Apolipoprotein A-II is catabolized in the kidney as a function of its plasma concentration

Dugué-Pujol, Sonia; Rousset, Xavier; Château, Danielle; Pastier, D.; Klein, Christophe; Demeurie, Jeannine; Cywiner-Golenzer, C; Chabert, M.; Verroust, P; Chambaz, Jean; Châtelet, F; Kalopissis, Athina-Despina

doi:10.1194/jlr.m700089-jlr200

Cited by 14 publications

(5 citation statements)

References 38 publications

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“…Apolipoprotein M is a lipocalin with antiatherogenic properties that is present in pre-β-HDL particles, chylomicrons, VLDLs and LDLs secreted by the liver and the kidney that use megalin as a receptor Faber et al, 2006;Dahlback and Nielsen, 2009). In addition to apoM, megalin with its coreceptor cubilin, internalizes apoA-I and apoA-II, structural components of HDLs (Hammad et al, 2000;Dugue-Pujol et al, 2007). Taken together, these data indicate that megalin contributes to the regulation of HDL metabolism.…”

Section: Role Of Megalin In Cholesterol Homeostasismentioning

confidence: 63%

New Insights into the Roles of Megalin/LRP2 and the Regulation of its Functional Expression

2011

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Since the discovery of the low-density lipoprotein receptor (LDLR) and its association with familial hypercholesterolemia in the early 1980s, a family of structurally related proteins has been discovered that has apolipoprotein E as a common ligand, and the broad functions of its members have been described. LRP2, or megalin, is a member of the LDLR family and was initially called gp330. Megalin is an endocytic receptor expressed on the apical surface of several epithelial cells that internalizes a variety of ligands including nutrients, hormones and their carrier proteins, signaling molecules, morphogens, and extracellular matrix proteins. Once internalized, these ligands are directed to the lysosomal degradation pathway or transported by transcytosis from one side of the cell to the opposite membrane. The availability of megalin at the cell surface is controlled by several regulatory mechanisms, including the phosphorylation of its cytoplasmic domain by GSK3, the proteolysis of the extracellular domain at the cell surface (shedding), the subsequent intramembrane proteolysis of the transmembrane domain by the gamma-secretase complex, and exosome secretion. Based on the important roles of its ligands and its tissue expression pattern, megalin has been recognized as an important component of many pathological conditions, including diabetic nephropathy, Lowe syndrome, Dent disease, Alzheimer's disease (AD) and gallstone disease. In addition, the expression of megalin and some of its ligands in the central and peripheral nervous system suggests a role for this receptor in neural regeneration processes. Despite its obvious importance, the regulation of megalin expression is poorly understood. In this review, we describe the functions of megalin and its association with certain pathological conditions as well as the current understanding of the mechanisms that underlie the control of megalin expression.

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Section: Role Of Megalin In Cholesterol Homeostasismentioning

confidence: 63%

New Insights into the Roles of Megalin/LRP2 and the Regulation of its Functional Expression

2011

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“…We analysed the expression of other receptors that have been described to participate in lipid internalization. Indeed, LRP2 contributes to HDL metabolism by internalizing ApoA-I and ApoA-II, which are structural components of HDLs 31; LRP8 is a component of the interactions between the endothelium and monocytes and leucocyte transendothelial migration, foam cell formation and activation of platelet aggregation 32; and the classical LDLR is known for its involvement in lipoprotein transport and plasmatic LDL cholesterol clearance 33. Lrp2 , Lrp8 and Ldlr expression levels were down-regulated in aortas from HC Lrp5 − / − indicating that they were not contributing to the observed lipid deposition in mice aortas.…”

Section: Discussionmentioning

confidence: 99%

LRP5 deficiency down‐regulates Wnt signalling and promotes aortic lipid infiltration in hypercholesterolaemic mice

Borrell-Pagès

Romero

2015

J Cellular Molecular Medi

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Low-density lipoprotein receptor-related protein 5 (LRP5) is a member of the LDLR family that orchestrates cholesterol homoeostasis. The role of LRP5 and the canonical Wnt pathway in the vascular wall of dyslipidaemic animals remains unknown. In this study, we analysed the role of LRP5 and the Wnt signalling pathway in mice fed a hypercholesterolaemic diet (HC) to trigger dyslipidaemia. We show that Lrp5−/− mice had larger aortic lipid infiltrations than wild-type mice, indicating a protective role for LRP5 in the vascular wall. Three members of the LDLR family, Lrp1, Vldlr and Lrp6, showed up-regulated gene expression levels in aortas of Lrp5−/− mice fed a hypercholesterolaemic diet. HC feeding in Lrp5−/− mice induced higher macrophage infiltration in the aortas and accumulation of inflammatory cytokines in blood. Wnt/β-CATENIN signalling proteins were down-regulated in HC Lrp5−/− mice indicating that LRP5 regulates the activation of Wnt signalling in the vascular wall. In conclusion, our findings show that LRP5 and the canonical Wnt pathway down-regulation regulate the dyslipidaemic profile by promoting lipid and macrophage retention in the vessel wall and increasing leucocyte-driven systemic inflammation.

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“…Small HDL particles, of a diameter of less than 8 nm, are filtered in the glomeruli to the urine, and then taken up by the receptors cubulin and megalin in the proximal tubule to be degraded in lysosomes [8]. The identity of the HDL proteins that mediate binding to megalin are debated, as some claim that these are only Apo-AI and Apo-AIV [14], while others present evidence for Apo-AII binding as well [15]. Hepatic degradation has also been suggested [8], although the receptors mediating this elimination pathway remain elusive.…”

Section: Hdl Functionmentioning

confidence: 99%

HDL dysfunction in diabetes: causes and possible treatments

Farbstein¹,

Levy

2012

Expert Review of Cardiovascular Therapy

138

105

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HDL is known to be inversely correlated with cardiovascular disease due to its diverse antiatherogenic functions. These functions include cholesterol efflux and reverse cholesterol transport, antioxidative and anti-inflammatory activities. However, HDL has been shown to undergo a loss of function in several pathophysiological states, as in the acute phase response, obesity and chronic inflammatory diseases. Some of these diseases were also shown to be associated with increased risk for cardiovascular disease. One such disease that is associated with HDL dysfunction and accelerated atherosclerosis is diabetes mellitus, a disease in which the HDL particle undergoes diverse structural modifications that result in significant changes in its function. This review will summarize the changes that occur in HDL in diabetes mellitus and how these changes lead to HDL dysfunction. Possible treatments for HDL dysfunction are also briefly described.

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Apolipoprotein A-II is catabolized in the kidney as a function of its plasma concentration

Cited by 14 publications

References 38 publications

New Insights into the Roles of Megalin/LRP2 and the Regulation of its Functional Expression

New Insights into the Roles of Megalin/LRP2 and the Regulation of its Functional Expression

LRP5 deficiency down‐regulates Wnt signalling and promotes aortic lipid infiltration in hypercholesterolaemic mice

HDL dysfunction in diabetes: causes and possible treatments

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