ArticleProceedings of the National Academy of Sciences of the United States of America2020
Unfolding of monomeric lipoprotein lipase by ANGPTL4: Insight into the regulation of plasma triglyceride metabolism.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 49 papers.
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Who cites it
49 citing papers in PubMed, 74 citations in OpenAlex.
- GPIHBP1 on oligodendrocytes binds lipoprotein lipase within the human brain.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Maternal exposure to urban particulate matter induces cardiac developmental toxicity in zebrafish offspring by disrupting mitochondrial homeostasis.Journal of advanced research · 2026Article
- Global knockout of VEGFB improves lipoprotein lipase activity leading to an improved lipid profile during diabetes.Frontiers in pharmacology · 2026Article
- Identifying senescent cells as prognostic biomarkers and therapeutic targets of nasopharyngeal carcinoma by integrated analysis of single-cell and bulk-RNA sequencing data.Translational cancer research · 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
- Comprehensive profiling of chemokine and NETosis-associated genes in sarcopenia: construction of a machine learning-based diagnostic nomogram.Frontiers in medicine · 2025Article
- ANGPTL4-the Link Binding Lipid Metabolism and Inflammation.Current medicinal chemistry · 2025Review
- Distinct strategies for intravascular triglyceride metabolism in hearts of mammals and lower vertebrate species.JCI insight · 2024Article
- A unified model for regulating lipoprotein lipase activity.Trends in endocrinology and metabolism: TEM · 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
- Endothelial lipase variant T111I does not alter inhibition by angiopoietin-like proteins.Scientific reports · 2024Article
- Macromolecular Interactions of Lipoprotein Lipase (LPL).Sub-cellular biochemistry · 2024Review
- Hypertriglyceridemia in Apoa5-/- mice results from reduced amounts of lipoprotein lipase in the capillary lumen.The Journal of clinical investigation · 2023Article
- Phylogenetic and expression analysis of the angiopoietin-like gene family and their role in lipid metabolism in pigs.Animal bioscience · 2023Article
- Inverse effects of APOC2 and ANGPTL4 on the conformational dynamics of lid-anchoring structures in lipoprotein lipase.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Angiopoietin-like 3: An important protein in regulating lipoprotein levels.Best practice & research. Clinical endocrinology & metabolism · 2023Review
- The Link between Magnesium Supplements and Statin Medication in Dyslipidemic Patients.Current issues in molecular biology · 2023Review
- Intracapillary LPL levels in brown adipose tissue, visualized with an antibody-based approach, are regulated by ANGPTL4 at thermoneutral temperatures.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Angiopoietin-like protein 4/8 complex-mediated plasmin generation leads to cleavage of the complex and restoration of LPL activity.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
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Authors and funding
9 authors at 7 institutions in 4 countries.
Funding
Abstract
The binding of lipoprotein lipase (LPL) to GPIHBP1 focuses the intravascular hydrolysis of triglyceride-rich lipoproteins on the surface of capillary endothelial cells. This process provides essential lipid nutrients for vital tissues (e.g., heart, skeletal muscle, and adipose tissue). Deficiencies in either LPL or GPIHBP1 impair triglyceride hydrolysis, resulting in severe hypertriglyceridemia. The activity of LPL in tissues is regulated by angiopoietin-like proteins 3, 4, and 8 (ANGPTL). Dogma has held that these ANGPTLs inactivate LPL by converting LPL homodimers into monomers, rendering them highly susceptible to spontaneous unfolding and loss of enzymatic activity. Here, we show that binding of an LPL-specific monoclonal antibody (5D2) to the tryptophan-rich lipid-binding loop in the carboxyl terminus of LPL prevents homodimer formation and forces LPL into a monomeric state. Of note, 5D2-bound LPL monomers are as stable as LPL homodimers (i.e., they are not more prone to unfolding), but they remain highly susceptible to ANGPTL4-catalyzed unfolding and inactivation. Binding of GPIHBP1 to LPL alone or to 5D2-bound LPL counteracts ANGPTL4-mediated unfolding of LPL. In conclusion, ANGPTL4-mediated inactivation of LPL, accomplished by catalyzing the unfolding of LPL, does not require the conversion of LPL homodimers into monomers. Thus, our findings necessitate changes to long-standing dogma on mechanisms for LPL inactivation by ANGPTL proteins. At the same time, our findings align well with insights into LPL function from the recent crystal structure of the LPL•GPIHBP1 complex.
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Registered trials
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.