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.
authors: The Lundbeck Foundation Research Center, MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, DK-8000 C Aarhus, Denmark.
authors: Camilla
authors: C
authors: Gustafsen
authors: The Lundbeck Foundation Research Center, MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, DK-8000 C Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE, Nordic EMBL Partnership, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, DK-8000 C Aarhus, Denmark; Department of Clinical Medicine, Aarhus University, and Department of Cardiology, Aarhus University Hospital, DK-8200 N Aarhus, Denmark.
authors: Mads
authors: M
authors: Kjolby
authors: The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, DK-8000 C Aarhus, Denmark.
authors: Mette
authors: M
authors: Nyegaard
authors: Center for Integrative Sequencing, iSEQ, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, DK-8000 C Aarhus, Denmark.
authors: Manuel
authors: M
authors: Mattheisen
authors: The Lundbeck Foundation Research Center, MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, DK-8000 C Aarhus, Denmark.
authors: Jesper
authors: J
authors: Lundhede
authors: The Lundbeck Foundation Initiative for Integrative Psychiatric Research, iPSYCH, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, DK-8000 C Aarhus, Denmark; Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, DK-8240 Risskov, Denmark.
authors: Henriette
authors: H
authors: Buttenschøn
authors: Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, DK-8240 Risskov, Denmark; Research Department P, Aarhus University Hospital, DK-8240 Risskov, Denmark.
authors: Ole
authors: O
authors: Mors
authors: Department of Clinical Medicine, Aarhus University, and Department of Cardiology, Aarhus University Hospital, DK-8200 N Aarhus, Denmark.
authors: Jacob F
authors: JF
authors: Bentzon
authors: The Lundbeck Foundation Research Center, MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, DK-8000 C Aarhus, Denmark.
authors: Peder
authors: P
authors: Madsen
authors: The Lundbeck Foundation Research Center, MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, DK-8000 C Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE, Nordic EMBL Partnership, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, DK-8000 C Aarhus, Denmark.
authors: Anders
authors: A
authors: Nykjaer
authors: The Lundbeck Foundation Research Center, MIND, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, DK-8000 C Aarhus, Denmark; Danish Research Institute of Translational Neuroscience DANDRITE, Nordic EMBL Partnership, Department of Biomedicine, Aarhus University, Vennelyst Boulevard 4, DK-8000 C Aarhus, Denmark. Electronic address: sg@biokemi.au.dk.
authors: Simon
authors: S
authors: Glerup
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000097:blood* / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D005455:Fluorescent Antibody Technique; D006801:Humans; D006937:Hypercholesterolemia / Q000097:blood* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases / Q000097:blood* / Q000378:metabolism; D011485:Protein Binding; D012697:Serine Endopeptidases / Q000097:blood* / Q000378:metabolism; D000099183:Sortilin
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; D000071449:Proprotein Convertase 9; D043484:Proprotein Convertases; D012697:Serine Endopeptidases; D000099183:Sortilin; C472125:PCSK9 protein, human