Journal article
ANGPTL3/8 is an atypical unfoldase that regulates intravascular lipolysis by catalyzing unfolding of lipoprotein lipase
Proceedings of the National Academy of Sciences - PNAS, Vol.122(12), e2420721122
03/25/2025
DOI: 10.1073/pnas.2420721122
PMCID: PMC11962473
PMID: 40112106
Abstract
Lipoprotein lipase (LPL) carries out the lipolytic processing of triglyceride-rich lipoproteins (TRL) along the luminal surface of capillaries. LPL activity is regulated by the angiopoietin-like proteins (ANGPTL3, ANGPTL4, ANGPTL8), which control the delivery of TRL-derived lipid nutrients to tissues in a temporal and spatial fashion. This regulation of LPL mediates the partitioning of lipid delivery to adipose tissue and striated muscle according to nutritional status. A complex between ANGPTL3 and ANGPTL8 (ANGPTL3/8) inhibits LPL activity in oxidative tissues, but its mode of action has remained unknown. Here, we used biophysical techniques to define how ANGPTL3/8 and ANGPTL3 interact with LPL and how they drive LPL inactivation. We demonstrate, by mass photometry, that ANGPTL3/8 is a heterotrimer with a 2:1 ANGPTL3:ANGPTL8 stoichiometry and that ANGPTL3 is a homotrimer. Hydrogen-deuterium exchange mass spectrometry (HDX-MS) studies revealed that ANGPTL3/8 and ANGPTL3 use the proximal portion of their N-terminal α-helices to interact with sequences surrounding the catalytic pocket in LPL. That binding event triggers unfolding of LPL's
-hydrolase domain and irreversible loss of LPL catalytic activity. The binding of LPL to its endothelial transporter protein (GPIHBP1) or to heparan-sulfate proteoglycans protects LPL from unfolding and inactivation, particularly against the unfolding triggered by ANGPTL3. Pulse-labeling HDX-MS studies revealed that ANGPTL3/8 and ANGPTL3
LPL unfolding in an ATP-independent fashion, which categorizes these LPL inhibitors as atypical unfoldases. The catalytic nature of LPL unfolding by ANGPTL3/8 explains why low plasma concentrations of ANGPTL3/8 are effective in inhibiting a molar excess of LPL in capillaries.
Details
- Title: Subtitle
- ANGPTL3/8 is an atypical unfoldase that regulates intravascular lipolysis by catalyzing unfolding of lipoprotein lipase
- Creators
- Anni Kumari - University of CopenhagenSanne W R Larsen - University of Southern DenmarkSigne Bondesen - University of CopenhagenYuewei Qian - Eli LillyHao D Tian - National Heart Lung and Blood InstituteSydney G Walker - University of IowaBrandon S J Davies - University of IowaAlan T Remaley - National Heart Lung and Blood InstituteStephen G Young - University of California, Los AngelesRobert J Konrad - Eli LillyThomas J D Jørgensen - University of Southern DenmarkMichael Ploug - University of Copenhagen
- Resource Type
- Journal article
- Publication Details
- Proceedings of the National Academy of Sciences - PNAS, Vol.122(12), e2420721122
- DOI
- 10.1073/pnas.2420721122
- PMID
- 40112106
- PMCID
- PMC11962473
- NLM abbreviation
- Proc Natl Acad Sci U S A
- ISSN
- 1091-6490
- eISSN
- 1091-6490
- Publisher
- NATL ACAD SCIENCES; WASHINGTON
- Grant note
- NNF20OC0063444 / Novo Nordisk Foundation Center for Basic Metabolic Research (NovoNordisk Foundation Center for Basic Metabolic Research) 23CVD02 19CVD04 / Fondation Leducq (Leducq Foundation) R01HL171737 R01HL162698 R35HL139725 P01HL146358 R01HL087228 / HHS | NIH | National Heart, Lung, and Blood Institute (NHLBI) 100 / The John and Birthe Meyer Foundation
- Language
- English
- Date published
- 03/25/2025
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology
- Record Identifier
- 9984801835402771
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