Small Dense LDL Enhances THP-1 Macrophage Foam Cell Formation

Tani, Makoto; Kawakami, Akio; Mizuno, Yuki; Imase, Reina; Ito, Yasuki; Kondo, Kazuo; Ishii, Hiroko; Yoshida, Masayuki

doi:10.5551/jat.7161

Cited by 29 publications

(16 citation statements)

References 24 publications

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“…However, LDL(−) upregulated LOX-1 and CD36 expression, as reported in other monocyte/macrophage cell lines [16,32]. Both receptors are related to modified LDL uptake, inflammation, and foam cell formation [40,41]. Their expression increases in differentiated macrophages vs. monocytes, as they are highly expressed in lipid-laden macrophages, and particularly in the presence of stimuli, such as OxLDL [42,43].…”

Section: Discussionmentioning

confidence: 74%

Electronegative LDL Promotes Inflammation and Triglyceride Accumulation in Macrophages

Puig

Montolio²,

Camps‐Renom

et al. 2020

Cells

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Electronegative low-density lipoprotein (LDL) (LDL(−)), a modified LDL that is present in blood and exerts atherogenic effects on endothelial cells and monocytes. This study aimed to determine the action of LDL(−) on monocytes differentiated into macrophages. LDL(−) and in vitro-modified LDLs (oxidized, aggregated, and acetylated) were added to macrophages derived from THP1 monocytes over-expressing CD14 (THP1-CD14). Then, cytokine release, cell differentiation, lipid accumulation, and gene expression were measured by ELISA, flow cytometry, thin-layer chromatography, and real-time PCR, respectively. LDL(−) induced more cytokine release in THP1-CD14 macrophages than other modified LDLs. LDL(−) also promoted morphological changes ascribed to differentiated macrophages. The addition of high-density lipoprotein (HDL) and anti-TLR4 counteracted these effects. LDL(−) was highly internalized by macrophages, and it was the major inductor of intracellular lipid accumulation in triglyceride-enriched lipid droplets. In contrast to inflammation, the addition of anti-TLR4 had no effect on lipid accumulation, thus suggesting an uptake pathway alternative to TLR4. In this regard, LDL(−) upregulated the expression of the scavenger receptors CD36 and LOX-1, as well as several genes involved in triglyceride (TG) accumulation. The importance and novelty of the current study is that LDL(−), a physiologically modified LDL, exerted atherogenic effects in macrophages by promoting differentiation, inflammation, and triglyceride-enriched lipid droplets formation in THP1-CD14 macrophages, probably through different receptors.

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Section: Discussionmentioning

confidence: 74%

Electronegative LDL Promotes Inflammation and Triglyceride Accumulation in Macrophages

Puig

Montolio²,

Camps‐Renom

et al. 2020

Cells

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“…Many studies have reported the relevance of small LDL to oxidation. Small dense LDL is more oxidizable in vitro than large buoyant LDL 4,5 and is able to enhance foam cell formation by THP-1 macrophages without copper-induced oxidation. 4 Furthermore, ML-25, or the antibody to MDA-LDL, has been reported to react with isolated small dense LDL.…”

Section: Discussionmentioning

confidence: 99%

“…Small dense LDL is more oxidizable in vitro than large buoyant LDL 4,5 and is able to enhance foam cell formation by THP-1 macrophages without copper-induced oxidation. 4 Furthermore, ML-25, or the antibody to MDA-LDL, has been reported to react with isolated small dense LDL. 9 LDL isolated from hypertriglyceridemic serum has reduced affinity for the LDL receptor 13 and a prolonged plasma half-life (3.2 days for hypertriglyceridemic LDL vs. 2.0 days for normal LDL), which may underlie the higher oxidizability in vivo of small LDL.…”

Section: Discussionmentioning

confidence: 99%

“…3 Many studies have reported on the relationship between the concentration of small dense LDL and the development of atherosclerosis. [3][4][5] However, there are few reports of serum oxidized lipoproteins other than small dense LDL, except for a report on the presence of phosphatidylcholine hydroperoxides in isolated remnant lipoproteins. 6 We developed a new monoclonal antibody, called G11-6, by immunizing mice with triglyceride (TG)-rich LDL isolated from the serum of a cholestatic patient with severe liver disease.…”

