Sort1, encoded by the cardiovascular risk locus 1p13.3, is a regulator of hepatic lipoprotein export.
Recent genome-wide association studies (GWAS) have revealed strong association of hypercholesterolemia and myocardial infarction with SNPs on human chromosome 1p13.3. This locus covers three genes: SORT1, CELSR2, and PSRC1. We demonstrate that sortilin, encoded by SORT1, is an intracellular sorting receptor for apolipoprotein (apo) B100. It interacts with apoB100 in the Golgi and facilitates the formation and hepatic export of apoB100-containing lipoproteins, thereby regulating plasma low-density lipoprotein (LDL) cholesterol. Absence of sortilin in gene-targeted mice reduces secretion of lipoproteins from the liver and ameliorates hypercholesterolemia and atherosclerotic lesion formation in LDL receptor-deficient animals. In contrast, sortilin overexpression stimulates hepatic release of lipoproteins and increases plasma LDL levels. Our data have uncovered a regulatory pathway in hepatic lipoprotein export and suggest a molecular explanation for the cardiovascular risk being associated with 1p13.3.
Kjolby
Mads
M
The Lundbeck Foundation Research Center MIND, Department of Medical Biochemistry, Aarhus University, Denmark.
Andersen
Olav M
OM
Breiderhoff
Tilman
T
Fjorback
Anja W
AW
Pedersen
Karen Marie
KM
Madsen
Peder
P
Jansen
Pernille
P
Heeren
Joerg
J
Willnow
Thomas E
TE
Nykjaer
Anders
A
D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D053299:Apolipoprotein B-100 / Q000378:metabolism*; D001692:Biological Transport; D002318:Cardiovascular Diseases / Q000235:genetics*; D002478:Cells, Cultured; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics*; D004032:Diet; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D006937:Hypercholesterolemia / Q000235:genetics / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000097:blood; D008099:Liver / Q000166:cytology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism; D000099183:Sortilin
D033942:Adaptor Proteins, Vesicular Transport; D053299:Apolipoprotein B-100; D008077:Lipoproteins, LDL; D011973:Receptors, LDL; D000099183:Sortilin