Journal article
Angiopoietin-like 3 monomers are abundant in human plasma but are unable to inhibit endothelial lipase
JCI insight, Vol.10(23), e197827
02/01/2026
DOI: 10.1172/jci.insight.197827
PMID: 41148215
Abstract
Angiopoietin-like 3 (ANGPTL3) is a major regulator of lipoprotein metabolism. ANGPTL3 deficiency results in lower levels of triglycerides, LDL-cholesterol (LDL-C), and HDL-cholesterol (HDL-C), and may protect from cardiovascular disease. ANGPTL3 oligomerizes with ANGPTL8 to inhibit lipoprotein lipase (LPL), the enzyme responsible for plasma triglyceride hydrolysis. Independently of ANGPTL8, oligomers of ANGPTL3 can inhibit endothelial lipase (EL), which regulates circulating HDL-C and LDL-C levels through the hydrolysis of lipoprotein phospholipids. The N-terminal region of ANGPTL3 is necessary for both oligomerization and lipase inhibition. However, our understanding of the specific residues that contribute to these functions is incomplete. In this study, we performed mutagenesis of the N-terminal region to identify residues important for EL inhibition and oligomerization. We also assessed the presence of different ANGPTL3 species in human plasma. We identified a motif important for lipase inhibition, and protein structure prediction suggested that this region interacted directly with EL. We also found that recombinant ANGPTL3 formed a homotrimer and was unable to inhibit EL activity when trimerization was disrupted. Surprisingly, we observed that human plasma contained more monomeric ANGPTL3 than trimeric ANGPTL3. An important implication of these findings is that previous correlations between circulating ANGPTL3 and circulating triglyceride-rich lipoproteins need to be revisited.
Details
- Title: Subtitle
- Angiopoietin-like 3 monomers are abundant in human plasma but are unable to inhibit endothelial lipase
- Creators
- Sydney G. Walker - University of IowaYan Q. Chen - Eli Lilly (United States)Kelli L. Sylvers-Davie - University of IowaAlex Dou - University of IowaEugene Y. Zhen - Eli Lilly (United States)Yuewei Qian - Eli Lilly (United States)Yi Wen - Eli Lilly (United States)Mariam Ehsani - Eli Lilly (United States)Sydney Smith - Eli Lilly (United States)Rakshya Thapa - University of IowaMaxwell J. Mercer - University of IowaLucy Langmack - University of IowaBharat Raj Bhattarai - University of IowaMichael Ploug - Copenhagen University HospitalRobert J. Konrad - Eli Lilly (United States)Brandon S.J. Davies - University of Iowa
- Resource Type
- Journal article
- Publication Details
- JCI insight, Vol.10(23), e197827
- DOI
- 10.1172/jci.insight.197827
- PMID
- 41148215
- eISSN
- 2379-3708
- Publisher
- American Society for Clinical investigation; ANN ARBOR
- Grant note
- National Heart, Lung, and Blood Institute, NIH grant: R01HL162698 American Heart Association grant: 24PRE1188556 American Heart Association (AHA): 24PRE1188556
This work is the result of NIH funding and is subject to the NIH Public Access Policy. Through acceptance of this federal funding, the NIH has been given a right to make the work publicly available in PubMed Central.center dot National Heart, Lung, and Blood Institute, NIH grant R01HL162698 (to BSJD) .center dot American Heart Association grant 24PRE1188556 (to SGW) .
- Language
- English
- Date published
- 02/01/2026
- Academic Unit
- Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology
- Record Identifier
- 9985218635102771
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