| First Author | Pal R | Year | 2016 |
| Journal | Am J Physiol Heart Circ Physiol | Volume | 311 |
| Issue | 6 | Pages | H1392-H1408 |
| PubMed ID | 27694217 | Mgi Jnum | J:237430 |
| Mgi Id | MGI:5812740 | Doi | 10.1152/ajpheart.00463.2016 |
| Citation | Pal R, et al. (2016) Carboxy-terminal deletion of the HDL receptor reduces receptor levels in liver and steroidogenic tissues, induces hypercholesterolemia, and causes fatal heart disease. Am J Physiol Heart Circ Physiol 311(6):H1392-H1408 |
| abstractText | 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 a 507Ala/STOP mutation that produces a truncated receptor (SR-BIDeltaCT). As expected, the dramatic reduction of hepatic receptor protein in SR-BIDeltaCT mice was similar to that in PDZK1 knockout (KO) mice. Unlike SR-BI KO females, SR-BIDeltaCT females were fertile. The severity of SR-BIDeltaCT 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-BIDeltaCT mice suggested that steroidogenic cells have an adaptor(s) functionally analogous to hepatic PDZK1. When SR-BIDeltaCT mice were crossed with apolipoprotein E KO mice (SR-BIDeltaCT/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-BIDeltaCT/apoE KO mice as a new animal model for the study of CHD. |
