Cathepsin D, a Lysosomal Protease, Regulates ABCA1-mediated Lipid Efflux

Haidar, Bassam; Kiss, Robert S.; Sarov‐Blat, Lea; Brunet, Roch; Harder, Christopher J.; McPherson, Ruth; Marcel, Yves L.

doi:10.1074/jbc.m605095200

Cited by 69 publications

(55 citation statements)

References 69 publications

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“…Suppression of Ctsd expression by a specific inhibitor, pepstatin A, or by specific short hairpin RNA reduces Abca1 expression and apoA-I-mediated cholesterol and phospholipid efflux in a dose-dependent manner. The mechanism of action of Ctsd includes the activation of prosaposins and its maturation into saposins, which regulates transport of glycosphingolipids and cholesterol through the late endosomes, which in turn regulates Abca1 expression and activity (40). Here we demonstrated that Ctsd activity was also responsible for the increased Abca1 observed in Npc1-null hepatocytes (Fig.…”

Section: Discussionsupporting

confidence: 54%

“…We have also shown that Npc1 inactivation increases Ctsd expression both transcriptionally and post-transcriptionally in Npc1-null hepatocytes, whereas no such effect is seen in macrophages. Ctsd, an aspartic protease involved in the degradation of proteins in the lysosome-late endosome compartment, has been recently identified by our laboratory as a positive enhancer of Abca1 protein expression (40). Suppression of Ctsd expression by a specific inhibitor, pepstatin A, or by specific short hairpin RNA reduces Abca1 expression and apoA-I-mediated cholesterol and phospholipid efflux in a dose-dependent manner.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, we identified a lysosomal protease, cathepsin D (Ctsd), whose expression positively regulated Abca1 protein expression (40). Here, Ctsd expression in Npc1-null hepatocytes and macrophages was measured by RT-PCR and Western blot (Fig.…”

Section: The Differential Expression Of Genes Regulating Lipid Transpmentioning

confidence: 99%

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Differential Regulation of ATP Binding Cassette Protein A1 Expression and ApoA-I Lipidation by Niemann-Pick Type C1 in Murine Hepatocytes and Macrophages

Wang

Franklin

Sundaram

et al. 2007

Journal of Biological Chemistry

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Niemann-Pick type C1 (Npc1) protein inactivation results in lipid accumulation in late endosomes and lysosomes, leading to a defect of ATP binding cassette protein A1 (Abca1)-mediated lipid efflux to apolipoprotein A-I (apoA-I) in macrophages and fibroblasts. However, the role of Npc1 in Abca1-mediated lipid efflux to apoA-I in hepatocytes, the major cells contributing to HDL formation, is still unknown. Here we show that, whereas lipid efflux to apoA-I in Npc1-null macrophages is impaired, the lipidation of endogenously synthesized apoA-I by low density lipoprotein-derived cholesterol or de novo synthesized cholesterol or phospholipids in Npc1-null hepatocytes is significantly increased by about 1-, 3-, and 8-fold, respectively. The increased cholesterol efflux reflects a major increase of Abca1 protein in Npc1-null hepatocytes, which contrasts with the decrease observed in Npc1-null macrophages. The increased Abca1 expression is largely post-transcriptional, because Abca1 mRNA is only slightly increased and Lxr␣ mRNA is not changed, and Lxr␣ target genes are reduced. This differs from the regulation of Abcg1 expression, which is up-regulated at both mRNA and protein levels in Npc1-null cells. Abca1 protein translation rate is higher in Npc1-null hepatocytes, compared with wild type hepatocytes as measured by [35 S]methionine incorporation, whereas there is no difference for the degradation of newly synthesized Abca1 in these two types of hepatocytes. Cathepsin D, which we recently identified as a positive modulator of Abca1, is markedly increased at both mRNA and protein levels by Npc1 inactivation in hepatocytes but not in macrophages. Consistent with this, inhibition of cathepsin D with pepstatin A reduced the Abca1 protein level in both Npc1-inactivated and WT hepatocytes. Therefore, Abca1 expression is specifically regulated in hepatocytes, where Npc1 activity modulates cathepsin D expression and Abca1 protein translation rate. Niemann-Pick type C (NPC)2 disease is an autosomal lipid storage disease resulting from mutations in either the Npc1 (95% of families) or Npc2 genes (1-3). It is characterized by progressive hepatosplenomegaly and neurodegeneration, leading to premature death (4, 5). The exact function of both proteins remains unknown, but there is much evidence that they facilitate the transport of lipids, primarily cholesterol, from late endosome to the Golgi apparatus, endoplasmic reticulum (ER), mitochondria, and plasma membrane (6, 7). Thus the storage involves the accumulation of unesterified cholesterol, sphingolipids, and other lipids within the endosomal/lysosomal compartments of cells in almost all body tissues (8). Impaired cholesterol traffic in NPC disease cells prevents the normal down-regulation of endogenous cholesterol synthesis and the low density lipoprotein (LDL) receptor (9, 10), through the interruption of normal cholesterol regulation by sterol regulatory element-binding protein at the ER and the interruption of generation of LDL cholesterol-derived oxysterols in the mitochond...

