta-oxidation. The detailed metabolic profile in human knockouts of ANGPTL3 reinforces inactivation of ANGPTL3 as a promising therapeutic target for decreasing cardiovascular risk. en
dc.format.extent 10
dc.language.iso eng
dc.relation.ispartof Arteriosclerosis, Thrombosis, and Vascular Biology
dc.rights.uri info:eu-repo/semantics/openAccess
dc.subject biomarkers
dc.subject fasting
dc.subject humans
dc.subject lipoproteins
dc.subject metabolomics
dc.subject FAMILIAL COMBINED HYPOLIPIDEMIA
dc.subject GENETIC INHIBITION
dc.subject ANGPTL3 GENE
dc.subject MUTATIONS
dc.subject RISK
dc.subject TRIGLYCERIDES
dc.subject EPIDEMIOLOGY
dc.subject LIPOPROTEINS
dc.subject LIPIDS
dc.subject 3121 General medicine, internal medicine and other clinical medicine
dc.title Metabolomic Signature of Angiopoietin-Like Protein 3 Deficiency in Fasting and Postprandial State en
dc.type Article
dc.contributor.organization Medicum
dc.contributor.organization University Management
dc.contributor.organization Department of Anatomy
dc.contributor.organization University of Helsinki
dc.description.reviewstatus Peer reviewed
dc.relation.doi https://doi.org/10.1161/ATVBAHA.118.312021
dc.relation.issn 1079-5642
dc.rights.accesslevel openAccess
dc.type.version publishedVersion

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