TY - JOUR
T1 - PCSK9 is not involved in the degradation of LDL receptors and BACE1 in the adult mouse brain
AU - Liu, Mali
AU - Wu, Guoxin
AU - Baysarowich, Jennifer
AU - Kavana, Michael
AU - Addona, George H.
AU - Bierilo, Kathleen K.
AU - Mudgett, John S.
AU - Pavlovic, Guillaume
AU - Sitlani, Ayesha
AU - Renger, John J.
AU - Hubbard, Brian K.
AU - Fisher, Timothy S.
AU - Zerbinatti, Celina V.
PY - 2010/9
Y1 - 2010/9
N2 - Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that regulates hepatic low-density lipoprotein receptor (LDLR) levels in humans. PCSK9 has also been shown to regulate the levels of additional membrane-bound proteins in vitro, including the very low-density lipoprotein receptor (VLDLR), apolipoprotein E receptor 2 (ApoER2) and the β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), which are all highly expressed in the CNS and have been implicated in Alzheimer's disease. To better understand the role of PCSK9 in regulating these additional target proteins in vivo, their steady-state levels were measured in the brain of wild-type, PCSK9-deficient, and human PCSK9 overexpressing transgenic mice. We found that while PCSK9 directly bound to recombinant LDLR, VLDLR, and apoER2 protein in vitro, changes in PCSK9 expression did not alter the level of these receptors in the mouse brain. In addition, we found no evidence that PCSK9 regulates BACE1 levels or APP processing in the mouse brain. In conclusion, our results suggest that while PCSK9 plays an important role in regulating circulating LDL cholesterol levels by reducing the number of hepatic LDLRs, it does not appear to modulate the levels of LDLR and other membrane-bound proteins in the adult mouse brain.
AB - Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that regulates hepatic low-density lipoprotein receptor (LDLR) levels in humans. PCSK9 has also been shown to regulate the levels of additional membrane-bound proteins in vitro, including the very low-density lipoprotein receptor (VLDLR), apolipoprotein E receptor 2 (ApoER2) and the β-site amyloid precursor protein (APP)-cleaving enzyme 1 (BACE1), which are all highly expressed in the CNS and have been implicated in Alzheimer's disease. To better understand the role of PCSK9 in regulating these additional target proteins in vivo, their steady-state levels were measured in the brain of wild-type, PCSK9-deficient, and human PCSK9 overexpressing transgenic mice. We found that while PCSK9 directly bound to recombinant LDLR, VLDLR, and apoER2 protein in vitro, changes in PCSK9 expression did not alter the level of these receptors in the mouse brain. In addition, we found no evidence that PCSK9 regulates BACE1 levels or APP processing in the mouse brain. In conclusion, our results suggest that while PCSK9 plays an important role in regulating circulating LDL cholesterol levels by reducing the number of hepatic LDLRs, it does not appear to modulate the levels of LDLR and other membrane-bound proteins in the adult mouse brain.
KW - β-site amyloid precursor protein-cleaving enzyme 1
KW - Alzheimer's disease
KW - Amyloid-β
KW - Atherosclerosis
KW - Low-density lipoprotein
KW - Proprotein convertase subtilisin/kexin type 9
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U2 - 10.1194/jlr.M006635
DO - 10.1194/jlr.M006635
M3 - Article
C2 - 20453200
AN - SCOPUS:77956844399
SN - 0022-2275
VL - 51
SP - 2611
EP - 2618
JO - Journal of Lipid Research
JF - Journal of Lipid Research
IS - 9
ER -