Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR that is shed by Furin
Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR that is shed by Furin
ABSTRACT The hepatic carbohydrate-recognizing asialoglycoprotein receptor (ASGR1) mediates the endocytosis/lysosomal degradation of desialylated glycoproteins following binding to terminal galactose/N-acetylgalactosamine. Human heterozygote-carriers of ASGR1-deletions exhibited ～34% lower risk of coronary artery disease and ～10-14% non-HDL-cholesterol reduction. Since PCSK9 is a major degrader of LDLR, the regulation of LDLR and/or PCSK9 by ASGR1 was studied. Thus, we investigated the role of endogenous/overexpressed ASGR1 on LDLR degradation and functionality by Western-blot and immunofluorescence in HepG2 na?ve and HepG2-PCSK9-knockout cells. ASGR1, like PCSK9, targets LDLR and both interact with/enhance the degradation of the receptor independently. Such lack of cooperativity between PCSK9 and ASGR1 on LDLR expression was confirmed in livers of wild-type (WT) versus Pcsk9-/- mice. ASGR1-knockdown in HepG2 na?ve cells significantly increased total (～1.2-fold) and cell-surface (～4-fold) LDLR protein. In HepG2-PCSK9-knockout cells ASGR1-silencing led to ～2-fold higher levels of LDLR protein and DiI-LDL uptake, associated with ～9-fold increased cell-surface LDLR. Overexpression of WT-ASGR1/2 reduced primarily the immature non-O-glycosylated LDLR (～110 kDa), whereas the triple Gln240/Trp244/Glu253 Ala-mutant (loss of carbohydrate-binding) reduced the mature form of the LDLR (～150 kDa), suggesting that ASGR1 binds the LDLR in sugar-dependent and -independent fashion. Furin sheds ASGR1 at RKMK103↓ into a secreted form, likely resulting in a loss-of-function on LDLR. LDLR is the first example of a liver-receptor ligand of ASGR1. Additionally, we demonstrate that lack of ASGR1 enhances LDLR levels and DiI-LDL incorporation, independently of PCSK9. Overall, silencing of ASGR1 and PCSK9 may lead to higher LDL-uptake by hepatocytes, thereby providing a novel approach to further reduce LDL-cholesterol.
Seidah Nabil G.、Girard Emmanuelle、Essalmani Rachid、Marcinkiewicz Jadwiga、Evagelidis Alexandra、Austin Richard C.、Susan-Resiga Delia、Derbali Rabeb M.、Roubtsova Anna、Byun Jae H.、Lebeau Paul F.
Montreal Clinical Research Institute (IRCM), affiliated to the University of Montreal, Laboratory of Biochemical NeuroendocrinologyMontreal Clinical Research Institute (IRCM), affiliated to the University of Montreal, Laboratory of Biochemical NeuroendocrinologyMontreal Clinical Research Institute (IRCM), affiliated to the University of Montreal, Laboratory of Biochemical NeuroendocrinologyMontreal Clinical Research Institute (IRCM), affiliated to the University of Montreal, Laboratory of Biochemical NeuroendocrinologyMontreal Clinical Research Institute (IRCM), affiliated to the University of Montreal, Laboratory of Biochemical NeuroendocrinologyDepartment of Medicine, Division of Nephrology, McMaster University, St. Joseph?ˉs Healthcare HamiltonMontreal Clinical Research Institute (IRCM), affiliated to the University of Montreal, Laboratory of Biochemical NeuroendocrinologyMontreal Clinical Research Institute (IRCM), affiliated to the University of Montreal, Laboratory of Biochemical NeuroendocrinologyMontreal Clinical Research Institute (IRCM), affiliated to the University of Montreal, Laboratory of Biochemical NeuroendocrinologyDepartment of Medicine, Division of Nephrology, McMaster University, St. Joseph?ˉs Healthcare HamiltonDepartment of Medicine, Division of Nephrology, McMaster University, St. Joseph?ˉs Healthcare Hamilton
基础医学生物化学分子生物学
ASGR1Cardiovascular diseaseLDL cholesterolLipid metabolismLiver
Seidah Nabil G.,Girard Emmanuelle,Essalmani Rachid,Marcinkiewicz Jadwiga,Evagelidis Alexandra,Austin Richard C.,Susan-Resiga Delia,Derbali Rabeb M.,Roubtsova Anna,Byun Jae H.,Lebeau Paul F..Asialoglycoprotein receptor 1 is a novel PCSK9-independent ligand of liver LDLR that is shed by Furin[EB/OL].(2025-03-28)[2025-04-26].https://www.biorxiv.org/content/10.1101/2021.04.11.439364.点此复制
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