Cholesterol and Lipid Metabolism
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Peer reviewed
Abstract
Abstract
Hypercholesterolemia is a major contributor to atherosclerotic cardiovascular disease and is closely linked to dysregulation of multiple lipid metabolic pathways. Although PCSK9 inhibitors effectively reduce LDL-C, their effects on other lipid regulators, including ANGPTL3, remain incompletely understood. The present study investigated the effect PCSK9-targeting aptamer (AP-1) on circulating and hepatic ANGPTL3 concentrations, plasma LPL levels, and hepatic ChREBP gene expression in a rat model of diet-induced hypercholesterolemic. Forty male Wistar rats were randomly divided into eight experimental groups (n = 5 per group) and fed either normal chow or a high-cholesterol diet for 90 days. Following induction of hypercholesterolemia, the animals received treatment with conjugated aptamer at concentrations of 1, 3, or 8 μM (APT1 μM, APT3 μM, APT8 μM), atorvastatin plus ezetimibe, phosphate-buffered saline (PBS), and combination of APT 3 μM and atorvastatin (APT3 μM plus STA) for four weeks. Plasma and hepatic ANGPTL3 concentrations, as well as plasma LPL levels, were measured using ELISA, whereas hepatic ChREBP mRNA expression was subsequently quantified by real-time quantitative PCR. High-dose aptamer (AP-1) treatment (APT8 μM) significantly reduced plasma ANGPTL3 levels by approximately 86.7% compared with the NC group ( p < 0.001) and markedly decreased hepatic ANGPTL3 expression. In addition, the APT8 μM group demonstrated partial restoration of plasma LPL concentrations and significant upregulation of hepatic ChREBP gene expression. Both the intermediate (APT3 μM) and high (APT8 μM) aptamer doses significantly upregulated hepatic ChREBP gene expression, demonstrating approximately 2.35-fold ( p = 0.033) and 2.53-fold ( p = 0.011) increases relative to the N group, respectively. These findings suggest that PCSK9-targeting aptamer therapy may modulate the ANGPTL3-LPL-ChREBP regulatory axis and exert broader metabolic effects beyond conventional LDL receptor-mediated cholesterol regulation.
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@article{Rasul2026Conjugated,
title = {Conjugated aptamer against PCSK9 lowers ANGPTL3 and elevates LPL via ChREBP gene upregulation},
author = {Ramyar Mohammed Rasul and Zhala Salih Abdalla and Abbas Ali Palizban and Yaser Eshaghi Milasi and Fariba Sakhaei},
journal = {Scientific Reports},
year = {2026},
doi = {10.1038/s41598-026-63622-9},
url = {https://doi.org/10.1038/s41598-026-63622-9}
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