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Section: Discussionsupporting

confidence: 54%

Section: Discussionmentioning

confidence: 99%

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Differential Regulation of ATP Binding Cassette Protein A1 Expression and ApoA-I Lipidation by Niemann-Pick Type C1 in Murine Hepatocytes and Macrophages

Wang

Franklin

Sundaram

et al. 2007

Journal of Biological Chemistry

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“…Hepatic LRP1 Deficiency Alters Cathepsin D and Prosaposin Processing-Membrane localization of ABCA1 is regulated by glycosphingolipid metabolism, with defective lysosomal conversion of hexosylceramides, including galactosyl-, glucosyl-, and lactosylceramide, to ceramide, resulting in reduced trafficking of ABCA1 to the cell surface (37). Comparison of total and hLrp1 ϩ/ϩ mice were cultured in serum-free medium for 20 h. A, equal volumes of conditioned media were resolved by SDS-polyacrylamide gels and immunoblotted using antibodies against apoA-I and apoE.…”

Section: Lrp1 Deficiency Alters Apolipoprotein Secretion and Decreasementioning

confidence: 99%

Hepatic Deficiency of Low Density Lipoprotein Receptor-related Protein-1 Reduces High Density Lipoprotein Secretion and Plasma Levels in Mice

Basford

Wancata

Hofmann

et al. 2011

Journal of Biological Chemistry

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The low density lipoprotein receptor-related protein-1 (LRP1) is known to serve as a chylomicron remnant receptor in the liver responsible for the binding and plasma clearance of apolipoprotein E-containing lipoproteins. Previous in vitro studies have provided evidence to suggest that LRP1 expression may also influence high density lipoprotein (HDL) metabolism. The current study showed that liver-specific LRP1 knock-out (hLrp1 Low density lipoprotein receptor-related protein-1 (LRP1), 2 the largest member of the low density lipoprotein (LDL) receptor gene family, is composed of an extracellular 515-kDa polypeptide covalently linked to an 85-kDa polypeptide that spans the plasma membrane and extrudes into the cytosol (1). The extracellular domain of LRP1 includes 31 cysteine-rich complement-like repeats responsible for ligand binding and 22 cysteine-rich repeats that are homologous to the ␤-propeller domains in the epidermal growth factor precursor protein (1).Structural similarities between these cysteine-rich repeats of LRP1 and the ligand-binding domain of the LDL receptor have led to its identification as the chylomicron remnant receptor responsible for hepatic clearance of apolipoprotein E (apoE)-containing lipoproteins (2-5). Subsequent studies revealed that LRP1 is also capable of binding and mediating cellular uptake of other ligands, including activated ␣ 2 -macroglobulin, proteaseprotease inhibitor complexes, and lysosomal hydrolases such as the saposin precursor protein prosaposin (6, 7). Additionally, recent evidence also established LRP1 as an integrator of signal transduction events in cell regulation, including the modulation of PDGF receptor and TGF␤-1 receptor activation (8 -10), Wnt signaling (11), and participation in neurotransmitter-dependent postsynaptic responses (12). The function of LRP1 as a cargo transporting endocytic receptor or a cell signaling receptor appears to be tissue-and cell type-specific (13). For example, LRP1 serves as a signaling receptor during adipocyte differentiation via activation of Wnt5a/␤-catenin pathway and inhibition of acetyl-CoA carboxylase phosphorylation (11). In contrast, LRP1 is a cargo transporting receptor in mature adipocytes responsible for the uptake of lipid nutrients from triglyceride-rich lipoproteins for storage and utilization (14). The function of LRP1 in smooth muscle cells is also unrelated to cargo transport, but its modulation of PDGF receptor and TGF␤-1 receptor activities is essential for maintenance of vascular reactivity and limiting hypercholesterolemia-induced atherosclerosis and injury-induced neointimal hyperplasia (8 -10). In the neurons of dendritic synapses, LRP1 interacts with the N-methyl-D-aspartate receptor to modulate neuronal calcium signaling (15). Neuronal expression of LRP1 also activates protein kinase B/Akt signaling in protection against stress-induced apoptosis (16). In addition, LRP1 has been shown to participate in focal adhesion and cell migration via direct association with integrins and/or modulation of calreticu...

