Influence of PDZK1 on lipoprotein metabolism and atherosclerosis.
PDZK1 is a scaffold protein containing four PDZ protein interaction domains, which bind to the carboxy termini of a number of membrane transporter proteins, including ion channels (e.g., CFTR) and cell surface receptors. One of these, the HDL receptor, scavenger receptor class B type I (SR-BI), exhibits a striking, tissue-specific dependence on PDZK1 for its expression and activity. In PDZK1 knockout (KO) mice there is a marked reduction of SR-BI protein expression (approximately 95%) in the liver, but not in steroidogenic tissues or, as we show in this report, in bone marrow- or spleen-derived macrophages, or lung-derived endothelial cells. Because of hepatic SR-BI deficiency, PDZK1 KO mice exhibit dyslipidemia characterized by elevated plasma cholesterol carried in abnormally large HDL particles. Here, we show that inactivation of the PDZK1 gene promotes the development of aortic root atherosclerosis in apolipoprotein E (apoE) KO mice fed with a high fat/high cholesterol diet. However, unlike complete SR-BI-deficiency in SR-BI/apoE double KO mice, PDZK1 deficiency in PDZK1/apoE double knockout mice did not result in development of occlusive coronary artery disease or myocardial infarction, presumably because of their residual expression of SR-BI. These findings demonstrate that deficiency of an adaptor protein essential for normal expression of a lipoprotein receptor promotes atherosclerosis in a murine model. They also define PDZK1 as a member of the family of proteins that is instrumental in preventing cardiovascular disease by maintaining normal lipoprotein metabolism.
Kocher
Olivier
O
Department of Pathology, Beth Israel-Deaconess Medical Center and Harvard Medical School, 330 Brookline Avenue, Boston, MA 02215, USA. okocher@bidmc.harvard.edu
Yesilaltay
Ayce
A
Shen
Ching-Hung
CH
Zhang
Songwen
S
Daniels
Kathleen
K
Pal
Rinku
R
Chen
Jianzhu
J
Krieger
Monty
M
D000818:Animals; D001011:Aorta / Q000378:metabolism / Q000473:pathology; D001057:Apolipoproteins E / Q000172:deficiency / Q000378:metabolism; D050197:Atherosclerosis / Q000097:blood / Q000378:metabolism*; D018955:CD36 Antigens / Q000378:metabolism; D004032:Diet; D042783:Endothelial Cells / Q000378:metabolism; D015151:Immunoblotting; D047908:Intracellular Signaling Peptides and Proteins / Q000172:deficiency / Q000378:metabolism*; D008055:Lipids / Q000097:blood; D008074:Lipoproteins / Q000378:metabolism*; D008264:Macrophages / Q000378:metabolism; D008565:Membrane Proteins; D051379:Mice; D008810:Mice, Inbred C57BL
D001057:Apolipoproteins E; D018955:CD36 Antigens; D047908:Intracellular Signaling Peptides and Proteins; D008055:Lipids; D008074:Lipoproteins; D008565:Membrane Proteins; C514896:PDZK1 protein, mouse