ArticleProceedings of the National Academy of Sciences of the United States of America2023
Inverse effects of APOC2 and ANGPTL4 on the conformational dynamics of lid-anchoring structures in lipoprotein lipase.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 18 citations in OpenAlex.
- Acute Effects of Interrupting Prolonged Sitting on Glucose, Insulin and Lipid Metabolism in Healthy Populations: A Three-Level Meta-Analysis.Metabolites · 2026Review
- GPIHBP1 on oligodendrocytes binds lipoprotein lipase within the human brain.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Effects of fenofibrate on angiopoietin-like 3/4/8 proteins and apolipoprotein A5.Journal of lipid research · 2026Article
- Cholesterol metabolism dysregulated by key HBV mutations revealed through multi-omics profiling.iScience · 2026Article
- Reduced activity of two LPL C-terminal variants, p.Glu396Val and novel p.Trp417Cys: a clinical, biochemical and structural study.Frontiers in physiology · 2026Article
- Lipoprotein lipase requires a flexible lid and stable C-terminal, both maintained by ApoC-II peptide binding.bioRxiv : the preprint server for biology · 2025Article
- APOC2 Promotes Clear Cell Renal Cell Carcinoma Progression via Activation of the JAK-STAT Signaling Pathway.Current issues in molecular biology · 2025Article
- ANGPTL3/8 is an atypical unfoldase that regulates intravascular lipolysis by catalyzing unfolding of lipoprotein lipase.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Competitive displacement of lipoprotein lipase from heparan sulfate is orchestrated by a disordered acidic cluster in GPIHBP1.Journal of lipid research · 2025Article
- Review
- Distinct strategies for intravascular triglyceride metabolism in hearts of mammals and lower vertebrate species.JCI insight · 2024Article
- APOA5 deficiency causes hypertriglyceridemia by reducing amounts of lipoprotein lipase in capillaries.Journal of lipid research · 2024Review
- Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Closing the gaps in patient management of dyslipidemia: stepping into cardiovascular precision diagnostics with apolipoprotein profiling.Clinical proteomics · 2024Review
- Macromolecular Interactions of Lipoprotein Lipase (LPL).Sub-cellular biochemistry · 2024Review
- Pancreatitis as a Main Consequence ofInternational journal of genomics · 2024Article
- The lipoprotein lipase that is shuttled into capillaries by GPIHBP1 enters the glycocalyx where it mediates lipoprotein processing.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Short hydrocarbon stapled ApoC2-mimetic peptides activate lipoprotein lipase and lower plasma triglycerides in mice.Frontiers in cardiovascular medicine · 2023Article
Corrections and comments
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
The lipolytic processing of triglyceride-rich lipoproteins (TRLs) by lipoprotein lipase (LPL) is crucial for the delivery of dietary lipids to the heart, skeletal muscle, and adipose tissue. The processing of TRLs by LPL is regulated in a tissue-specific manner by a complex interplay between activators and inhibitors. Angiopoietin-like protein 4 (ANGPTL4) inhibits LPL by reducing its thermal stability and catalyzing the irreversible unfolding of LPL's α/β-hydrolase domain. We previously mapped the ANGPTL4 binding site on LPL and defined the downstream unfolding events resulting in LPL inactivation. The binding of LPL to glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 protects against LPL unfolding. The binding site on LPL for an activating cofactor, apolipoprotein C2 (APOC2), and the mechanisms by which APOC2 activates LPL have been unclear and controversial. Using hydrogen-deuterium exchange/mass spectrometry, we now show that APOC2's C-terminal α-helix binds to regions of LPL surrounding the catalytic pocket. Remarkably, APOC2's binding site on LPL overlaps with that for ANGPTL4, but their effects on LPL conformation are distinct. In contrast to ANGPTL4, APOC2 increases the thermal stability of LPL and protects it from unfolding. Also, the regions of LPL that anchor the lid are stabilized by APOC2 but destabilized by ANGPTL4, providing a plausible explanation for why APOC2 is an activator of LPL, while ANGPTL4 is an inhibitor. Our studies provide fresh insights into the molecular mechanisms by which APOC2 binds and stabilizes LPL-and properties that we suspect are relevant to the conformational gating of LPL's active site.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.