Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.4.23.5 (cathepsin D)
 4,130 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The transport and removal of lipoproteins from the blood in the laying hen is of particular interest because it is a system in which the massive transport of lipid to one organ (the ovary) coexists with regulatory mechanisms for the control of lipid homeostasis in extraovarian tissues. In order to achieve this dual task, the laying hen expresses dichotomous receptor-mediated pathways. On one hand, very low density lipoproteins (VLDL) and vitellogenin (VTG), which together form over 95% of the lipid in a fully grown oocyte (i.e., an egg yolk), are transported into oocytes via a 95-kDa receptor protein. This receptor, termed oocyte VLDL/VTG receptor, is exclusively produced in growing oocytes and is absent from somatic cells. It shows a high degree of structural similarity to other members of the so-called low density lipoprotein (LDL) receptor family, but in contrast to the LDL receptor, its expression is not suppressed by sterols. On the other hand, somatic cells, but not oocytes, synthesize a 130-kDa receptor that recognizes VLDL-derived, cholesterol-rich lipoproteins. This receptor is the functional analogue to the mammalian LDL receptor in that it mediates, at least in part, extraoocytic lipid homeostasis. The somatic LDL receptor of the chicken recognizes apolipoprotein (apo)B, but not VTG, in accordance with VTG's exclusive routing to growing oocytes. Within oocytes, both apoB of VLDL and VTG undergo limited specific postendocytic proteolytic processing. Recent studies have shown that this breakdown of macromolecular plasma precursor molecules is catalyzed by an endosomal form of cathepsin D and is a key event in the formation of yolk, the major nutrient source for the developing embryo.
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PMID:Lipoprotein receptors in oocyte growth. 131 30

Preincubation of human skin fibroblasts in the presence of 10(-6)-10(-5) mol/l glucocorticoids (dexamethasone) causes a concentration and time-dependent increase of receptor-mediated internalisation of [125I]LDL. This increase is due to a glucocorticoid-specific stimulation by 40-50% of LDL receptor synthesis as demonstrated by an increased incorporation of [35S]methionine into immune precipitated receptor protein. In contrast the rate of synthesis of total cell protein and of lysosomal cathepsin D is not significantly influenced by dexamethasone. The increased LDL receptor synthesis is accompanied by an enhanced synthesis of cholesterol from [2-3H]mevalonolactone and [1-14C]acetate. The glucocorticoid-induced enhancement of LDL receptor and cholesterol synthesis is abolished by preincubation of the cells with dexamethasone in combination with 25-hydroxycholesterol.
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PMID:Glucocorticoid-stimulated biosynthesis of low density lipoprotein receptor in cultured fibroblasts. 299 17

We asked at what point in the metabolic cascade of very low density lipoproteins (VLDL) to low density lipoproteins (LDL) the accessibility of proteolytic cleavage sites in B-100 changes, and we evaluated the effect of hypertriglyceridemia on the proteolytic accessibility, secondary structure, and receptor-binding affinity of B-100 in LDL subspecies of varying density. Limited proteolysis with Staphylococcus aureus V8 protease and cathepsin D identified the density (about 1.033 g/ml) between two LDL subspecies, designated LDL-1 and -2, as the transition point during VLDL metabolism of both normolipidemic (N-) and hypertriglyceridemic (HTG-) subjects at which accessibility to protease attack changed in three peptide regions of B-100. Hypertriglyceridemia greatly altered proteolytic accessibility of B-100 in the denser LDL subspecies. Specifically, B-100 in HTG-LDL exposed more cleavage sites than in N-LDL, including two novel sites, approximately 120 and approximately 130 kDa from the NH2 terminus in the small and dense subspecies (designated LDL-4, -4.5 or -5, d = 1.048-1.062 g/ml). Analysis of circular dichroic spectra indicated no difference in helical content between B-100 in N- and HTG-LDL but showed a greater content of beta-structure in HTG-LDL. Binding affinity for the LDL receptor of human fibroblasts decreased markedly with increasing density among HTG-LDL subspecies (by approximately 50% for LDL-4.5 or -5). We conclude that the changes in proteolytic accessibility observed between LDL-1 and -2 and in LDL-4, -4.5, or -5 indicate significant differences in local conformation of B-100 at specific peptide regions. The association of exposure of more cleavage sites, especially novel sites in the NH2-terminal regions, with greatly decreased receptor-binding affinity in LDL-4.5 or -5 suggests that altered local conformation in B-100 apart from the putative receptor-binding domain might affect interaction with the receptor.
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PMID:Conformational differences in human apolipoprotein B-100 among subspecies of low density lipoproteins (LDL). Association of altered proteolytic accessibility with decreased receptor binding of LDL subspecies from hypertriglyceridemic subjects. 796 78

