Oxidized LDL Downregulates ABCA1 Expression via MEK/ERK/LXR Pathway in INS-1 Cells

Lyu, Jingya; Fukunaga, Kohji; Imachi, Hitomi; Sato, Seisuke; Kobayashi, Toshihiro; Saheki, Takanobu; Ibata, Tomohiro; Yoshimura, Takafumi; Iwama, Hisakazu; Murao, Koji

doi:10.3390/nu13093017

Cited by 6 publications

(4 citation statements)

References 52 publications

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“…We found that Rb1, Rg1, Rg3 and CK induced cholesterol e ux in TMZ-resistant GBM cells, reduced intracellular cholesterol concentrations, and redistributed lipid rafts at different levels. It has been reported that CK promoted cholesterol e ux by stimulating LXRα(Huang et al 2017;Zhou et al 2016), and we not only identi ed the increased transcription and translation of LXRα in resistant GBM cells after treated with Rg1, Rg3 and CK, but also found the induction of Rb1 and Rg1 on the expression of cholesterol e ux transporter ABCA1, whose promoter is directly bound by LXRα for transcriptional activation(Lyu et al 2021). We further observed that Rg1 and CK increased the sensitivity of resistant GBM cells to TMZ, and this effect was via upregulation of LXRα.…”

supporting

confidence: 54%

Cholesterol Analogs Ginsenosides Rg1 and Compound K Control Temozolomide Resistance in Glioblastoma Cells by Regulating Cholesterol Efflux and Lipid Raft Distribution

Qiu,

Zhang,

et al. 2022

Preprint

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Enriched cholesterol in brain is involved in the resistance of glioblastoma to temozolomide treatment. Cholesterol efflux and lipid raft redistribution contribute to improving resistance. Ginsenosides are structurally similar to cholesterol and can alter cholesterol metabolism and lipid raft distribution, whose subtypes Rb1, Rg1, Rg3 and Compound K showed brain permeability. From CGGA database, the expression of cholesterol efflux gene NR1H3 (LXRα) in tumor tissues of patients treated with temozolomide was positively correlated with long-term survival, and was negatively correlated with multidrug resistance protein (MDR)-1 located in lipid rafts. MDR1 level was correlated with cholesterol uptake (LDLR) and synthesis (SREBF2) genes, suggesting that cholesterol is involved in temozolomide resistance. We demonstrated that cholesterol protected the survival of resistant U251 cells from temozolomide stress, and upregulated MDR1. Resistant U251 cells tended to store cholesterol intracellularly, with weaker cholesterol efflux and LXRα expression to maintain a uniform distribution of lipid rafts. Ginsenosides Rb1, Rg1, Rg3 and Compound K reduced intracellular cholesterol content and promoted cholesterol efflux in resistant cells, making lipid raft distribution no longer uniform. Rg1 and Compound K also upregulated LXRα expression and induced the cytotoxicity of temozolomide in the presence of cholesterol. We further found that cholesterol efflux induction, lipid raft redistribution, and temozolomide sensitization by Rg1 and Compound K were induced through stimulation of LXRα. Therefore, ginsenoside Rg1 and Compound K can control temozolomide resistance in glioblastoma cells by regulating cholesterol metabolism, which are potential synergists for temozolomide therapy.

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supporting

confidence: 54%

Cholesterol Analogs Ginsenosides Rg1 and Compound K Control Temozolomide Resistance in Glioblastoma Cells by Regulating Cholesterol Efflux and Lipid Raft Distribution

Qiu,

Zhang,

et al. 2022

Preprint

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“…Interestingly, in pancreatic beta cell selective ABCA1 knockout mice, the lipid content in pancreatic beta cells was increased and GSIS was impaired (6). Previously, we reported that TNF-α, angiotensin II, and oxidized low-density lipoprotein increase intracellular cholesterol content and reduce the expression of ABCA1 in pancreatic β cells [13][14][15]. We also reported that GSIS is decreased in INS-1 cells with accumulated cholesterol.…”

Section: Discussionmentioning

confidence: 88%

Selective Peroxisome Proliferator-Activated Receptor-α Modulator K-877 Stimulated the Expression of ABCA1 in Pancreatic Beta Cells in a Glucotoxic State

