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 a 507Ala/STOP mutation that produces a truncated receptor (SR-BICT). As expected, the dramatic reduction of hepatic receptor protein in SR-BICT mice was similar to that in PDZK1 knockout (KO) mice. Unlike SR-BI KO females, SR-BICT females were fertile. The severity of SR-BICT 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-BICT mice suggested that steroidogenic cells have an adaptor(s) functionally analogous to hepatic PDZK1. When SR-BICT mice were crossed with apolipoprotein E KO mice (SR-BICT/apoE KO), pathologies including hypercholesterolemia, macrocytic anemia, hepatic and splenic extramedullary hematopoiesis, massive splenomegaly, reticulocytosis, thrombocytopenia, and rapid-onse...
Source: AJP: Heart and Circulatory Physiology - Category: Cardiology Authors: Pal, R., Ke, Q., Pihan, G. A., Yesilaltay, A., Penman, M. L., Wang, L., Chitraju, C., Kang, P. M., Krieger, M., Kocher, O. Tags: SIGNALING AND STRESS RESPONSE Source Type: research
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