LRP1 controls cPLA2 phosphorylation, ABCA1 expression and cellular cholesterol export.
BACKGROUND
ATP-binding cassette transporter A1 mediates apolipoprotein AI-dependent efflux of cholesterol and thereby removes cholesterol from peripheral tissues. ABCA1 expression is tightly regulated and deficiency of this cholesterol transporter results in cholesterol accumulation within cells. Low-density lipoprotein receptor-related protein 1 (LRP1) participates in lipid metabolism and energy homeostasis by endocytosis of apolipoprotein E-containing lipoproteins and modulation of cellular proliferation signals.


RESULTS
In the present study, we demonstrate a new role for LRP1 in reverse cholesterol transport. Absence of LRP1 expression results in increased PDGFRbeta signaling and sequential activation of the mitogen-activated protein kinase signaling pathway, which increases phosphorylation of cytosolic phospholipase A(2) (cPLA(2)). Phosphorylated and activated cPLA(2) releases arachidonic acid from the phospholipid pool. Overproduction of arachidonic acid suppresses the activation of LXR/RXR heterodimers bound to the promoter of LXR regulated genes such as ABCA1, resulting in greatly reduced ABCA1 expression.


CONCLUSIONS
LRP1 regulates LXR-mediated gene transcription and participates in reverse cholesterol transport by controlling cPLA(2) activation and ABCA1 expression. LRP1 thus functions as a physiological integrator of cellular lipid homeostasis with signals that regulate cellular proliferation and vascular wall integrity.
Zhou
Li
L
Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, Texas, United States of America.
Choi
Hong Y
HY
Li
Wei-Ping
WP
Xu
Fang
F
Herz
Joachim
J
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D001692:Biological Transport; D015153:Blotting, Western; D002784:Cholesterol / Q000378:metabolism*; D002855:Chromatography, Thin Layer; D017931:DNA Primers; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008856:Microscopy, Fluorescence; D054467:Phospholipases A2 / Q000378:metabolism*; D010766:Phosphorylation; D016133:Polymerase Chain Reaction; D011973:Receptors, LDL / Q000235:genetics / Q000502:physiology*; D014158:Transcription, Genetic; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D017931:DNA Primers; D026503:Low Density Lipoprotein Receptor-Related Protein-1; C486645:Lrp1 protein, mouse; D011973:Receptors, LDL; D025521:Tumor Suppressor Proteins; D002784:Cholesterol; D054467:Phospholipases A2