Section: Introductionmentioning

confidence: 99%

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Immunological detection of large oxidized lipoproteins in hypertriglyceridemic serum

et al. 2013

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Background: Triglyceride-rich, low-density lipoproteins (TG-rich LDL) have been reported as an oxidized lipoprotein species in patients with severe liver disease. Using TG-rich LDL as an immunogen, we obtained a monoclonal antibody (G11-6) that reacted with TG-rich LDL from patients with liver disease and with metal-oxidized LDL only in the early process of the oxidation reaction. This study determined the G11-6-reactive lipoproteins in hypertriglyceridemic serum. Methods: Serum samples from healthy volunteers (n ¼ 12) and hypertriglyceridemic patients (n ¼ 9) were fractionated by gel filtration and subjected to a sandwich enzyme-linked immunosorbent assay (ELISA) using G11-6 and polyclonal anti-apolipoprotein B antibodies. Results: Small LDL and larger lipoproteins reacted with G11-6. G11-6-reactive small LDL was identified in both the healthy subjects and hypertriglyceridemic patients, whereas G11-6-reactive larger lipoproteins were found only in the hypertriglyceridemic patients. Conclusions: G11-6 is a useful tool for detecting increased large oxidized lipoproteins in hypertriglyceridemic patients.

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“…considered as one of the major and important regulatory factors in the cholesterol efflux mechanism study. [39][40][41] The possible mechanisms involved in these processes outlined above might be due to the suppressed lipid accumulation by PPARa upregulation and PPARc downregulation. As mentioned above, KME and HDMPPA enhanced PPARa expression and inhibited PPARc expression.…”

Section: Figmentioning

confidence: 99%

Kimchi Methanol Extract and the Kimchi Active Compound, 3′-(4′-Hydroxyl-3′,5′-Dimethoxyphenyl)Propionic Acid, Downregulate CD36 in THP-1 Macrophages Stimulated by oxLDL

Yun

Kim²,

Song

2014

Journal of Medicinal Food

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Macrophage foam cell formation by oxidized low-density lipoprotein (oxLDL) is a key step in the progression of atherosclerosis, which is involved in cholesterol influx and efflux in macrophages mediated by related proteins such as peroxisome proliferator-activated receptor c (PPARc), CD36, PPARa, liver-X receptor a (LXRa), and ATP-binding cassette transporter A1 (ABCA1). The aim of this study was to investigate the beneficial effects of kimchi methanol extract (KME) and a kimchi active compound, 3-(4 0 -hydroxyl-3 0 ,5 0 -dimethoxyphenyl)propionic acid (HDMPPA) on cholesterol flux in THP-1-derived macrophages treated with oxLDL. The effects of KME and HDMPPA on cell viability and lipid peroxidation were determined. Furthermore, the protein expression of PPARc, CD36, PPARa, LXRa, and ABCA1 was examined. OxLDL strongly induced cell death and lipid peroxidation in THP-1-derived macrophages. However, KME and HDMPPA significantly improved cell viability and inhibited lipid peroxidation induced by oxLDL in THP-1-derived macrophages (P < .05). Moreover, KME and HDMPPA suppressed CD36 and PPARc expressions, both of which participate in cholesterol influx. In contrast, KME and HDMPPA augmented LXRa, PPARa, and ABCA1 expression, which are associated with cholesterol efflux. Consequently, KME and HDMPPA suppressed lipid accumulation. These results indicate that KME and HDMPPA may inhibit lipid accumulation, in part, by regulating cholesterol influx-and efflux-related proteins. These findings will thus be useful for future prevention strategies against atherosclerosis.

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Small Dense LDL Enhances THP-1 Macrophage Foam Cell Formation

Cited by 29 publications

References 24 publications

Electronegative LDL Promotes Inflammation and Triglyceride Accumulation in Macrophages

Electronegative LDL Promotes Inflammation and Triglyceride Accumulation in Macrophages

Immunological detection of large oxidized lipoproteins in hypertriglyceridemic serum

Kimchi Methanol Extract and the Kimchi Active Compound, 3′-(4′-Hydroxyl-3′,5′-Dimethoxyphenyl)Propionic Acid, Downregulate CD36 in THP-1 Macrophages Stimulated by oxLDL

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