ER stress is associated with reduced ABCA-1 protein levels in macrophages treated with advanced glycated albumin – Reversal by a chemical chaperone

Castilho, Gabriela; Okuda, Ligia Shimabukuro; Pinto, Raphael; Iborra, Rodgiro T.; Nakandakare, Edna Regina; Santos, Célio X.C.; Laurindo, Francisco Rafael Martins; Passarelli, Marisa

doi:10.1016/j.biocel.2012.03.016

Cited by 32 publications

(30 citation statements)

References 32 publications

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“…By microarray analysis, we observed that genes intimately related to the ABCA‐1‐mediated cholesterol efflux were selectively altered. We found a reduction in the stearoyl‐Coenzyme A desaturase 1 ( scd ‐1) mRNA level in DM2‐HSA‐treated cells, which could mediate the increase in ER stress and the reduction in ABCA‐1 protein content and cholesterol efflux, as previously demonstrated by our group (Castilho et al, ). In scd ‐1 siRNA‐treated macrophages, a lipid‐induced ER stress response and apoptosis were observed (Erbay et al, ).…”

Section: Discussionsupporting

confidence: 85%

“…Our group (Passarelli et al, 2005;Castilho et al, 2012;Machado-Lima et al, 2013) and others (Isoda et al, 2007) have shown that AGE reduce ABCA-1 protein content independent of changes in its mRNA expression. In fact, this reduction was observed in the present study in incubations with DM2-HSA, which affected protein content without changes in mRNA levels.…”

Section: Discussionmentioning

confidence: 69%

“…ER stress markers have been found elevated in rupture‐sensitive areas of human atherosclerotic lesions (Myoishi et al, ). Notably, AGE‐albumin evokes ER stress, which seems to be the mechanism linking protein glycation, oxidative stress and the loss of ABCA‐1 protein content because the use of a chemical chaperone (phenyl butyric acid) that alleviates ER stress restores both the ABCA‐1 content and cholesterol efflux (Castilho et al, ). In addition, chemical compounds, such as, tunicamycin and thapsigargin, which disrupt ER function and induce ER‐stress and unfolded protein responses, also promote a reduction in the ABCA‐1 protein level (Castilho et al, ; Hsieh et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

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In Type 2 Diabetes Mellitus Glycated Albumin Alters Macrophage Gene Expression Impairing ABCA1‐Mediated Cholesterol Efflux

Machado-Lima

Iborra

Pinto

et al. 2015

Journal Cellular Physiology

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Advanced glycation end products (AGE) are elevated in diabetes mellitus (DM) and predict the development of atherosclerosis. AGE-albumin induces oxidative stress, which is linked to a reduction in ABCA-1 and cholesterol efflux. We characterized the glycation level of human serum albumin (HSA) isolated from poorly controlled DM2 (n = 11) patients compared with that of control (C, n = 12) individuals and determined the mechanism by which DM2-HSA can interfere in macrophage lipid accumulation. The HSA glycation level was analyzed by MALDI/MS. Macrophages were treated for 18 h with C- or DM2-HSA to measure the (14) C-cholesterol efflux, the intracellular lipid accumulation and the cellular ABCA-1 protein content. Agilent arrays (44000 probes) were used to analyze gene expression, and the differentially expressed genes were validated by real-time RT-PCR. An increased mean mass was observed in DM2-HSA compared with C-HSA, reflecting the condensation of at least 5 units of glucose. The cholesterol efflux mediated by apo AI, HDL3 , and HDL2 was impaired in DM2-HSA-treated cells, which was related to greater intracellular lipid accumulation. DM2-HSA decreased Abcg1 mRNA expression by 26%. Abca1 mRNA was unchanged, although the final ABCA-1 protein content decreased. Compared with C-HAS-treated cells, NADPH oxidase 4 mRNA expression increased in cells after DM2-HSA treatment. Stearoyl-Coenzyme A desaturase 1, janus kinase 2, and low density lipoprotein receptor mRNAs were reduced by DM2-HSA. The level of glycation that occurs in vivo in DM2-HSA-treated cells selectively alters macrophage gene expression, impairing cholesterol efflux and eliciting intracellular lipid accumulation, which contribute to atherogenesis, in individuals with DM2.

