Apolipoprotein E (apoE) is hypothesized to mediate lipoprotein clearance by binding to two receptors: (i) the low density lipoprotein receptor (LDLR) and (ii) a chylomicron remnant receptor. To test this hypothesis, we have compared plasma lipoproteins in mice that are homozygous for targeted disruptions of the genes for apoE [apoE(-/-)], the LDLR [LDLR(-/-)], and both molecules [poE(-/-); LDLR...

OBJECTIVE Natural killer (NK) cells have been identified in human vascular pathologies. In this study, we identified NK cells in aortic root atherosclerotic lesions of low density lipoprotein (LDL) receptor-deficient (LDLr-/-) mice. To characterize the role of NK cell-mediated cytolysis in atherosclerosis, we generated C57Bl/6 double-mutant mice by crossing LDLr-/- mice with NK cell-defective L...

Elevated low density lipoprotein cholesterol (LDL-C) and reduced high density lipoprotein cholesterol (HDL-C) concentrations are independent risk factors for coronary heart disease. We have previously demonstrated that overexpression of an enzyme with a well established role in HDL metabolism, lecithin:cholesterol acyltransferase (LCAT), in New Zealand White rabbits not only raises HDL-C concen...

Low-density lipoprotein (LDL) receptor (LDLR) and LDLR-related protein (LRP) are members of the LDLR family of endocytic receptors. LRP recognizes a wide spectrum of structurally and functionally unrelated ligands, including coagulation factor VIII (FVIII). In contrast, the ligand specificity of LDLR is restricted to apolipoproteins E and B-100. Ligand binding to the LDLR family is inhibited by...

Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease that regulates low density lipoprotein receptor (LDLR) protein levels. The mechanisms of this action, however, remain to be defined. We show here that recombinant human PCSK9 expressed in HEK293 cells was readily secreted into the medium, with the prosegment associated with the C-terminal domain. Secreted PCSK9 mediated cell su...

BACKGROUND AND PURPOSE Mutations in the low-density lipoprotein receptor (LDLR) gene cause familial hypercholesterolaemia in humans and deletion of the LDLR induces lesion development in mice fed a high-fat diet. LDLR expression is predominantly regulated by sterol regulatory element-binding protein 2 (SREBP2). Fenofibrate, a peroxisome proliferator-activated receptor alpha (PPARalpha) ligand, ...

The low-density lipoprotein (LDL) receptor (LDLR) binds to and internalizes lipoproteins that contain apolipoproteinB100 (apoB100) or apolipoproteinE (apoE). Internalization of the apoB100 lipoprotein ligand, LDL, requires the FDNPVY(807) sequence on the LDLR cytoplasmic domain, which binds to the endocytic machinery of coated pits. We show here that inactivation of the FDNPVY(807) sequence by ...

Acquiring sufficient amounts of high-quality cells remains an impediment to cell-based therapies. Induced pluripotent stem cells (iPSC) may be an unparalleled source, but autologous iPSC likely retain deficiencies requiring correction. We present a strategy for restoring physiological function in genetically deficient iPSC utilizing the low-density lipoprotein receptor (LDLR) deficiency Familia...

Low-density lipoprotein receptor (LDLR) internalization clears cholesterol-laden LDL particles from circulation in humans. Defects in clathrin-dependent LDLR endocytosis promote elevated serum cholesterol levels and can lead to atherosclerosis. However, our understanding of the mechanisms that control LDLR uptake remains incomplete. To identify factors critical to LDLR uptake, we pursued a geno...

RATIONALE Familial hypercholesterolemia is a genetic disorder that arises because of loss-of-function mutations in the low-density lipoprotein receptor (LDLR) and homozygous familial hypercholesterolemia is a candidate for gene therapy using adeno-associated viral vectors. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and inducible degrader of LDLR (IDOL) negatively regulate LDLR protei...