Bundschuh J, Neumann M, Zimny S, Spirk M, Buechler C. Transforming growth factor beta reduces proprotein convertase subtilisin/kexin type 9 in the supernatant of hepatic stellate cells. World J Hepatol 2026; 18(1): 113896 [DOI: 10.4254/wjh.v18.i1.113896]
Corresponding Author of This Article
Christa Buechler, PhD, Associate Professor, Senior Researcher, Department of Internal Medicine I, University Hospital Regensburg, Franz-Josef-Strauss Allee 11, Regensburg 93053, Bavaria, Germany. christa.buechler@klinik.uni-regensburg.de
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This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Jan 27, 2026 (publication date) through Jan 27, 2026
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World Journal of Hepatology
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1948-5182
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Bundschuh J, Neumann M, Zimny S, Spirk M, Buechler C. Transforming growth factor beta reduces proprotein convertase subtilisin/kexin type 9 in the supernatant of hepatic stellate cells. World J Hepatol 2026; 18(1): 113896 [DOI: 10.4254/wjh.v18.i1.113896]
World J Hepatol. Jan 27, 2026; 18(1): 113896 Published online Jan 27, 2026. doi: 10.4254/wjh.v18.i1.113896
Transforming growth factor beta reduces proprotein convertase subtilisin/kexin type 9 in the supernatant of hepatic stellate cells
Jan Bundschuh, Maximilian Neumann, Sebastian Zimny, Marlen Spirk, Christa Buechler
Jan Bundschuh, Maximilian Neumann, Sebastian Zimny, Marlen Spirk, Christa Buechler, Department of Internal Medicine I, University Hospital Regensburg, Regensburg 93053, Bavaria, Germany
Author contributions: Bundschuh J, Neumann M, Zimny S, and Spirk M performed the study; Bundschuh J and Buechler C analyzed the data; Buechler C designed the research study and wrote the manuscript. All authors have read and approved the final manuscript.
Institutional review board statement: Experimental procedures were performed according to the guidelines of the charitable state-controlled foundation Human Tissue and Cell Research, with the written informed patient’s consent approved by the local ethical committee of the University Hospital of Regensburg (Approval No. 12-101-0048).
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Data sharing statement: The dataset supporting the conclusions of this article is available from the corresponding author.
Open Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Christa Buechler, PhD, Associate Professor, Senior Researcher, Department of Internal Medicine I, University Hospital Regensburg, Franz-Josef-Strauss Allee 11, Regensburg 93053, Bavaria, Germany. christa.buechler@klinik.uni-regensburg.de
Received: September 8, 2025 Revised: October 10, 2025 Accepted: November 26, 2025 Published online: January 27, 2026 Processing time: 143 Days and 23.9 Hours
Abstract
BACKGROUND
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is abundantly expressed by hepatocytes and regulates the uptake of low-density lipoprotein by these parenchymal cells. Little research has been conducted on PCSK9 expression in non-hepatocyte liver cells.
AIM
To investigate PCSK9 levels in the supernatant of different liver cells and its regulation in hepatic stellate cells (HSCs).
METHODS
PCSK9 levels were measured in the cell culture medium of primary human hepatocytes, HepG2 and Huh7 cells, primary human HSCs, the HSC cell line LX-2, primary human Kupffer cells, and primary human sinusoidal endothelial cells. The effects of cytokines, adipokines, lipopolysaccharide, transforming growth factor beta (TGF-β) and ligands of nuclear receptors on PCSK9 levels in LX-2 cells during 24 hours of culture were determined using enzyme-linked immunosorbent assay.
RESULTS
Primary human hepatocytes, HepG2, Huh7, HSCs, and LX-2 cells secreted significant levels of PCSK9. There were low levels of PCSK9 in the supernatant of Kupffer cells and sinusoidal endothelial cells. Interleukin-6 reduced PCSK9 in LX-2 cells to 86% of controls and lipopolysaccharide increased it by 7%, whereas tumor necrosis factor, as well as exogenous adiponectin and leptin had no effect. Chemerin-156, but not chemerin-155 or chemerin-157 isoform overexpressed in LX-2 cells, reduced PCSK9 to 84% of the controls. TGF-β reduced PCSK9 in LX-2 cell culture media to 68% of controls and lowered its cellular level. Activation of liver X receptor but not farnesoid X receptor or peroxisome proliferator-activated receptor gamma, reduced PCSK9 levels by 42% in LX-2 cell culture medium.
CONCLUSION
Profibrotic TGF-β and the antifibrotic liver X receptor ligand both reduced PCSK9 in LX-2 medium, showing that PCSK9 is not a marker of HSC activation.
Core Tip: This study showed that primary hepatic stellate cells and the LX-2 cell line secrete proprotein convertase subtilisin/kexin type 9 (PCSK9). Levels of PCSK9 in the medium of LX-2 cells were found to be reduced by interleukin-6, chemerin-156, and transforming growth factor beta, and increased by lipopolysaccharide. The liver X receptor agonist lowered PCSK9 levels in the cell medium. As transforming growth factor beta is a fibrotic cytokine and activation of the liver X receptor exerts antifibrotic effects, PCSK9 levels in the cell medium cannot be used as a marker of activated hepatic stellate cells.
