A Nutrient-Dependent ANGPTL3–PCSK9-Containing Complex in HepG2 Cells and Human Plasma
- 1Department of Translational and Precision Medicine, Sapienza University of Rome, 00161 Rome, Italy
- 2Unità di Neuroimmunologia, IRCCS Fondazione Santa Lucia, 00175 Rome, Italy
Abstract
ANGPTL3 and PCSK9 are key regulators of lipoprotein metabolism, with emerging evidence suggestive of a functional regulatory interrelationship. Indeed, patients lacking ANGPTL3 due to loss-of-function variants exhibit reduced circulating PCSK9 levels. This study aimed to determine whether ANGPTL3 and PCSK9 are part of the same complex. Co-immunoprecipitation (Co-IP) experiments in HepG2 cells and human plasma assessed whether ANGPTL3 and PCSK9 co-immunoprecipitated. A hypothetical interaction between the two proteins was also modeled in silico using two software packages: AlphaFold2 and ZDOCK. HepG2 cells overexpressing ANGPTL3, PCSK9, and ANGPTL3-PCSK9 were generated to investigate the relationship between ANGPTL3 and PCSK9 under different nutrient conditions. Reciprocal Co-IP experiments in HepG2 cells and human plasma showed that ANGPTL3 and PCSK9 could be recovered in the same co-immunoprecipitated sample, both intracellularly and in the culture medium. Structural modeling supported the experimental observations and identified a 2:1 ANGPTL3:PCSK9 arrangement as a plausible configuration. We observed higher association under fasting conditions and lower association under simulated feeding conditions. The latter was also confirmed in postprandial human plasma, where ANGPTL3 is known to bind ANGPTL8 in a 2:1 complex. Moreover, incubation of HepG2 cells with LDL appeared to reduce ANGPTL3-PCSK9 association. In summary, our study identifies a dynamic ANGPTL3–PCSK9 association that is regulated in a nutrient-dependent fashion. These findings may broaden current understanding of ANGPTL3 and PCSK9 biology and support further mechanistic studies, particularly in the context of therapeutic inhibition of these proteins.
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BibTeX
@article{bini2026nutrientdependent,
title = {{A Nutrient-Dependent ANGPTL3–PCSK9-Containing Complex in HepG2 Cells and Human Plasma}},
author = {Simone Bini and Valeria Pecce and Alessandra Pinzon Grimaldos and Alessia Di Costanzo and Ilenia Minicocci and Stella Covino and Daniele Tramontano and Silvia Piconese and Laura D’Erasmo and Marcello Arca},
journal = {Biomolecules},
year = {2026},
month = oct,
doi = {10.3390/biom16101531},
url = {https://www.mdpi.com/2218-273X/16/10/1531},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - A Nutrient-Dependent ANGPTL3–PCSK9-Containing Complex in HepG2 Cells and Human Plasma
AU - Simone Bini
AU - Valeria Pecce
AU - Alessandra Pinzon Grimaldos
AU - Alessia Di Costanzo
AU - Ilenia Minicocci
AU - Stella Covino
AU - Daniele Tramontano
AU - Silvia Piconese
AU - Laura D’Erasmo
AU - Marcello Arca
PY - 2026
DA - 2026/10/01
JO - Biomolecules
DO - 10.3390/biom16101531
UR - https://www.mdpi.com/2218-273X/16/10/1531
AB - ANGPTL3 and PCSK9 are key regulators of lipoprotein metabolism, with emerging evidence suggestive of a functional regulatory interrelationship. Indeed, patients lacking ANGPTL3 due to loss-of-function variants exhibit reduced circulating PCSK9 levels. This study aimed to determine whether ANGPTL3 and PCSK9 are part of the same complex. Co-immunoprecipitation (Co-IP) experiments in HepG2 cells and human plasma assessed whether ANGPTL3 and PCSK9 co-immunoprecipitated. A hypothetical interaction between the two proteins was also modeled in silico using two software packages: AlphaFold2 and ZDOCK. HepG2 cells overexpressing ANGPTL3, PCSK9, and ANGPTL3-PCSK9 were generated to investigate the relationship between ANGPTL3 and PCSK9 under different nutrient conditions. Reciprocal Co-IP experiments in HepG2 cells and human plasma showed that ANGPTL3 and PCSK9 could be recovered in the same co-immunoprecipitated sample, both intracellularly and in the culture medium. Structural modeling supported the experimental observations and identified a 2:1 ANGPTL3:PCSK9 arrangement as a plausible configuration. We observed higher association under fasting conditions and lower association under simulated feeding conditions. The latter was also confirmed in postprandial human plasma, where ANGPTL3 is known to bind ANGPTL8 in a 2:1 complex. Moreover, incubation of HepG2 cells with LDL appeared to reduce ANGPTL3-PCSK9 association. In summary, our study identifies a dynamic ANGPTL3–PCSK9 association that is regulated in a nutrient-dependent fashion. These findings may broaden current understanding of ANGPTL3 and PCSK9 biology and support further mechanistic studies, particularly in the context of therapeutic inhibition of these proteins.
SN - 2218-273X
ER -