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Updated: May 3, 2026

A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9
08:14

A High-Throughput Luciferase Assay to Evaluate Proteolysis of the Single-Turnover Protease PCSK9

Published on: August 28, 2018

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The hypercholesterolemia-risk gene SORT1 facilitates PCSK9 secretion

Camilla Gustafsen1, Mads Kjolby2, Mette Nyegaard3

  • 1The Lundbeck Foundation Research Center, MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, DK-8000 C Aarhus, Denmark.

Cell Metabolism
|February 11, 2014
PubMed

Insights

Sortilin acts as a receptor for PCSK9, a protein that increases LDL cholesterol. This finding reveals a new mechanism regulating PCSK9 secretion and offers potential therapeutic targets for hypercholesterolemia.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Genetics

Background:

  • Circulating PCSK9 promotes LDL receptor degradation, elevating LDL cholesterol levels.
  • PCSK9 is a key drug target for hypercholesterolemia, with promising clinical trial outcomes.
  • The precise intracellular mechanisms governing PCSK9 activity are not fully understood.

Purpose of the Study:

  • To identify novel proteins involved in the regulation of PCSK9 secretion.
  • To elucidate the role of sortilin in PCSK9 trafficking and activity.

Main Methods:

  • Investigated the interaction between sortilin and PCSK9 using cell biology techniques.
  • Utilized sortilin-deficient mice and liver-specific sortilin overexpression models.
  • Analyzed the correlation between circulating PCSK9 and sortilin levels in a human cohort.

Main Results:

  • Identified sortilin as a high-affinity binding partner for PCSK9.
  • Demonstrated that sortilin colocalizes with PCSK9 and facilitates its secretion from hepatocytes.
  • Sortilin deficiency in mice reduced circulating PCSK9, while overexpression increased it.
  • Observed a positive correlation between circulating PCSK9 and sortilin in humans.

Conclusions:

  • Sortilin is a critical regulator of PCSK9 secretion and activity.
  • Findings suggest sortilin's involvement in human PCSK9 regulation.
  • Establishes a novel molecular pathway influencing cholesterol metabolism.

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