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Resident mouse peritoneal macrophages were shown to take up and degrade acetylated (125)I-labeled low density lipoprotein ((125)I-acetyl-LDL) in vitro at rates that were 20-fold greater than those for the uptake and degradation of (125)I-LDL. The uptake of (125)I-acetyl-LDL and its subsequent degradation in lysosomes were attributable to a high-affinity,(More)
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a member of the proteinase K subfamily of subtilases that reduces the number of LDL receptors (LDLRs) in liver through an undefined posttranscriptional mechanism. We show that purified PCSK9 added to the medium of HepG2 cells reduces the number of cell-surface LDLRs in a dose- and time-dependent(More)
A cDNA encoding a cytoplasmic oxysterol binding protein was expressed at high levels by transfection in animal cells. This protein binds oxysterols such as 25-hydroxycholesterol that regulate sterol metabolism by transcriptional and posttranscriptional effects. In the transfected cells, some of the oxysterol binding protein (OSBP) was distributed diffusely(More)
PCSK9 encodes proprotein convertase subtilisin/kexin type 9a (PCSK9), a member of the proteinase K subfamily of subtilases. Missense mutations in PCSK9 cause an autosomal dominant form of hypercholesterolemia in humans, likely due to a gain-of-function mechanism because overexpression of either WT or mutant PCSK9 reduces hepatic LDL receptor protein (LDLR)(More)
Mouse peritoneal macrophages take up acetylated human low density lipoprotein by receptor-mediated endocytosis, hydrolyze its cholesteryl esters in lysosomes, and re-esterify the cholesterol in the cytoplasm. The re-esterified cholesterol accumulates as cytoplasmic lipid droplets that resemble the droplets seen in “foam cells” of atherosclerotic lesions. In(More)
SREBP cleavage-activating protein (SCAP) stimulates the proteolytic cleavage of membrane-bound SREBPs, thereby initiating the release of NH2-terminal fragments from cell membranes. The liberated fragments enter the nucleus and stimulate transcription of genes involved in synthesis and uptake of cholesterol and fatty acids. Sterols repress cleavage of(More)
The ability of mouse peritoneal macrophages to hydrolyze and excrete cytoplasmic cholesteryl ester droplets was studied. The macrophages were loaded with cholesteryl esters by incubation with acetylated low density lipoprotein (acetyl-LDL), which is internalized by adsorptive endocytosis. The cholesteryl esters of acetyl-LDL are hydrolyzed within lysosomes(More)
A 39-kDa protein of unknown function has previously been reported to copurify with the low density lipoprotein receptor-related protein (LRP)/alpha 2-macroglobulin receptor. In this study we demonstrate that a recombinant 39-kDa fusion protein can reversibly bind to the 515-kDa subunit of the LRP/alpha 2-macroglobulin receptor. This interaction inhibits the(More)
The cholesterol analogue 25-hydroxycholesterol kills animal cells by blocking the proteolytic activation of two sterol-regulated transcription factors designated sterol regulatory element binding protein-1 and -2 (SREBP-1 and SREBP-2). These proteins, each approximately 1150 amino acids in length, are embedded in the membranes of the nucleus and endoplasmic(More)
Macrophages isolated from a variety of organs in several animal species exhibit high affinity binding sites that recognize chemically modified proteins. One of these binding sites recognizes human plasma low density lipoprotein (LDL) in which the positive charges on the epsilon-amino groups of lysine have been removed or neutralized by chemical(More)