TY - JOUR
T1 - Plasma PCSK9 preferentially reduces liver LDL receptors in mice
AU - Grefhorst, Aldo
AU - McNutt, Markey C.
AU - Lagace, Thomas A.
AU - Horton, Jay D.
PY - 2008/6/1
Y1 - 2008/6/1
N2 - Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that regulates the expression of LDL receptor (LDLR) protein. Gain-of-function mutations in PCSK9 cause hypercholesterolemia, and loss-offunction mutations result in lower plasma LDL-cholesterol. Here, we investigate the kinetics and metabolism of circulating PCSK9 relative to tissue levels of LDLRs. The administration of recombinant human PCSK9 (32 μg) to mice by a single injection reduced hepatic LDLRs by ∼90% within 60 min, and the receptor levels returned to normal within 6 h. The half-life of the PCSK9 was estimated to be ∼5 min. Continuous infusion of PCSK9 (32 μg/h) into wild-type mice caused a ∼90% reduction in hepatic LDLRs within 2 h and no associated change in the level of LDLR in the adrenals. Parallel studies were performed using a catalytically inactive form of PCSK9, PCSK9(S386A), and similar results were obtained. Infusion of PCSK9(D374Y), a gain-of-function mutation, resulted in accelerated clearance of the mutant PCSK9 and a greater reduction in hepatic LDLRs. Combined, these data suggest that exogenously administrated PCSK9 in plasma preferentially reduces LDLR protein levels in liver at concentrations found in human plasma and that PCSK9's action on the LDLR is not dependent on catalytic activity in vivo.
AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that regulates the expression of LDL receptor (LDLR) protein. Gain-of-function mutations in PCSK9 cause hypercholesterolemia, and loss-offunction mutations result in lower plasma LDL-cholesterol. Here, we investigate the kinetics and metabolism of circulating PCSK9 relative to tissue levels of LDLRs. The administration of recombinant human PCSK9 (32 μg) to mice by a single injection reduced hepatic LDLRs by ∼90% within 60 min, and the receptor levels returned to normal within 6 h. The half-life of the PCSK9 was estimated to be ∼5 min. Continuous infusion of PCSK9 (32 μg/h) into wild-type mice caused a ∼90% reduction in hepatic LDLRs within 2 h and no associated change in the level of LDLR in the adrenals. Parallel studies were performed using a catalytically inactive form of PCSK9, PCSK9(S386A), and similar results were obtained. Infusion of PCSK9(D374Y), a gain-of-function mutation, resulted in accelerated clearance of the mutant PCSK9 and a greater reduction in hepatic LDLRs. Combined, these data suggest that exogenously administrated PCSK9 in plasma preferentially reduces LDLR protein levels in liver at concentrations found in human plasma and that PCSK9's action on the LDLR is not dependent on catalytic activity in vivo.
KW - LDL-cholesterol
KW - Proprotein convertase subtilisin/kexin type 9
KW - Sterol-regulatory element binding protein
UR - http://www.scopus.com/inward/record.url?scp=48349092091&partnerID=8YFLogxK
U2 - https://doi.org/10.1194/jlr.M800027-JLR200
DO - https://doi.org/10.1194/jlr.M800027-JLR200
M3 - Article
C2 - 18354138
SN - 0022-2275
VL - 49
SP - 1303
EP - 1311
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 6
ER -