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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 3

Sortilin expression promotes LDL uptake and lysosomal catabolism in vitro.

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Sortilin expression promotes LDL uptake and lysosomal catabolism in vitr...
(A and B) HuH7 cells expressing wild-type sortilin, Sort.Stop, Sort.LAYA, or GFP (control) under control of a dox-inducible promoter were assayed for (A) LDL cell association and (B) LDL degradation after incubation with 125I-LDL for 3 hours. Both wild-type sortilin and Sort.LAYA increased 125I-LDL cell association 5-fold, while only wild-type sortilin increased 125I-LDL degradation. Sort.Stop did not increase 125I-LDL cell association or degradation (C–G) Cells were incubated with fluorescently labeled LDL for 6 hours and subjected to confocal microscopy to visualize intracellular LDL. Compared with cells containing only endogenous sortilin (C), wild-type sortilin (D) increases intracellular LDL, while Sort.Stop (E) does not increase intracellular LDL. Sort.LAYA (F) resulted in profound accumulation of LDL at the cell surface without increasing intracellular LDL (G) Sortilin and LDL show strong colocalization with the lysosomal marker LAMP1. Scale bars: 15 μm.

Copyright © 2022 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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