AGE-albumin enhances ABCA1 degradation by ubiquitin-proteasome and lysosomal pathways in macrophages

Iborra, Rodrigo Tallada; Machado-Lima, Adriana; Okuda, Ligia Shimabukuro; Pinto, Paula Ramos; Nakandakare, Edna Regina; Machado, Ubiratan Fabres; Côrrea-Giannella, Maria Lúcia; Pickford, Russell; Woods, Tom M.; Brimble, Margaret A.; Rye, Kerry‐Anne; Lu, Rui; Yokoyama, Shinji; Passarelli, Marisa

doi:10.1016/j.jdiacomp.2017.09.012

Cited by 21 publications

(20 citation statements)

References 48 publications

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“…In the present work, the absence of RAGE prevented alterations in the macrophage cholesterol efflux induced by both sources of glycated albumin, isolated from poorly controlled DM subjects and produced in vitro. This result agrees with recent observations from our group [ 23 ] demonstrating that a 54% RAGE knockdown in THP-1 cells prevented the reduction in ABCA-1 elicited by AGE-albumin. Those results likely point to a role of RAGE in mediating the activation of the ubiquitin-proteasome and lysosomal-related degradation pathways that are responsible for the intracellular degradation of ABCA-1 protein elicited by AGE.…”

Section: Discussionsupporting

confidence: 93%

“…It is worth noting that the final content of ABCA1 protein in cells is mainly dictated by posttranslational mechanisms represented by protease-mediated degradation, ubiquitin-proteasome and lysosomal degradation [ 34 , 35 ]. Thus, the elevation in ABCA1 mRNA levels that we observed may not account for the final protein level, which is reduced by AGE albumin [ 7 , 16 ], as described by the increased ABCA-1 ubiquitination and degradation [ 23 ].…”

Section: Discussionmentioning

confidence: 99%

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RAGE Mediates Cholesterol Efflux Impairment in Macrophages Caused by Human Advanced Glycated Albumin

Machado-Lima

López‐Díez

Iborra

et al. 2020

IJMS

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We addressed the involvement of the receptor for advanced glycation end products (RAGE) in the impairment of the cellular cholesterol efflux elicited by glycated albumin. Albumin was isolated from type 1 (DM1) and type 2 (DM2) diabetes mellitus (HbA1c > 9%) and non-DM subjects (C). Moreover, albumin was glycated in vitro (AGE-albumin). Macrophages from Ager null and wild-type (WT) mice, or THP-1 transfected with siRNA-AGER, were treated with C, DM1, DM2, non-glycated or AGE-albumin. The cholesterol efflux was reduced in WT cells exposed to DM1 or DM2 albumin as compared to C, and the intracellular lipid content was increased. These events were not observed in Ager null cells, in which the cholesterol efflux and lipid staining were, respectively, higher and lower when compared to WT cells. In WT, Ager, Nox4 and Nfkb1, mRNA increased and Scd1 and Abcg1 diminished after treatment with DM1 and DM2 albumin. In Ager null cells treated with DM-albumin, Nox4, Scd1 and Nfkb1 were reduced and Jak2 and Abcg1 increased. In AGER-silenced THP-1, NOX4 and SCD1 mRNA were reduced and JAK2 and ABCG1 were increased even after treatment with AGE or DM-albumin. RAGE mediates the deleterious effects of AGE-albumin in macrophage cholesterol efflux.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionmentioning

confidence: 99%

RAGE Mediates Cholesterol Efflux Impairment in Macrophages Caused by Human Advanced Glycated Albumin

Machado-Lima

López‐Díez

Iborra

et al. 2020

IJMS

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“…Additionally, in diabetic conditions, advanced glycation end products (AGE) are reported to make ABCA1 dysfunctional [24]. The ABCA1 dysfunction may occur indirectly by oxidative modification of HDL/apoA-I protein [50][51][52][53][54] as well as by direct effect on ABCA1 [24,25,55]. This was confirmed in type 2 diabetic patients showing reduced ABCA1 mRNA and protein in leukocytes with an inverse correlation between ABCA1 expression and HbA1c and blood glucose, and positive correlation between ABCA1 expression and plasma HDL concentration [25].…”

