title: Hepatic sortilin regulates both apolipoprotein B secretion and LDL catabolism.
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: Institute for Translational Medicine and Therapeutics, Cardiovascular Institute, and Institute for Diabetes, Obesity and Metabolism, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
authors: Alanna
authors: A
authors: Strong
authors: Qiurong
authors: Q
authors: Ding
authors: Andrew C
authors: AC
authors: Edmondson
authors: John S
authors: JS
authors: Millar
authors: Katherine V
authors: KV
authors: Sachs
authors: Xiaoyu
authors: X
authors: Li
authors: Arthi
authors: A
authors: Kumaravel
authors: Margaret Ye
authors: MY
authors: Wang
authors: Ding
authors: D
authors: Ai
authors: Liang
authors: L
authors: Guo
authors: Eric T
authors: ET
authors: Alexander
authors: David
authors: D
authors: Nguyen
authors: Sissel
authors: S
authors: Lund-Katz
authors: Michael C
authors: MC
authors: Phillips
authors: Carlos R
authors: CR
authors: Morales
authors: Alan R
authors: AR
authors: Tall
authors: Sekar
authors: S
authors: Kathiresan
authors: Edward A
authors: EA
authors: Fisher
authors: Kiran
authors: K
authors: Musunuru
authors: Daniel J
authors: DJ
authors: Rader
mesh_terms: D000071479:APOBEC-1 Deaminase; D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism*; D001483:Base Sequence; D002460:Cell Line; D003564:Cytidine Deaminase / Q000172:deficiency / Q000235:genetics; D017931:DNA Primers / Q000235:genetics; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007700:Kinetics; D008077:Lipoproteins, LDL / Q000378:metabolism*; D008079:Lipoproteins, VLDL / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008247:Lysosomes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008954:Models, Biological; D016297:Mutagenesis, Site-Directed; D011973:Receptors, LDL / Q000172:deficiency / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000099183:Sortilin
chemical_list: D000071479:APOBEC-1 Deaminase; D033942:Adaptor Proteins, Vesicular Transport; D001055:Apolipoproteins B; D003564:Cytidine Deaminase; D017931:DNA Primers; D008077:Lipoproteins, LDL; D008079:Lipoproteins, VLDL; D011973:Receptors, LDL; D011994:Recombinant Proteins; D000099183:Sortilin; C000605089:APOBEC1 protein, human; C000605090:Apobec1 protein, mouse