Cholesterol efflux via HDL resecretion occurs when cholesterol transport out of the lysosome is impaired

Pagler, Tamara A.; Neuhofer, Angelika; Laggner, Hilde; Strobl, Wolfgang; Stangl, Herbert

doi:10.1194/jlr.m700056-jlr200

Cited by 19 publications

(7 citation statements)

References 45 publications

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“…In support of this hypothesis, previous studies have successfully shown that the antiviral activity of chloroquine against several caliciviridae, another family of RNA viruses, occurs through chloroquine's ability to inhibit cathepsin L 71 . Furthermore, chloroquine also inhibits the transport of cholesterol out of the lysosomes, including to the plasma membrane, which would be expected to reduce the abundance, and alter the composition of membrane rafts, 72 thereby mimicking the raft alterations seen in NPC. Additionally, chloroquine has also been shown to interfere with the trimming of the N‐glycosylated side chain of ACE2, which may affect the internalization of ACE2, and subsequently, viral entry 73 .…”

Section: The Lysosomotropic Activities Of Different Drugs Undergoing mentioning

confidence: 79%

The lysosome: A potential juncture between SARS‐CoV‐2 infectivity and Niemann‐Pick disease type C, with therapeutic implications

et al. 2020

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Drug repurposing is potentially the fastest available option in the race to identify safe and efficacious drugs that can be used to prevent and/or treat COVID‐19. By describing the life cycle of the newly emergent coronavirus, SARS‐CoV‐2, in light of emerging data on the therapeutic efficacy of various repurposed antimicrobials undergoing testing against the virus, we highlight in this review a possible mechanistic convergence between some of these tested compounds. Specifically, we propose that the lysosomotropic effects of hydroxychloroquine and several other drugs undergoing testing may be responsible for their demonstrated in vitro antiviral activities against COVID‐19. Moreover, we propose that Niemann‐Pick disease type C (NPC), a lysosomal storage disorder, may provide new insights into potential future therapeutic targets for SARS‐CoV‐2, by highlighting key established features of the disorder that together result in an “unfavorable” host cellular environment that may interfere with viral propagation. Our reasoning evolves from previous biochemical and cell biology findings related to NPC, coupled with the rapidly evolving data on COVID‐19. Our overall aim is to suggest that pharmacological interventions targeting lysosomal function in general, and those particularly capable of reversibly inducing transient NPC‐like cellular and biochemical phenotypes, constitute plausible mechanisms that could be used to therapeutically target COVID‐19.

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Section: The Lysosomotropic Activities Of Different Drugs Undergoing mentioning

confidence: 79%

The lysosome: A potential juncture between SARS‐CoV‐2 infectivity and Niemann‐Pick disease type C, with therapeutic implications

et al. 2020

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“…Sviridov et al ( 42 ) reported an antibody against the HDL-binding protein enhanced HDL uptake that was not accompanied by parallel changes in cholesterol efflux in rat hepatoma cells. In contrast, Pagler et al ( 43 ) demonstrated the involvement of HDL uptake and re-secretion in the maintenance of cholesterol homeostasis in cases of disturbed intracellular cholesterol efflux. The authors also showed that SR-BI mediated HDL endocytosis, leading to cholesterol efflux ( 44 ).…”

Section: Discussionmentioning

confidence: 95%

CC-Chemokine Ligand 2 (CCL2) Suppresses High Density Lipoprotein (HDL) Internalization and Cholesterol Efflux via CC-Chemokine Receptor 2 (CCR2) Induction and p42/44 Mitogen-activated Protein Kinase (MAPK) Activation in Human Endothelial Cells

