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ORIGINAL RESEARCH article

Front. Pharmacol.
Sec. Gastrointestinal and Hepatic Pharmacology
Volume 16 - 2025 | doi: 10.3389/fphar.2025.1528250

Conditional knockdown of hepatic PCSK9 ameliorates high-fat diet-induced liver inflammation in mice

Provisionally accepted
Xue-Ying Zhang Xue-Ying Zhang Qing-Qing Lu Qing-Qing Lu Yan-Jie Li Yan-Jie Li Shan-Rui Shi Shan-Rui Shi Chao-Nan Ma Chao-Nan Ma Miao Miao Miao Miao Shoudong Guo Shoudong Guo *
  • Shandong Second Medical University, Weifang, Shandong Province, China

The final, formatted version of the article will be published soon.

    Accumulating evidence has shown that proprotein convertase subtilisin/kexin type 9 (PCSK9) is associated with inflammation in the vascular system. However, the roles of PCSK9 in hepatic inflammation remain unclear. Because PCSK9 is mainly expressed in the liver and modulates lipid uptake through low-density lipoprotein receptor family members, the present study aimed to elucidate the effect of conditional knockdown of hepatic PCSK9 on hyperlipidemia-induced inflammation and the underlying mechanisms of action. PCSK9flox/flox mice were bred with ALB-Cre+ mice to obtain hepatic PCSK9(-/-), PCSK9(+/-), and PCSK9(+/+) mice. These mice were fed with a high-fat diet for 9 weeks to induce inflammation. Conditional knockdown of hepatic PCSK9 remarkably decreased plasma levels of total cholesterol and alleviated hyperlipidemia-induced liver injury. Mechanistically, conditional knockdown of hepatic PCSK9 significantly reduced the levels of pro-inflammatory factors by downregulating the expression of Toll-like receptors, mitogen-activated protein kinase (MAPK), and phosphoinositide-3 kinase/protein kinase B, which subsequently attenuated the expression of downstream molecules, namely nuclear factor kappa-B and activator protein-1. The related mechanisms were confirmed using lipid-loaded HepG2 cells together with PCSK9 siRNA, alirocumab (anti-PCSK9 antibody), and/or a p38-MAPK inhibitor. These findings confirmed that conditional knockdown of hepatic PCSK9 attenuates liver inflammation following hyperlipidemia induction by modulating multiple signaling pathways; this suggests that targeting PCSK9 knockdown/inhibition with appropriate agents is useful not only for treating hyperlipidemia but also for ameliorating hyperlipidemia-induced liver inflammation.

    Keywords: Inflammation, MAPK, PCSK9 inhibitor, PCSK9 siRNA, Toll-like receptor

    Received: 19 Nov 2024; Accepted: 08 Jan 2025.

    Copyright: © 2025 Zhang, Lu, Li, Shi, Ma, Miao and Guo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

    * Correspondence: Shoudong Guo, Shandong Second Medical University, Weifang, 261053, Shandong Province, China

    Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.