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 ((505)QEAKL(509)) must bind to the cytoplasmic adaptor PDZK1 for normal hepatic-but not steroidogenic cellexpression 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 (507)Ala/STOP mutation that produces a truncated receptor (SR-BI Delta CT). As expected, the dramatic reduction of hepatic receptor protein in SR-BI Delta CT mice was similar to that in PDZK1 knockout (KO) mice. Unlike SR-BI KO females, SR-BI Delta CT females were fertile. The severity of SR-BI Delta CT 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-BI Delta CT mice suggested that steroidogenic cells have an adaptor(s) functionally analogous to hepatic PDZK1. When SR-BI Delta CT mice were crossed with apolipoprotein E KO mice (SR-BI Delta CT/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-BI Delta CT/apoE KO mice as a new animal model for the study of CHD.