Proprotein convertase subtilisin/kexin type 9 regulates the production of acute‐phase reactants from the liver

Abstract

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.

The Multifaceted Biology of PCSK9

“…Analysis of mouse and rat PCSK9 mRNA expression showed that it is restricted to discrete areas of the brain during development ( 51 , 95 , 144 ), and that its antisense morpholino-oligonucleotide knockdown in zebrafish leads to embryonic death with major neuronal deficits ( 145 ), although CRISPR/Cas9 deletion of its gene in zebrafish did not ( 146 ). Based on the previously observed embryonic lethality of Furin, PC5 and SKI-1/S1P KO in mice ( 28 ), we opted to develop a conditional mouse Pcsk9 KO strategy.…”