The Hypercholesterolemia-Risk Gene SORT1 Facilitates PCSK9 Secretion

Camilla Gustafsen; Mads Kjolby; Mette Nyegaard; Manuel Mattheisen; Jesper Lundhede; Henriette Buttenschøn; Ole Mors; Jacob F Bentzon; Peder Madsen; Anders Nykjaer; Simon Glerup

doi:10.1016/j.cmet.2013.12.006

The Hypercholesterolemia-Risk Gene SORT1 Facilitates PCSK9 Secretion

Camilla Gustafsen, Mads Kjolby, Mette Nyegaard, Manuel Mattheisen, Jesper Lundhede, Henriette Buttenschøn, Ole Mors, Jacob F Bentzon, Peder Madsen, Anders Nykjaer, Simon Glerup

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaper › Journal article › Research › peer-review

138 Citations (Scopus)

Abstract

Circulating PCSK9 destines low-density lipoprotein receptor for degradation in lysosomes, resulting in increased LDL cholesterol. Accordingly, it is an attractive drug target for hypercholesterolemia, and results from clinical trials are promising. While the physiological role of PCSK9 in cholesterol metabolism is well described, its complex mechanism of action remains poorly understood, although it is known to depend on intracellular trafficking. We here identify sortilin, encoded by the hypercholesterolemia-risk gene SORT1, as a high-affinity sorting receptor for PCSK9. Sortilin colocalizes with PCSK9 in the trans-Golgi network and facilitates its secretion from primary hepatocytes. Accordingly, sortilin-deficient mice display decreased levels of circulating PCSK9, while sortilin overexpression in the liver confers increased plasma PCSK9. Furthermore, circulating PCSK9 and sortilin were positively correlated in a human cohort of healthy individuals, suggesting that sortilin is involved in PCSK9 secretion in humans. Taken together, our findings establish sortilin as a critical regulator of PCSK9 activity.

Original language	English
Journal	Cell Metabolism
Volume	19
Issue	2
Pages (from-to)	310-8
Number of pages	9
ISSN	1550-4131
DOIs	https://doi.org/10.1016/j.cmet.2013.12.006
Publication status	Published - 10 Feb 2014

Access to Document

10.1016/j.cmet.2013.12.006

Cite this

@article{89ebe5a9e4fd4b58879d5392bfe5abe1,

title = "The Hypercholesterolemia-Risk Gene SORT1 Facilitates PCSK9 Secretion",

abstract = "Circulating PCSK9 destines low-density lipoprotein receptor for degradation in lysosomes, resulting in increased LDL cholesterol. Accordingly, it is an attractive drug target for hypercholesterolemia, and results from clinical trials are promising. While the physiological role of PCSK9 in cholesterol metabolism is well described, its complex mechanism of action remains poorly understood, although it is known to depend on intracellular trafficking. We here identify sortilin, encoded by the hypercholesterolemia-risk gene SORT1, as a high-affinity sorting receptor for PCSK9. Sortilin colocalizes with PCSK9 in the trans-Golgi network and facilitates its secretion from primary hepatocytes. Accordingly, sortilin-deficient mice display decreased levels of circulating PCSK9, while sortilin overexpression in the liver confers increased plasma PCSK9. Furthermore, circulating PCSK9 and sortilin were positively correlated in a human cohort of healthy individuals, suggesting that sortilin is involved in PCSK9 secretion in humans. Taken together, our findings establish sortilin as a critical regulator of PCSK9 activity.",

author = "Camilla Gustafsen and Mads Kjolby and Mette Nyegaard and Manuel Mattheisen and Jesper Lundhede and Henriette Buttensch{\o}n and Ole Mors and Bentzon, {Jacob F} and Peder Madsen and Anders Nykjaer and Simon Glerup",

year = "2014",

month = feb,

day = "10",

doi = "10.1016/j.cmet.2013.12.006",

language = "English",

volume = "19",

pages = "310--8",

journal = "Cell Metabolism",

issn = "1550-4131",

publisher = "Cell Press",

number = "2",

}

TY - JOUR

T1 - The Hypercholesterolemia-Risk Gene SORT1 Facilitates PCSK9 Secretion

AU - Gustafsen, Camilla

AU - Kjolby, Mads

AU - Nyegaard, Mette

AU - Mattheisen, Manuel

AU - Lundhede, Jesper

AU - Buttenschøn, Henriette

AU - Mors, Ole

AU - Bentzon, Jacob F

AU - Madsen, Peder

AU - Nykjaer, Anders

AU - Glerup, Simon

PY - 2014/2/10

Y1 - 2014/2/10

N2 - Circulating PCSK9 destines low-density lipoprotein receptor for degradation in lysosomes, resulting in increased LDL cholesterol. Accordingly, it is an attractive drug target for hypercholesterolemia, and results from clinical trials are promising. While the physiological role of PCSK9 in cholesterol metabolism is well described, its complex mechanism of action remains poorly understood, although it is known to depend on intracellular trafficking. We here identify sortilin, encoded by the hypercholesterolemia-risk gene SORT1, as a high-affinity sorting receptor for PCSK9. Sortilin colocalizes with PCSK9 in the trans-Golgi network and facilitates its secretion from primary hepatocytes. Accordingly, sortilin-deficient mice display decreased levels of circulating PCSK9, while sortilin overexpression in the liver confers increased plasma PCSK9. Furthermore, circulating PCSK9 and sortilin were positively correlated in a human cohort of healthy individuals, suggesting that sortilin is involved in PCSK9 secretion in humans. Taken together, our findings establish sortilin as a critical regulator of PCSK9 activity.

AB - Circulating PCSK9 destines low-density lipoprotein receptor for degradation in lysosomes, resulting in increased LDL cholesterol. Accordingly, it is an attractive drug target for hypercholesterolemia, and results from clinical trials are promising. While the physiological role of PCSK9 in cholesterol metabolism is well described, its complex mechanism of action remains poorly understood, although it is known to depend on intracellular trafficking. We here identify sortilin, encoded by the hypercholesterolemia-risk gene SORT1, as a high-affinity sorting receptor for PCSK9. Sortilin colocalizes with PCSK9 in the trans-Golgi network and facilitates its secretion from primary hepatocytes. Accordingly, sortilin-deficient mice display decreased levels of circulating PCSK9, while sortilin overexpression in the liver confers increased plasma PCSK9. Furthermore, circulating PCSK9 and sortilin were positively correlated in a human cohort of healthy individuals, suggesting that sortilin is involved in PCSK9 secretion in humans. Taken together, our findings establish sortilin as a critical regulator of PCSK9 activity.

U2 - 10.1016/j.cmet.2013.12.006

DO - 10.1016/j.cmet.2013.12.006

M3 - Journal article

C2 - 24506872

SN - 1550-4131

VL - 19

SP - 310

EP - 318

JO - Cell Metabolism

JF - Cell Metabolism

IS - 2

ER -

The Hypercholesterolemia-Risk Gene SORT1 Facilitates PCSK9 Secretion

Abstract

Access to Document

Fingerprint

Cite this