Proprotein convertase subtilisin/kexin type 9 (PCSK9) affects gene expression pathways beyond cholesterol metabolism in liver cells

J Cell Physiol. 2010 Jul;224(1):273-81. doi: 10.1002/jcp.22130.


Proprotein convertase subtilisin/kexin type 9 (PCSK9) induces degradation of low-density lipoprotein receptor (LDLR) in the liver. It is being pursued as a therapeutic target for LDL-cholesterol reduction. Earlier genome-wide gene expression studies showed that PCSK9 over-expression in HepG2 cells resulted in up-regulation of genes in cholesterol biosynthesis and down-regulation of genes in stress response pathways; however, it was not known whether these changes were directly regulated by PCSK9 or were secondary to PCSK9-induced changes to the intracellular environment. In order to further understand the biological function of PCSK9 we treated HepG2 cells with purified recombinant wild type (WT) and D374Y gain-of-function PCSK9 proteins for 8, 24, and 48 h, and used microarray analysis to identify genome-wide expression changes and pathways. These results were compared to the changes induced by culturing HepG2 cells in cholesterol-free medium, mimicking the intracellular environment of cholesterol starvation. We determined that PCSK9-induced up-regulation of cholesterol biosynthesis genes resulted from intracellular cholesterol starvation. In addition, we identified novel pathways that are presumably regulated by PCSK9 and are independent of its effects on cholesterol uptake. These pathways included "protein ubiquitination," "xenobiotic metabolism," "cell cycle," and "inflammation and stress response." Our results indicate that PCSK9 affects metabolic pathways beyond cholesterol metabolism in HepG2 cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cholesterol / biosynthesis
  • Cholesterol / deficiency
  • Cholesterol / metabolism*
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic*
  • Gene Regulatory Networks*
  • Hep G2 Cells
  • Humans
  • Lipid Metabolism / genetics*
  • Liver Neoplasms / enzymology
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / pathology
  • Mutation
  • Oligonucleotide Array Sequence Analysis
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Recombinant Proteins / metabolism
  • Serine Endopeptidases / genetics
  • Serine Endopeptidases / metabolism*
  • Time Factors


  • Recombinant Proteins
  • Cholesterol
  • PCSK9 protein, human
  • Proprotein Convertase 9
  • Proprotein Convertases
  • Serine Endopeptidases