Production of alpha-1-antitrypsin (AAT) by human monocytes is an important factor in controlling tissue damage by proteases in the microenvironment of inflammation. Increases, of four- to eightfold, in numbers of macrophages and levels of AAT and its cleavage fragments have been found in various inflammatory loci. We have found that the C-terminal peptide (C-36) of AAT, produced by specific proteinase cleavage when added in its fibrillar form at concentrations >/=5 microM to monocytes in culture for 24 h, significantly increases low density lipoprotein (LDL) binding and uptake, up-regulates levels of LDL receptors and also induces proinflammatory cytokine (interleukin-1, interleukin-6 and tumour necrosis factor alpha) production and glutathione reductase activity. Because it is known that various cells selectively internalize surface receptors and their ligands through receptor-mediated endocytosis via clathrin-coated pits, we tested whether antibodies raised against the clathrin heavy chain would block the effects of the fibrillar form of C-36 on human monocytes in culture. Addition of excess anti-(clathrin HC) with 10 microM fibrillar C-36 diminished the stimulatory effects of the latter on LDL binding, uptake and LDL receptor levels. In contrast, however, in the presence of anti-(clathrin HC), the potentially cytotoxic effects of fibrils, such as induction of cytokines, free radicals and cytosolic activity of cathepsin D, were much greater than those observed when cells were treated with fibrils alone. These results suggest that endocytosis is the pathway by which C-36 fibrils upregulate LDL receptors, and may be the natural mechanism for fibril clearance. We infer that human monocytes clear C-36 fibrils by a clathrin-dependent pathway, presumably endocytotic, and that loss of this pathway amplifies the cytotoxic effects of the fibrils by increasing their availability to other specific or nonspecific sites through which they exert their cytotoxic effects.
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PMID:Human monocyte activation by cleaved form of alpha-1-antitrypsin involvement of the phagocytic pathway. 1051 80

LRP1 (LDL receptor-related protein-1) is a ubiquitous receptor with both cell signaling and ligand endocytosis properties. In the liver, LRP1 serves as a chylomicron remnant receptor and also participates in the transport of extracellular cathepsin D to the lysosome for prosaposin activation. The current study showed that in comparison with wild type mice, hepatocyte-specific LRP1 knock-out (hLrp1(-/-)) mice were more susceptible to fasting-induced lipid accumulation in the liver. Primary hepatocytes isolated from hLrp1(-/-) mice also accumulated more intracellular lipids and experienced higher levels of endoplasmic reticulum (ER) stress after palmitate treatment compared with similarly treated hLrp1(+/+) hepatocytes. Palmitate-treated hLrp1(-/-) hepatocytes displayed similar LC3-II levels, but the levels of p62 were elevated in comparison with palmitate-treated hLrp1(+/+) hepatocytes, suggesting that the elevated lipid accumulation in LRP1-defective hepatocytes was not due to defects in autophagosome formation but was due to impairment of lipophagic lipid hydrolysis in the lysosome. Additional studies showed increased palmitate-induced oxidative stress, mitochondrial and lysosomal permeability, and cell death in hLrp1(-/-) hepatocytes. Importantly, the elevated cell death and ER stress observed in hLrp1(-/-) hepatocytes were abrogated by E64D treatment, whereas inhibiting ER stress diminished cell death but not lysosomal permeabilization. Taken together, these results documented that LRP1 deficiency in hepatocytes promotes lipid accumulation and lipotoxicity through lysosomal-mitochondrial permeabilization and ER stress that ultimately result in cell death. Hence, LRP1 dysfunction may be a major risk factor in fatty liver disease progression.
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PMID:LRP1 Protein Deficiency Exacerbates Palmitate-induced Steatosis and Toxicity in Hepatocytes. 2731 62