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Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism
Alanna Strong, … , Kiran Musunuru, Daniel J. Rader
Alanna Strong, … , Kiran Musunuru, Daniel J. Rader
Published July 2, 2012
Citation Information: J Clin Invest. 2012;122(8):2807-2816. https://doi.org/10.1172/JCI63563.
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Research Article Metabolism

Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism

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Abstract

Genome-wide association studies (GWAS) have identified a genetic variant at a locus on chromosome 1p13 that is associated with reduced risk of myocardial infarction, reduced plasma levels of LDL cholesterol (LDL-C), and markedly increased expression of the gene sortilin-1 (SORT1) in liver. Sortilin is a lysosomal sorting protein that binds ligands both in the Golgi apparatus and at the plasma membrane and traffics them to the lysosome. We previously reported that increased hepatic sortilin expression in mice reduced plasma LDL-C levels. Here we show that increased hepatic sortilin not only reduced hepatic apolipoprotein B (APOB) secretion, but also increased LDL catabolism, and that both effects were dependent on intact lysosomal targeting. Loss-of-function studies demonstrated that sortilin serves as a bona fide receptor for LDL in vivo in mice. Our data are consistent with a model in which increased hepatic sortilin binds intracellular APOB-containing particles in the Golgi apparatus as well as extracellular LDL at the plasma membrane and traffics them to the lysosome for degradation. We thus provide functional evidence that genetically increased hepatic sortilin expression both reduces hepatic APOB secretion and increases LDL catabolism, providing dual mechanisms for the very strong association between increased hepatic sortilin expression and reduced plasma LDL-C levels in humans.

Authors

Alanna Strong, Qiurong Ding, Andrew C. Edmondson, John S. Millar, Katherine V. Sachs, Xiaoyu Li, Arthi Kumaravel, Margaret Ye Wang, Ding Ai, Liang Guo, Eric T. Alexander, David Nguyen, Sissel Lund-Katz, Michael C. Phillips, Carlos R. Morales, Alan R. Tall, Sekar Kathiresan, Edward A. Fisher, Kiran Musunuru, Daniel J. Rader

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Figure 1

Sortilin demonstrates high-affinity binding to APOB.

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Sortilin demonstrates high-affinity binding to APOB.
(A) Preparations of...
(A) Preparations of LDL at the indicated concentrations in HBS-EP buffer (pH 7.4) were passed across the sensor chip for 240 seconds to monitor the association of LDL, HDL, and APOE DMPC discs and sortilin, and then the chip was exposed to buffer alone for an additional 240 seconds to monitor the dissociation phase. (B) 100 μg/μl of LDL was bound to immobilized human sortilin in HBS-EP buffer at pH 7.4. At the indicated time point, the buffer was exchanged with HBS-EP at lower pH values.
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