Carboxy-terminal deletion of the HDL receptor reduces receptor levels in liver and steroidogenic tissues, induces hypercholesterolemia, and causes fatal heart disease
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Kocher_AJP_Heart_accepted_version.pdf
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Author(s)
Pal, Rinku
Ke, Qingen
Pihan, German A.
Chitraju, Chandramohan
Kang, Peter M.
Kocher, Olivier
Yesilaltay, Ayce
Penman, Marsha L
Wang, Li
Krieger, Monty
Date Issued
December 2016
Journal
American Journal of Physiology - Heart and Circulatory Physiology
Publisher
American Physiological Society
Citation
Pal, Rinku et al. “Carboxy-Terminal Deletion of the HDL Receptor Reduces Receptor Levels in Liver and Steroidogenic Tissues, Induces Hypercholesterolemia, and Causes Fatal Heart Disease.” American Journal of Physiology-Heart and Circulatory Physiology 311, 6 (December 2016): H1392–H1408 © 2016 the American Physiological Society
Version
Author's final manuscript
Abstract
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-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.
MIT Department
Massachusetts Institute of Technology. Department of Biology
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DOI of Published Version
https://doi.org/10.1152/ajpheart.00463.2016
