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Analysis of circulating angiopoietin-like protein 3 and genetic variants in lipid metabolism and liver health: the DiOGenes study

BACKGROUND: Angiopoietin-like protein 3 (ANGPTL3), a liver-derived protein, plays an important role in the lipid and lipoprotein metabolism. Using data available from the DiOGenes study, we assessed the link with clinical improvements (weight, plasma lipid, and insulin levels) and changes in liver m...

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Autores principales: Hess, Anne Lundby, Carayol, Jérôme, Blædel, Trine, Hager, Jörg, Di Cara, Alessandro, Astrup, Arne, Saris, Wim H. M., Larsen, Lesli Hingstrup, Valsesia, Armand
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2018
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Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879874/
https://www.ncbi.nlm.nih.gov/pubmed/29619113
http://dx.doi.org/10.1186/s12263-018-0597-3
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author Hess, Anne Lundby
Carayol, Jérôme
Blædel, Trine
Hager, Jörg
Di Cara, Alessandro
Astrup, Arne
Saris, Wim H. M.
Larsen, Lesli Hingstrup
Valsesia, Armand
author_facet Hess, Anne Lundby
Carayol, Jérôme
Blædel, Trine
Hager, Jörg
Di Cara, Alessandro
Astrup, Arne
Saris, Wim H. M.
Larsen, Lesli Hingstrup
Valsesia, Armand
author_sort Hess, Anne Lundby
collection PubMed
description BACKGROUND: Angiopoietin-like protein 3 (ANGPTL3), a liver-derived protein, plays an important role in the lipid and lipoprotein metabolism. Using data available from the DiOGenes study, we assessed the link with clinical improvements (weight, plasma lipid, and insulin levels) and changes in liver markers, alanine aminotransferase, aspartate aminotransferase (AST), adiponectin, fetuin A and B, and cytokeratin 18 (CK-18), upon low-calorie diet (LCD) intervention. We also examined the role of genetic variation in determining the level of circulating ANGPTL3 and the relation between the identified genetic markers and markers of hepatic steatosis. METHODS: DiOGenes is a multicenter, controlled dietary intervention where obese participants followed an 8-week LCD (800 kcal/day, using a meal replacement product). Plasma ANGPTL3 and liver markers were measured using the SomaLogic (Boulder, CO) platform. Protein quantitative trait locus (pQTL) analyses assessed the link between more than four million common variants and the level of circulating ANGPTL3 at baseline and changes in levels during the LCD intervention. RESULTS: Changes in ANGPTL3 during weight loss showed only marginal association with changes in triglycerides (nominal p = 0.02) and insulin (p = 0.04); these results did not remain significant after correcting for multiple testing. However, significant association (after multiple-testing correction) were observed between changes in ANGPTL3 and AST during weight loss (p = 0.004) and between ANGPTL3 and CK-18 (baseline p = 1.03 × 10(−7), during weight loss p = 1.47 × 10(−13)). Our pQTL study identified two loci significantly associated with changes in ANGPTL3. One of these loci (the APOA4-APOA5-ZNF259-BUD13 gene cluster) also displayed significant association with changes in CK-18 levels during weight loss (p = 0.007). CONCLUSION: We clarify the link between circulating levels of ANGPTL3 and specific markers of liver function. We demonstrate that changes in ANGPLT3 and CK-18 during LCD are under genetic control from trans-acting variants. Our results suggest an extended function of ANGPTL3 in the inflammatory state of liver steatosis and toward liver metabolic processes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12263-018-0597-3) contains supplementary material, which is available to authorized users.
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spelling pubmed-58798742018-04-04 Analysis of circulating angiopoietin-like protein 3 and genetic variants in lipid metabolism and liver health: the DiOGenes study Hess, Anne Lundby Carayol, Jérôme Blædel, Trine Hager, Jörg Di Cara, Alessandro Astrup, Arne Saris, Wim H. M. Larsen, Lesli Hingstrup Valsesia, Armand Genes Nutr Research BACKGROUND: Angiopoietin-like protein 3 (ANGPTL3), a liver-derived protein, plays an important role in the lipid and lipoprotein metabolism. Using data available from the DiOGenes study, we assessed the link with clinical improvements (weight, plasma lipid, and insulin levels) and changes in liver markers, alanine aminotransferase, aspartate aminotransferase (AST), adiponectin, fetuin A and B, and cytokeratin 18 (CK-18), upon low-calorie diet (LCD) intervention. We also examined the role of genetic variation in determining the level of circulating ANGPTL3 and the relation between the identified genetic markers and markers of hepatic steatosis. METHODS: DiOGenes is a multicenter, controlled dietary intervention where obese participants followed an 8-week LCD (800 kcal/day, using a meal replacement product). Plasma ANGPTL3 and liver markers were measured using the SomaLogic (Boulder, CO) platform. Protein quantitative trait locus (pQTL) analyses assessed the link between more than four million common variants and the level of circulating ANGPTL3 at baseline and changes in levels during the LCD intervention. RESULTS: Changes in ANGPTL3 during weight loss showed only marginal association with changes in triglycerides (nominal p = 0.02) and insulin (p = 0.04); these results did not remain significant after correcting for multiple testing. However, significant association (after multiple-testing correction) were observed between changes in ANGPTL3 and AST during weight loss (p = 0.004) and between ANGPTL3 and CK-18 (baseline p = 1.03 × 10(−7), during weight loss p = 1.47 × 10(−13)). Our pQTL study identified two loci significantly associated with changes in ANGPTL3. One of these loci (the APOA4-APOA5-ZNF259-BUD13 gene cluster) also displayed significant association with changes in CK-18 levels during weight loss (p = 0.007). CONCLUSION: We clarify the link between circulating levels of ANGPTL3 and specific markers of liver function. We demonstrate that changes in ANGPLT3 and CK-18 during LCD are under genetic control from trans-acting variants. Our results suggest an extended function of ANGPTL3 in the inflammatory state of liver steatosis and toward liver metabolic processes. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1186/s12263-018-0597-3) contains supplementary material, which is available to authorized users. BioMed Central 2018-04-02 /pmc/articles/PMC5879874/ /pubmed/29619113 http://dx.doi.org/10.1186/s12263-018-0597-3 Text en © The Author(s) 2018 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Hess, Anne Lundby
Carayol, Jérôme
Blædel, Trine
Hager, Jörg
Di Cara, Alessandro
Astrup, Arne
Saris, Wim H. M.
Larsen, Lesli Hingstrup
Valsesia, Armand
Analysis of circulating angiopoietin-like protein 3 and genetic variants in lipid metabolism and liver health: the DiOGenes study
title Analysis of circulating angiopoietin-like protein 3 and genetic variants in lipid metabolism and liver health: the DiOGenes study
title_full Analysis of circulating angiopoietin-like protein 3 and genetic variants in lipid metabolism and liver health: the DiOGenes study
title_fullStr Analysis of circulating angiopoietin-like protein 3 and genetic variants in lipid metabolism and liver health: the DiOGenes study
title_full_unstemmed Analysis of circulating angiopoietin-like protein 3 and genetic variants in lipid metabolism and liver health: the DiOGenes study
title_short Analysis of circulating angiopoietin-like protein 3 and genetic variants in lipid metabolism and liver health: the DiOGenes study
title_sort analysis of circulating angiopoietin-like protein 3 and genetic variants in lipid metabolism and liver health: the diogenes study
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5879874/
https://www.ncbi.nlm.nih.gov/pubmed/29619113
http://dx.doi.org/10.1186/s12263-018-0597-3
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