Carboxy-terminal deletion of the HDL receptor reduces receptor levels in liver and steroidogenic tissues, induces hypercholesterolemia, and causes fatal heart disease.
The HDL receptor SR-BI mediates the transfer of cholesteryl esters from HDL to cells and controls HDL abundance and structure. Depending on the genetic background, loss of SR-BI causes hypercholesterolemia, anemia, reticulocytosis, splenomegaly, thrombocytopenia, female infertility, and fatal coronary heart disease (CHD). The carboxy terminus of SR-BI (505QEAKL509) must bind to the cytoplasmic adaptor PDZK1 for normal hepatic-but not steroidogenic cell-expression of SR-BI protein. To determine whether SR-BI's carboxy terminus is also required for normal protein levels in steroidogenic cells, we introduced into SR-BI's gene a507Ala/STOP mutation that produces a truncated receptor (SR-BIΔCT). As expected, the dramatic reduction of hepatic receptor protein in SR-BIΔCT mice was similar to that in PDZK1 knockout (KO) mice. Unlike SR-BI KO females, SR-BIΔCT females were fertile. The severity of SR-BIΔCT mice's hypercholesterolemia was intermediate between those of SR-BI KO and PDZK1 KO mice. Substantially reduced levels of the receptor in adrenal cortical cells, ovarian cells, and testicular Leydig cells in SR-BIΔCT mice suggested that steroidogenic cells have an adaptor(s) functionally analogous to hepatic PDZK1. When SR-BIΔCT mice were crossed with apolipoprotein E KO mice (SR-BIΔCT/apoE KO), pathologies including hypercholesterolemia, macrocytic anemia, hepatic and splenic extramedullary hematopoiesis, massive splenomegaly, reticulocytosis, thrombocytopenia, and rapid-onset and fatal occlusive coronary arterial atherosclerosis and CHD (median age of death: 9 wk) were observed. These results provide new insights into the control of SR-BI in steroidogenic cells and establish SR-BIΔCT/apoE KO mice as a new animal model for the study of CHD.
Department of Pathology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Rinku
R
Pal
Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Qingen
Q
Ke
Department of Pathology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
German A
GA
Pihan
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts; and.
Ayce
A
Yesilaltay
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts; and.
Marsha L
ML
Penman
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts; and.
Li
L
Wang
Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, Massachusetts.
Chandramohan
C
Chitraju
Division of Cardiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
Peter M
PM
Kang
Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts; and.
Monty
M
Krieger
Department of Pathology and Center for Vascular Biology Research, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; okocher@bidmc.harvard.edu.
Olivier
O
Kocher
D000302:Adrenal Cortex / Q000378:metabolism*; D000748:Anemia, Macrocytic / Q000235:genetics; D000818:Animals; D001057:Apolipoproteins E / Q000235:genetics; D003324:Coronary Artery Disease / Q000235:genetics / Q000401:mortality; D003327:Coronary Disease / Q000235:genetics / Q000401:mortality; D054059:Coronary Occlusion / Q000235:genetics / Q000401:mortality; D005260:Female; D055879:Gene Knock-In Techniques; D006411:Hematopoiesis, Extramedullary / Q000235:genetics; D006937:Hypercholesterolemia / Q000235:genetics*; D015151:Immunoblotting; D007985:Leydig Cells / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000235:genetics; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D009154:Mutation; D010053:Ovary / Q000378:metabolism*; D016133:Polymerase Chain Reaction; D018110:Receptors, Lipoprotein / Q000235:genetics; D045262:Reticulocytosis / Q000235:genetics; D051122:Scavenger Receptors, Class B / Q000235:genetics*; D013163:Splenomegaly / Q000235:genetics; D013921:Thrombocytopenia / Q000235:genetics; D059467:Transcriptome
D001057:Apolipoproteins E; D008075:Lipoproteins, HDL; D018110:Receptors, Lipoprotein; C454739:Scarb1 protein, mouse; D051122:Scavenger Receptors, Class B; C031616:high density lipoprotein receptors
PDZ domains; SR-BI; atherosclerosis; myocardial infarction; steroidogenic organs
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