Jacome Sanz, D, Saralahti, AK, Pekkarinen, M, et al. Proprotein convertase subtilisin/kexin type 9 regulates the production of acute-phase reactants from the liver. Liver Int. 2021; 41: 2511– 2522. https://doi.org/10.1111/liv.14993
Proprotein convertase subtilisin/kexin type 9 regulates the production of acute-phase reactants from the liver
|Author:||Sanz, Dafne Jacome1; Saralahti, Anni K.2; Pekkarinen, Meeri3;|
1Laboratory of Immunoregulation, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
2Laboratory of Experimental Immunology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
3Laboratory of Computational Biology, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
4Vaccine Research Center, Faculty of Medicine and Health Technology, Tampere University, Tampere, Finland
5PEDEGO Research Unit, Medical Research Center, University of Oulu, Oulu, Finland
6Department of Children and Adolescents, Oulu University Hospital, Oulu, Finland
7Fimlab laboratories Ltd, Tampere, Finland
|Online Access:||PDF Full Text (PDF, 1.3 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe202201189184
John Wiley & Sons,
|Publish Date:|| 2022-01-18
Background & Aims: Proprotein convertase subtilisin/kexin type 9 (PCSK9) controls blood cholesterol levels by fostering the LDL receptor (LDLR) degradation in hepatocytes. Additionally, PCSK9 has been suggested to participate in immunoregulation by modulating cytokine production. We studied the immunological role of PCSK9 in Streptococcus pneumoniae bacteraemia in vivo and in a human hepatocyte cell line.
Methods: CRISPR/Cas9 mutagenesis was utilized to create pcsk9 knock-out (KO) zebrafish, which were infected with S pneumoniae to assess the role of PCSK9 for the survival of the fish and in the transcriptomic response of the liver. The direct effects of PCSK9 on the expression of acute-phase reaction (APR) genes were studied in HepG2 cells.
Results: The pcsk9 KO zebrafish lines (pcsk9tpu-13 and pcsk9tpu-2,+15) did not show developmental defects or gross phenotypical differences. In the S pneumoniae infected zebrafish, the mortality of pcsk9 KOs was similar to the controls. A liver-specific gene expression analysis revealed that a pneumococcal challenge upregulated pcsk9, and that the pcsk9 deletion reduced the expression of APR genes, including hepcidin antimicrobial peptide (hamp) and complement component 7b (c7b). Accordingly, silencing PCSK9 in vitro in HepG2 cells using small interfering RNAs (siRNAs) decreased HAMP expression.
Conclusions: We demonstrate that PCSK9 is not critical for zebrafish survival in a systemic pneumococcal infection. However, PCSK9 deficiency was associated with the lower expression of APR genes in zebrafish and altered the expression of innate immunity genes in a human hepatocyte cell line. Overall, our data suggest an evolutionarily conserved function for PCSK9 in APR in the liver.
|Pages:||2511 - 2522|
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
This study was financially supported by the Academy of Finland (Grant 295814; MO/Ma.P.), the Cancer Foundation of Finland (Grant 180138; Ma.P. and 190146; MO/Ma.P.), the Paulo Foundation (MO), Tampere ImmunoExcellence—Vaccines and Immunomodulation Platform (AS, MO), the Tampere University Doctoral Programme in Medicine and Health Technology (DS), the Tampere Tuberculosis Foundation (DS, MR, MO, Ma.P.), the Competitive State Research Financing of the Expert Responsibility Area of Tampere University Hospital (Grant X50070; Ma.P.). The funding parties were not involved in study design, in the collection, analysis and interpretation of data, in the writing of the report or in the decision to submit the article for publication.
© 2021 The Authors. Liver International published by John Wiley & Sons Ltd. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.