ANGPTL3/8 is an atypical unfoldase that regulates intravascular lipolysis by catalyzing unfolding of lipoprotein lipase

• 成果类型: Article
• 署名作者: Kumari, Anni; Larsen, Sanne W. R.; Bondesen, Signe; Qian, Yuewei; Tian, Hao D.; Walker, Sydney G.; Davies, Brandon S. J.; Remaley, Alan T.; Young, Stephen G.; Konrad, Robert J.; Jorgensen, Thomas J. D.; Ploug, Michael
• 署名单位: University of Copenhagen; Copenhagen University Hospital; Rigshospitalet; University of Copenhagen; University of Southern Denmark; Eli Lilly; Lilly Research Laboratories; National Institutes of Health (NIH) - USA; NIH National Heart Lung & Blood Institute (NHLBI); University of Iowa; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-9222
• DOI: 10.1073/pnas.2420721122
• 发表日期: 2025-03-25
• 关键词: angiopoietin-like protein; plasma; gpihbp1; BIND

摘要

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 alpha- helices to interact with sequences surrounding the catalytic pocket in LPL. That binding event triggers unfolding of LPL's alpha/beta- 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 catalyze 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.