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Section: Discussionsupporting

confidence: 85%

Section: Discussionmentioning

confidence: 69%

Section: Discussionmentioning

confidence: 99%

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In Type 2 Diabetes Mellitus Glycated Albumin Alters Macrophage Gene Expression Impairing ABCA1‐Mediated Cholesterol Efflux

Machado-Lima

Iborra

Pinto

et al. 2015

Journal Cellular Physiology

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“…Endoplasmic reticulum (ER) stress can have marked affects on the immune-stimulatory capacity of antigen presenting cells (17–19). Since inhibition of fatty-acid synthesis induces ER stress in neoplastic cells (20), we postulated that TOFA-grown BMDC would exhibit high ER stress.…”

Section: Resultsmentioning

confidence: 99%

Role of Fatty-Acid Synthesis in Dendritic Cell Generation and Function

Rehman

Hemmert

Ochi

et al. 2013

The Journal of Immunology

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Dendritic cells (DC) are professional antigen presenting cells that regulate innate and adaptive immunity. The role of fatty-acid synthesis in DC development and function is uncertain. We found that blockade of fatty-acid synthesis markedly decreases dendropoiesis in the liver and in primary and secondary lymphoid organs in mice. Human DC development from PBMC precursors was also diminished by blockade of fatty-acid synthesis. This was associated with higher rates of apoptosis in precursor cells and increased expression of Cleaved Caspase 3 and BCL-xL, and down-regulation of Cyclin B1. Further, blockade of fatty-acid synthesis decreased DC expression of MHCII, ICAM-1, B7-1, B7-2 but increased their production of selected pro-inflammatory cytokines including IL-12 and MCP-1. Accordingly, inhibition of fatty-acid synthesis enhanced DC capacityto activate allogeneic as well as antigen-restricted CD4+ and CD8+ T cells and induce CTL responses. Further, blockade of fatty-acid synthesis increased DC expression of Notch ligands and enhanced their ability to activate NK cell immune-phenotype and IFN-γ production. Since endoplasmic reticular (ER)-stress can augment the immunogenic function of APC, we postulated that this may account for the higher DC immunogenicity. We found that inhibition of fatty-acid synthesis resulted in elevated expression of numerous markers of ER stress in humans and mice and was associated with increased MAP kinase and Akt signaling. Further, lowering ER-stress by 4-phenylbutyrate mitigated the enhanced immune-stimulation associated with fatty-acid synthesis blockade. Our findings elucidate the role of fatty-acid synthesis in DC development and function and have implications to the design of DC vaccines for immunotherapy.

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“…9) without causing significant changes of ABCA1 mRNA (data not shown). Advanced glycated albumin, which induces ER stress, reduced ABCA1 protein expression without altered ABCA1 transcription in macrophages (48). …”

Section: Discussionmentioning

confidence: 99%

Endoplasmic reticulum stress impairs cholesterol efflux and synthesis in hepatic cells

Röhrl

Eigner

Winter

et al. 2014

Journal of Lipid Research

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Metabolic disorders such as type 2 diabetes cause hepatic endoplasmic reticulum (ER) stress, which affects neutral lipid metabolism. However, the role of ER stress in cholesterol metabolism is incompletely understood. Here, we show that induction of acute ER stress in human hepatic HepG2 cells reduced ABCA1 expression and caused ABCA1 redistribution to tubular perinuclear compartments. Consequently, cholesterol efflux to apoA-I, a key step in nascent HDL formation, was diminished by 80%. Besides ABCA1, endogenous apoA-I expression was reduced upon ER stress induction, which contributed to reduced cholesterol efflux. Liver X receptor, a key regulator of ABCA1 in peripheral cells, was not involved in this process. Despite reduced cholesterol efflux, cellular cholesterol levels remained unchanged during ER stress. This was due to impaired de novo cholesterol synthesis by reduction of HMG-CoA reductase activity by 70%, although sterol response element-binding protein-2 activity was induced. In mice, ER stress induction led to a marked reduction of hepatic ABCA1 expression. However, HDL cholesterol levels were unaltered, presumably because of scavenger receptor class B, type I downregulation under ER stress. Taken together, our data suggest that ER stress in metabolic disorders reduces HDL biogenesis due to impaired hepatic ABCA1 function.

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ER stress is associated with reduced ABCA-1 protein levels in macrophages treated with advanced glycated albumin – Reversal by a chemical chaperone

Cited by 32 publications

References 32 publications

In Type 2 Diabetes Mellitus Glycated Albumin Alters Macrophage Gene Expression Impairing ABCA1‐Mediated Cholesterol Efflux

In Type 2 Diabetes Mellitus Glycated Albumin Alters Macrophage Gene Expression Impairing ABCA1‐Mediated Cholesterol Efflux

Role of Fatty-Acid Synthesis in Dendritic Cell Generation and Function

Endoplasmic reticulum stress impairs cholesterol efflux and synthesis in hepatic cells

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