Sun

Huang

Bao

et al. 2016

Journal of Biological Chemistry

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High density lipoprotein (HDL) has been proposed to be internalized and to promote reverse cholesterol transport in endothelial cells (ECs). However, the mechanism underlying these processes has not been studied. In this study, we aim to characterize HDL internalization and cholesterol efflux in ECs and regulatory mechanisms. We found mature HDL particles were reduced in patients with coronary artery disease (CAD), which was associated with an increase in CC-chemokine ligand 2 (CCL2). In cultured primary human coronary artery endothelial cells and human umbilical vein endothelial cells, we determined that CCL2 suppressed the binding (4 °C) and association (37 °C) of HDL to/with ECs and HDL cellular internalization. Furthermore, CCL2 inhibited [3H]cholesterol efflux to HDL/apoA1 in ECs. We further found that CCL2 induced CC-chemokine receptor 2 (CCR2) expression and siRNA-CCR2 reversed CCL2 suppression on HDL binding, association, internalization, and on cholesterol efflux in ECs. Moreover, CCL2 induced p42/44 mitogen-activated protein kinase (MAPK) phosphorylation via CCR2, and p42/44 MAPK inhibition reversed the suppression of CCL2 on HDL metabolism in ECs. Our study suggests that CCL2 was elevated in CAD patients. CCL2 suppressed HDL internalization and cholesterol efflux via CCR2 induction and p42/44 MAPK activation in ECs. CCL2 induction may contribute to impair HDL function and form atherosclerosis in CAD.

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“…Further evidences for HDL endocytosis as a redundant pathway come from our findings in cells derived from patients with Niemann–Pick disease, where the LDL-receptor pathway and late endosomal cholesterol trafficking are impaired. In fibroblasts from these patients, HDL retro-endocytosis is still functional in maintaining cellular cholesterol homeostasis [113]. Similarly, HDL and LDL resecretion mediates cholesterol efflux in fibroblasts from patients with Tangier disease, where ABCA1 function and cholesterol efflux to apoA-I are defective (Neuhofer and Stangl, unpublished data).…”

Section: Discussionmentioning

confidence: 99%

HDL endocytosis and resecretion

Röhrl

Stangl

2013

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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HDL removes excess cholesterol from peripheral tissues and delivers it to the liver and steroidogenic tissues via selective lipid uptake without catabolism of the HDL particle itself. In addition, endocytosis of HDL holo-particles has been debated for nearly 40 years. However, neither the connection between HDL endocytosis and selective lipid uptake, nor the physiological relevance of HDL uptake has been delineated clearly. This review will focus on HDL endocytosis and resecretion and its relation to cholesterol transfer. We will discuss the role of HDL endocytosis in maintaining cholesterol homeostasis in tissues and cell types involved in atherosclerosis, focusing on liver, macrophages and endothelium. We will critically summarize the current knowledge on the receptors mediating HDL endocytosis including SR-BI, F1-ATPase and CD36 and on intracellular HDL transport routes. Dependent on the tissue, HDL is either resecreted (retro-endocytosis) or degraded after endocytosis. Finally, findings on HDL transcytosis across the endothelial barrier will be summarized. We suggest that HDL endocytosis and resecretion is a rather redundant pathway under physiologic conditions. In case of disturbed lipid metabolism, however, HDL retro-endocytosis represents an alternative pathway that enables tissues to maintain cellular cholesterol homeostasis.

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Cholesterol efflux via HDL resecretion occurs when cholesterol transport out of the lysosome is impaired

Abstract: Recently, we showed that holo HDL particle uptake and resecretion occur in physiologically relevant cell lines and that HDL uptake is mediated by scavenger receptor class B type I (SR-BI). Furthermore, we established that HDL resecretion is accompanied by [ 3

Cited by 19 publications

References 45 publications

The lysosome: A potential juncture between SARS‐CoV‐2 infectivity and Niemann‐Pick disease type C, with therapeutic implications

The lysosome: A potential juncture between SARS‐CoV‐2 infectivity and Niemann‐Pick disease type C, with therapeutic implications

CC-Chemokine Ligand 2 (CCL2) Suppresses High Density Lipoprotein (HDL) Internalization and Cholesterol Efflux via CC-Chemokine Receptor 2 (CCR2) Induction and p42/44 Mitogen-activated Protein Kinase (MAPK) Activation in Human Endothelial Cells

HDL endocytosis and resecretion

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