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A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
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Published on: August 28, 2018

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

Hong Lan1, Ling Pang, Marsha M Smith

  • 1Cardiovascular and Metabolic Disease Research, Merck Research Laboratories, Kenilworth, New Jersey 0703, USA.

Journal of Cellular Physiology
|March 25, 2010
PubMed

Insights

Proprotein convertase subtilisin/kexin type 9 (PCSK9) influences cholesterol metabolism by upregulating cholesterol biosynthesis genes due to intracellular cholesterol starvation. PCSK9 also impacts other pathways, including protein ubiquitination and xenobiotic metabolism, independent of cholesterol uptake.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Genomics

Background:

  • Proprotein convertase subtilisin/kexin type 9 (PCSK9) targets the low-density lipoprotein receptor (LDLR) for degradation, making it a therapeutic target for lowering LDL-cholesterol.
  • Previous studies indicated PCSK9 overexpression in HepG2 cells altered cholesterol biosynthesis and stress response genes, but the direct role of PCSK9 versus intracellular environment changes was unclear.

Purpose of the Study:

  • To elucidate the direct biological functions of PCSK9 beyond its known role in LDLR degradation.
  • To differentiate PCSK9-mediated gene expression changes from those induced by intracellular cholesterol levels.

Main Methods:

  • HepG2 cells were treated with wild-type and gain-of-function PCSK9 proteins for varying durations (8, 24, 48 hours).
  • Microarray analysis was employed to identify genome-wide expression changes and affected pathways.
  • Gene expression profiles were compared to cells cultured in cholesterol-free medium to simulate cholesterol starvation.

Main Results:

  • PCSK9-induced upregulation of cholesterol biosynthesis genes was attributed to intracellular cholesterol starvation, not direct PCSK9 regulation.
  • Novel PCSK9-regulated pathways independent of cholesterol uptake were identified, including protein ubiquitination, xenobiotic metabolism, cell cycle, and inflammation/stress response.
  • PCSK9 demonstrated a broader impact on metabolic pathways in HepG2 cells than previously recognized.

Conclusions:

  • PCSK9's effect on cholesterol biosynthesis genes is primarily a consequence of intracellular cholesterol starvation.
  • PCSK9 regulates distinct cellular pathways, including protein ubiquitination, xenobiotic metabolism, cell cycle, and stress responses, independent of its cholesterol-lowering mechanism.
  • PCSK9 plays a multifaceted role in cellular metabolism extending beyond cholesterol homeostasis.

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