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.
Key Words: Hepatic stellate cells; Kupffer cells; Leptin; Lipopolysaccharide; Transforming growth factor beta; Proprotein convertase subtilisin/kexin type 9; Liver X receptor

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.

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 [PMID: 41640949 DOI: 10.4254/wjh.v18.i1.113896 ]