Section: Discussionmentioning

confidence: 89%

Rapid degradation of ABCA1 protein following cAMP withdrawal and treatment with PKA inhibitor suggests ABCA1 is a short-lived protein primarily regulated at the transcriptional level

Srivastava

Cefalù

Averna

et al. 2020

J Diabetes Metab Disord

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Objectives ATP-binding cassette transporter A1 (ABCA1) is a key player in the reverse cholesterol transport (RCT) and HDL biogenesis. Since RCT is compromised as a result of ABCA1 dysfunction in diabetic state, the objective of this study was to investigate the regulation of ABCA1 in a stably transfected 293 cells expressing ABCA1 under the control of cAMP response element. Methods To delineate transcriptional and posttranscriptional regulation of ABCA1, 293 cells were stably transfected with the full length ABCA1 cDNA under the control of CMV promoter harboring cAMP response element. cAMP-mediated regulation of ABCA1 and cholesterol efflux were studied in the presence of 8-Br-cAMP and after withdrawal of 8-Br-cAMP. The mechanism of cAMP-mediated transcriptional induction of the ABCA1 gene was studied in protein kinase A (PKA) inhibitors-treated cells. Results The transfected 293 cells expressed high levels of ABCA1, while non-transfected wild-type 293 cells showed very low levels of ABCA1. Treatments of transfected cells with 8-Br-cAMP increased ABCA1 protein by 10-fold and mRNA by 20-fold. Cholesterol efflux also increased in parallel. Withdrawal of 8-Br-cAMP caused time-dependent rapid diminution of ABCA1 protein and mRNA, suggesting ABCA1 regulation at the transcriptional level. Treatment with PKA inhibitors abolished the cAMP-mediated induction of the ABCA1 mRNA and protein, resulting dampening of ABCA1-dependent cholesterol efflux. Conclusions These results demonstrate that transfected cell line mimics cAMP response similar to normal cells with natural ABCA1 promoter and suggest that ABCA1 is a short-lived protein primarily regulated at the transcriptional level to maintain cellular cholesterol homeostasis.

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“…Studies have clearly demonstrated that advanced glycated albumin, which is prevalent in diabetes, disturbs reverse cholesterol transport through cellular mechanisms involving induction of ER stress, production of reactive oxygen species and reprogramming of gene expression towards a pro-inflammatory phenotype [ 115 , 116 , 117 ]. It was recently demonstrated that advanced glycated end products (AGE) degrade ABCA1 through the proteasomal and lysosomal systems [ 118 ]. In this study, the authors observed that knockdown of RAGE, the receptor for AGEs, prevented the reduction in ABCA1.…”

Section: Conditions That Impair the Efficiency Of The Rctmentioning

confidence: 99%

Molecular Pathways Underlying Cholesterol Homeostasis

et al. 2018

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Cholesterol is an essential molecule that exerts pleiotropic actions. Although its presence is vital to the cell, its excess can be harmful and, therefore, sustaining cholesterol homeostasis is crucial to maintaining proper cellular functioning. It is well documented that high plasma cholesterol concentration increases the risk of atherosclerotic heart disease. In the last decades, several studies have investigated the association of plasma cholesterol concentrations and the risk of cardiovascular diseases as well as the signaling pathways involved in cholesterol homeostasis. Here, we present an overview of several mechanisms involved in intestinal cholesterol absorption, the regulation of cholesterol synthesis and uptake. We also discuss the importance of reverse cholesterol transport and transintestinal cholesterol transport to maintain cholesterol homeostasis and prevent atherosclerosis development. Additionally, we discuss the influence of dietary cholesterol on plasma cholesterol concentration and the new recommendations for cholesterol intake in a context of a healthy dietary pattern.

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AGE-albumin enhances ABCA1 degradation by ubiquitin-proteasome and lysosomal pathways in macrophages

Cited by 21 publications

References 48 publications

RAGE Mediates Cholesterol Efflux Impairment in Macrophages Caused by Human Advanced Glycated Albumin

RAGE Mediates Cholesterol Efflux Impairment in Macrophages Caused by Human Advanced Glycated Albumin

Rapid degradation of ABCA1 protein following cAMP withdrawal and treatment with PKA inhibitor suggests ABCA1 is a short-lived protein primarily regulated at the transcriptional level

Molecular Pathways Underlying Cholesterol Homeostasis

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