Lipid efflux mechanisms, relation to disease and potential therapeutic aspects

Castaño, David; Rattanasopa, Chutima; Monteiro-Cardoso, Vera F.; Corlianò, Maria; Liu, Yiran; Zhong, Shengyi; Rusu, Mihaela; Liehn, Elisa A.; Singaraja, Roshni R.

doi:10.1016/j.addr.2020.04.013

Cited by 23 publications

(17 citation statements)

References 660 publications

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“…During hyperlipidemia, macrophages play a crucial role in maintaining balanced cholesterol levels by regulating scavenger receptors, cholesterol metabolism enzymes, and cholesterol transporters [ 22 ]. After scavenger receptors initially interact with free cholesterol, cholesterol transporters facilitate uptake of free cholesterol by macrophages; mitochondria then use cholesterol to generate ATP through cholesterol metabolism enzymes [ 41 ]. Importantly, cholesterol transporters can also facilitate excretion of excess cholesterol from cells [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Oxidized LDL Disrupts Metabolism and Inhibits Macrophage Survival by Activating a miR-9/Drp1/Mitochondrial Fission Signaling Pathway

Xin

Zhang

et al. 2020

Oxidative Medicine and Cellular Longevity

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Mitochondrial dysfunction is associated with macrophage damage, but the role of mitochondrial fission in macrophage cholesterol metabolism is not fully understood. In this study, we explored the influences of miR-9 and mitochondrial fission on macrophage viability and cholesterol metabolism. Macrophages were incubated with oxidized low-density lipoprotein (ox-LDL) in vitro, after which mitochondrial fission, cell viability, and cholesterol metabolism were examined using qPCR, ELISAs, and immunofluorescence. ox-LDL treatment significantly increased Drp1-associated mitochondrial fission. Transfection of Drp1 siRNA significantly reduced cell death, attenuated oxidative stress, and inhibited inflammatory responses in ox-LDL-treated macrophages. Interestingly, inhibition of Drp1-related mitochondrial fission also improved cholesterol metabolism by balancing the transcription of cholesterol influx/efflux enzymes. We also found that miR-9 was downregulated in ox-LDL-treated macrophages, and administration of a miR-9 mimic decreased Drp1 transcription and mitochondrial fission, as well as its effects. These results indicate that signaling via the novel miR-9/Drp1/mitochondrial fission axis is a key determinant of macrophage viability and cholesterol metabolism.

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Section: Discussionmentioning

confidence: 99%

Oxidized LDL Disrupts Metabolism and Inhibits Macrophage Survival by Activating a miR-9/Drp1/Mitochondrial Fission Signaling Pathway

Xin

Zhang

et al. 2020

Oxidative Medicine and Cellular Longevity

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“…The lipid homeostasis of macrophages depends on the dynamic balance of cholesterol uptake, efflux and endogenous synthesis. Excessive oxidised low-density lipoprotein (ox-LDL) uptake mediated by macrophage scavenger receptor A (SR-A), the class B scavenger receptor CD36 ( 3 ), low-density lipoprotein receptor (LDL-R) and lectin-like ox-LDL receptor-1 (LOX-1), as well as reduced cholesterol efflux via ATP-binding cassette transporter A1 (ABCA1) or ATP-binding cassette transporter G1 (ABGA1) ( 4 ) contributes to lipid accumulation.…”

Section: Introductionmentioning

confidence: 99%

Perivascular Adipose-Derived Exosomes Reduce Foam Cell Formation by Regulating Expression of Cholesterol Transporters

Liu

Sun

Lin

et al. 2021

Front. Cardiovasc. Med.

