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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 5

Sortilin deficiency is associated with reduced or normal plasma cholesterol and reduced APOB/VLDL secretion.

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Sortilin deficiency is associated with reduced or normal plasma choleste...
(A–D) Mice (8- to 10-week-old females) were fasted for 4 hours, and blood was drawn by retroorbital bleed; plasma total cholesterol was measured by autoanalyzer and FPLC. (A and B) Sort1 deficiency on an Ldlr–/– background was associated with a 20% reduction in plasma cholesterol. (C–E) Sort1 deficiency on an APOBEC1–/–;APOB transgenic background did not affect plasma cholesterol or APOB levels. (F) Mice (8- to 10-week-old females) were fasted for 4 hours and injected intraperitoneally with the detergent Pluronic to inhibit lipolysis followed by radiolabeling. Mice were sacrificed 1 hour after radiolabeling, plasma was collected, and VLDL was isolated by ultracentrifugation. Sort1 deficiency was associated with a 60% reduction in VLDL/APOB secretion on an APOBEC1–/–;APOB transgenic background.

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

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