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Genetic mimicry analysis reveals the specific lipases targeted by the ANGPTL3-ANGPTL8 complex and ANGPTL4
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.ORCID iD: 0000-0002-5695-2276
Umeå University, Faculty of Medicine, Department of Public Health and Clinical Medicine, Section of Medicine.ORCID iD: 0000-0002-8057-1684
Nutrition, Metabolism and Genomics group, Division of Human Nutrition and Health, Wageningen University, Wageningen, Netherlands.
2023 (English)In: Journal of Lipid Research, ISSN 0022-2275, E-ISSN 1539-7262, Vol. 64, no 1, article id 100313Article in journal (Refereed) Published
Abstract [en]

Angiopoietin-like proteins, ANGPTL3, ANGPTL4, and ANGPTL8, are involved in regulating plasma lipids. In vitro and animal-based studies point to LPL and endothelial lipase (EL, LIPG) as key targets of ANGPTLs. To examine the ANGPTL mechanisms for plasma lipid modulation in humans, we pursued a genetic mimicry analysis of enhancing or suppressing variants in the LPL, LIPG, lipase C hepatic type (LIPC), ANGPTL3, ANGPTL4, and ANGPTL8 genes using data on 248 metabolic parameters derived from over 110,000 nonfasted individuals in the UK Biobank and validated in over 13,000 overnight fasted individuals from 11 other European populations. ANGPTL4 suppression was highly concordant with LPL enhancement but not HL or EL, suggesting ANGPTL4 impacts plasma metabolic parameters exclusively via LPL. The LPL-independent effects of ANGPTL3 suppression on plasma metabolic parameters showed a striking inverse resemblance with EL suppression, suggesting ANGPTL3 not only targets LPL but also targets EL. Investigation of the impact of the ANGPTL3-ANGPTL8 complex on plasma metabolite traits via the ANGPTL8 R59W substitution as an instrumental variable showed a much higher concordance between R59W and EL activity than between R59W and LPL activity, suggesting the R59W substitution more strongly affects EL inhibition than LPL inhibition. Meanwhile, when using a rare and deleterious protein-truncating ANGPTL8 variant as an instrumental variable, the ANGPTL3-ANGPTL8 complex was very LPL specific. In conclusion, our analysis provides strong human genetic evidence that the ANGPTL3-ANGPTL8 complex regulates plasma metabolic parameters, which is achieved by impacting LPL and EL. By contrast, ANGPTL4 influences plasma metabolic parameters exclusively via LPL.

Place, publisher, year, edition, pages
Elsevier, 2023. Vol. 64, no 1, article id 100313
Keywords [en]
angiopoietin-like proteins, cardiovascular disease, dyslipidemias, lipase/endothelial, lipase/hepatic, lipidomics, lipids, lipolysis and fatty acid metabolism, lipoprotein/metabolism, triglycerides
National Category
Medicinal Chemistry
Identifiers
URN: urn:nbn:se:umu:diva-204492DOI: 10.1016/j.jlr.2022.100313ISI: 000993186300001PubMedID: 36372100Scopus ID: 2-s2.0-85147047013OAI: oai:DiVA.org:umu-204492DiVA, id: diva2:1735370
Funder
Region Västerbotten, RV-970117Available from: 2023-02-08 Created: 2023-02-08 Last updated: 2023-09-05Bibliographically approved

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Landfors, FredrikChorell, Elin

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