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Background: Accumulating evidence demonstrates that perivascular adipose tissue (PVAT) plays an important role in maintaining vascular homeostasis. The formation of macrophage foam cells is a central feature of atherosclerosis. This study aimed to evaluate the effect of PVAT-derived exosomes (EXOs) on the lipid accumulation of macrophages and verify the anti-atherogenic characteristics of PVAT.Methods and Results: We extracted EXOs from the PVAT and subcutaneous adipose tissue (SCAT) of wild-type C57BL/6J mice. After coincubation, the EXOs were taken up by RAW264.7 cells. Oil Red O staining revealed that macrophage foam cell formation and intracellular lipid accumulation were ameliorated by PVAT-EXOs. Flow cytometry showed that PVAT-EXOs significantly reduced macrophage uptake of fluorescence-labelled oxidised low-density lipoprotein (ox-LDL). In addition, high-density lipoprotein-induced cholesterol efflux was promoted by PVAT-EXOs. Western blot analysis showed the downregulation of macrophage scavenger receptor A and the upregulation of ATP-binding cassette transporter A1 and ATP-binding cassette transporter G1, which could be mediated by the overexpression of peroxisome proliferator-activated receptor γ and was independent of liver X receptor α.Conclusion: Our findings suggest that PVAT-EXOs reduce macrophage foam cell formation by regulating the expression of cholesterol transport proteins, which provides a novel mechanism by which PVAT protects the vasculature from atherosclerosis.

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“…Cholesterol in the enterocytes either transports back into the intestinal lumen by abcg5/8 or transports into basolateral by Abca1 and Abcg1. 26 The expression of Abcg5/8 was upregulated 2–3 times than that in the Cana treated duodenum and jejunum ( Figure 3A ), suggesting higher efflux of cholesterol back to the lumen. The expressions of Abca1 and Abcg1 were also higher 1.5–2 times in the duodenum and jejunum ( Figure 3B ).…”

Section: Resultsmentioning

confidence: 92%

Canagliflozin Facilitates Reverse Cholesterol Transport Through Activation of AMPK/ABC Transporter Pathway

Zhao¹,

Li²,

Liu³

et al. 2021

DDDT

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Background and Purpose: Cholesterol is an essential lipid and its homeostasis is a major factor for many diseases, such as hyperlipidemia, atherosclerosis, diabetes, and obesity. Sodium-glucose cotransporter 2 (SGLT2) inhibitor canagliflozin (Cana) is a new kind of hypoglycemic agent, which decreases urinary glucose reabsorption and reduces hyperglycemia. Cana has been shown to regulate serum lipid, decrease serum triglyceride and increase serum high-density lipoprotein-cholesterol (HDL-C), and improve cardiovascular outcomes. But evidence of how Cana impacted the cholesterol metabolism remains elusive. Methods: We treated Cana on mice with chow diet or western diet and then detected cholesterol metabolism in the liver and intestine. To explore the mechanism, we also treated hepG2 cells and Caco2 cells with different concentrations of Cana. Results: In this study, we showed that Cana facilitated hepatic and intestinal cholesterol efflux. Mechanically, Cana via activating adenosine monophosphate-activated protein kinase (AMPK) increased the expression of ATP-binding cassette (ABC) transporters ABCG5 and ABCG8 in liver and intestine, increased biliary and fecal cholesterol excretion. Conclusion:This research confirms that Cana regulates cholesterol efflux and improves blood and hepatic lipid; this may be a partial reason for improving cardiovascular disease.

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Lipid efflux mechanisms, relation to disease and potential therapeutic aspects

Cited by 23 publications

References 660 publications

Oxidized LDL Disrupts Metabolism and Inhibits Macrophage Survival by Activating a miR-9/Drp1/Mitochondrial Fission Signaling Pathway

Oxidized LDL Disrupts Metabolism and Inhibits Macrophage Survival by Activating a miR-9/Drp1/Mitochondrial Fission Signaling Pathway

Perivascular Adipose-Derived Exosomes Reduce Foam Cell Formation by Regulating Expression of Cholesterol Transporters

Canagliflozin Facilitates Reverse Cholesterol Transport Through Activation of AMPK/ABC Transporter Pathway

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