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“…Recently, it has been shown that CD expression is reduced in macrophages of low HDLcholesterol subjects and the role of CD in intracellular metabolism and transport of phospholipids and cholesterol was suggested [166].…”

Section: Atherosclerosismentioning

confidence: 99%

Cathepsin D—Many functions of one aspartic protease

Beneš

Větvička

Fusek

2008

Critical Reviews in Oncology/Hematology

540

474

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For years, it has been held that cathepsin D (CD) is involved in rather nonspecific protein degradation in a strongly acidic milieu of lysosomes. Studies with CD knock-out mice revealed that CD is not necessary for embryonal development but it is indispensable for postnatal tissue homeostasis. Mutation that abolishes CD enzymatic activity causes neuronal ceroid lipofuscinosis (NCL) characterized by severe neurodegeneration, developmental regression, visual loss and epilepsy in both animals and humans.In the last decade, however, an increasing number of studies demonstrated that enzymatic function of CD is not restricted solely to acidic milieu of lysosomes with important consequences in regulation of apoptosis. In addition to CD enzymatic activity, it has been shown that apoptosis is also regulated by catalytically inactive mutants of CD which suggests that CD interacts with other important molecules and influences cell signaling.Moreover, procathepsin D, secreted from cancer cells, acts as a mitogen on both cancer and stromal cells and stimulates their pro-invasive and pro-metastatic properties. Numerous studies found that pCD/CD level represents an independent prognostic factor in a variety of cancers and is therefore considered to be a potential target of anti-cancer therapy.Studies dealing with functions of cathepsin D are complicated by the fact that there are several simultaneous forms of CD in a cell -pCD, intermediate enzymatically active CD and mature heavy and light chain CD. It became evident that these forms may differently regulate the above mentioned processes.In this article, we review the possible functions of CD and its various forms in cells and organisms during physiological and pathological conditions.

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Cathepsin D, a Lysosomal Protease, Regulates ABCA1-mediated Lipid Efflux

Cited by 69 publications

References 69 publications

Differential Regulation of ATP Binding Cassette Protein A1 Expression and ApoA-I Lipidation by Niemann-Pick Type C1 in Murine Hepatocytes and Macrophages

Differential Regulation of ATP Binding Cassette Protein A1 Expression and ApoA-I Lipidation by Niemann-Pick Type C1 in Murine Hepatocytes and Macrophages

Hepatic Deficiency of Low Density Lipoprotein Receptor-related Protein-1 Reduces High Density Lipoprotein Secretion and Plasma Levels in Mice

Cathepsin D—Many functions of one aspartic protease

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