Fukunaga

2024

BJSTR

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Background: ATP-binding cassette protein A1 (ABCA1) is a critical regulator of cholesterol and phospholipid efflux from cells to HDL. Additionally, ABCA1 is important for insulin secretion, as evidenced by impaired glucose tolerance and decreased insulin secretion in mice lacking ABCA1 in pancreatic β cells. Long-term hyperglycemia in type 2 diabetes mellitus, a phenomenon that causes dysfunction of pancreatic β-cells and insulin resistance, is called "glucotoxicity" and is clinically important as it aggravates diabetes. Here, we investigated the effects of pemafibrate (K-877), a novel selective PPARα modulator, on insulin secretion under glucotoxic conditions. Methods:The pancreatic beta cell line INS-1 cells were cultured in 11.2 mmol/l and 22.4 mmol/l glucose for 7 days and the expression of ABCA1 and CaMKIV was examined by western blotting and real-time polymerase chain reaction (PCR) methods. Furthermore, changes in cholesterol content when INS-1 cells were cultured under hyperglycaemic conditions were confirmed by Oil Red O staining. Changes in Glucose stimulate insulin secretion (GSIS) were also examined.Results: ABCA1 was downregulated in INS-1 cells under high glucose conditions for seven days; however, K-877 upregulated ABCA1. Moreover, chronic hyperglycemia caused intracellular lipid accumulation, which was ameliorated by K-877. Similarly, K-877 increased glucose-stimulated insulin secretion, which was suppressed under high glucose conditions. Furthermore, CaMKIV expression was suppressed under chronic high glucose conditions, but improved by K-877.Conclusions: These findings suggest that K-877 may affect insulin secretion by controlling ABCA1 expression in pancreatic beta cells in a glucotoxic state.

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“…Hyperinsulinism was associated with ER stress, metainflammation, and a compensatory response of ABCA1 overexpression. On the other hand, the highly proatherogenic oxidized LDL has been described as downregulating ABCA1 expression via the MEK/ERK/LXR pathway, leading to impaired insulin synthesis and GSIS in a β-cell model [69]. Indeed, ABCA1 reduction could lead to cholesterol accumulation coupled with an increased risk of islet amyloid polypeptide (IAPP) aggregation [70], which suggests the importance of ABCA1.…”

Section: Discussionmentioning

confidence: 99%

LDL Promotes Disorders in β-Cell Cholesterol Metabolism, Implications on Insulin Cellular Communication Mediated by EVs

et al. 2022

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Dyslipidemia is described as a hallmark of metabolic syndrome, promoting a stage of metabolic inflammation (metainflammation) that could lead to misbalances in energetic metabolism, contributing to insulin resistance, and modifying intracellular cholesterol pathways and the renin–angiotensin system (RAS) in pancreatic islets. Low-density lipoprotein (LDL) hypercholesterolemia could disrupt the tissue communication between Langerhans β-cells and hepatocytes, wherein extracellular vesicles (EVs) are secreted by β-cells, and exposition to LDL can impair these phenomena. β-cells activate compensatory mechanisms to maintain insulin and metabolic homeostasis; therefore, the work aimed to characterize the impact of LDL on β-cell cholesterol metabolism and the implication on insulin secretion, connected with the regulation of cellular communication mediated by EVs on hepatocytes. Our results suggest that β-cells can endocytose LDL, promoting an increase in de novo cholesterol synthesis targets. Notably, LDL treatment increased mRNA levels and insulin secretion; this hyperinsulinism condition was associated with the transcription factor PDX-1. However, a compensatory response that maintains basal levels of intracellular calcium was described, mediated by the overexpression of calcium targets PMCA1/4, SERCA2, and NCX1, together with the upregulation of the unfolded protein response (UPR) through the activation of IRE1 and PERK arms to maintain protein homeostasis. The LDL treatment induced metainflammation by IL-6, NF-κB, and COX-2 overexpression. Furthermore, LDL endocytosis triggered an imbalance of the RAS components. LDL treatment increased the intracellular levels of cholesterol on lipid droplets; the adaptive β-cell response was portrayed by the overexpression of cholesterol transporters ABCA1 and ABCG1. Therefore, lipotoxicity and hyperinsulinism induced by LDL were regulated by the natural compound auraptene, a geranyloxyn coumarin modulator of cholesterol-esterification by ACAT1 enzyme inhibition. EVs isolated from β-cells impaired insulin signaling via mTOR/p70S6Kα in hepatocytes, a phenomenon regulated by auraptene. Our results show that LDL overload plays a novel role in hyperinsulinism, mechanisms associated with a dysregulation of intracellular cholesterol, lipotoxicity, and the adaptive UPR, which may be regulated by coumarin-auraptene; these conditions explain the affectations that occur during the initial stages of insulin resistance.

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Oxidized LDL Downregulates ABCA1 Expression via MEK/ERK/LXR Pathway in INS-1 Cells

Cited by 6 publications

References 52 publications

Cholesterol Analogs Ginsenosides Rg1 and Compound K Control Temozolomide Resistance in Glioblastoma Cells by Regulating Cholesterol Efflux and Lipid Raft Distribution

Cholesterol Analogs Ginsenosides Rg1 and Compound K Control Temozolomide Resistance in Glioblastoma Cells by Regulating Cholesterol Efflux and Lipid Raft Distribution

Selective Peroxisome Proliferator-Activated Receptor-α Modulator K-877 Stimulated the Expression of ABCA1 in Pancreatic Beta Cells in a Glucotoxic State

LDL Promotes Disorders in β-Cell Cholesterol Metabolism, Implications on Insulin Cellular Communication Mediated by EVs

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