Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice

Yvan‐Charvet, Laurent; Ranalletta, Mollie; Wang, Nan; Han, Seongah; Terasaka, Naoki; Li, Rong; Welch, Carrie L.; Tall, Alan R.

doi:10.1172/jci33372

Cited by 348 publications

(431 citation statements)

References 61 publications

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“…Notably, expression of Abca1 in adipocytes was recently reported to influence adipocyte lipid homeostasis (19). This observation may be important because Abcg1 deficiency in mouse macrophages was proposed to be compensated by an increase in Abca1 expression (20). However, such elevation of Abca1 expression was not observed in our conditions when Abcg1 was knocked down in 3T3-L1 adipocytes (Fig.…”

Section: Impaired Maturation In Stable Abcg1 Kd 3t3-l1 Adipocytesmentioning

confidence: 65%

Adipocyte ATP-Binding Cassette G1 Promotes Triglyceride Storage, Fat Mass Growth, and Human Obesity

et al. 2014

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The role of the ATP-binding cassette G1 (ABCG1) transporter in human pathophysiology is still largely unknown. Indeed, beyond its role in mediating free cholesterol efflux to HDL, the ABCG1 transporter equally promotes lipid accumulation in a triglyceride (TG)-rich environment through regulation of the bioavailability of lipoprotein lipase (LPL). Because both ABCG1 and LPL are expressed in adipose tissue, we hypothesized that ABCG1 is implicated in adipocyte TG storage and therefore could be a major actor in adipose tissue fat accumulation. Silencing of Abcg1 expression by RNA interference in 3T3-L1 preadipocytes compromised LPL-dependent TG accumulation during the initial phase of differentiation. Generation of stable Abcg1 knockdown 3T3-L1 adipocytes revealed that Abcg1 deficiency reduces TG storage and diminishes lipid droplet size through inhibition of Pparγ expression. Strikingly, local inhibition of adipocyte Abcg1 in adipose tissue from mice fed a high-fat diet led to a rapid decrease of adiposity and weight gain. Analysis of two frequent ABCG1 single nucleotide polymorphisms (rs1893590 [A/C] and rs1378577 [T/G]) in morbidly obese individuals indicated that elevated ABCG1 expression in adipose tissue was associated with increased PPARγ expression and adiposity concomitant to increased fat mass and BMI (haplotype AT>GC). The critical role of ABCG1 in obesity was further confirmed in independent populations of severe obese and diabetic obese individuals. This study identifies for the first time a major role of adipocyte ABCG1 in adiposity and fat mass growth and suggests that adipose ABCG1 might represent a potential therapeutic target in obesity.

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Section: Impaired Maturation In Stable Abcg1 Kd 3t3-l1 Adipocytesmentioning

confidence: 65%

Adipocyte ATP-Binding Cassette G1 Promotes Triglyceride Storage, Fat Mass Growth, and Human Obesity

et al. 2014

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“…Although passive diffusion plays a minor role, active transport via several transporters is responsible for the bulk of the efflux of cholesterol from macrophages into the serum; this process includes the transport to lipid-poor ApoA1 or HDL by ABCA1 and ABCG1 (Adorni et al, 2007). Although the selective deletion of ABCA1 in macrophages (Brunham et al, 2009) and the overexpression of ABCG1 (Burgess et al, 2008) did not significantly modulate the development of atherosclerotic plaques, simultaneous deficiency in both ABCA1 and ABCG1 promoted atherosclerosis in mice (Yvan-Charvet et al, 2007). In addition to ABCA1 and ABCG1, SR-BI, another type B scavenger receptor, protects against atherosclerosis when expressed in macrophages by stimulating cholesterol efflux, whereas genetically suppressing SR-BI activity in ApoE-deficient mice dramatically accelerates the onset of atherosclerosis (Trigatti et al, 1999).…”

Section: Cholesterol Effluxmentioning

confidence: 99%

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

2012

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“…In particular, bone marrow transplantation of ABCA1-KO mice with wild type macrophages [10] or macrophages that specifically over-express ABCA1 [11] resulted in a substantial decrease in atherosclerosis. The combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice [12] . Therefore, up-regulation of ABCA1 and ABCG1 has been proposed as a therapeutic target in treating atherosclerosis.…”

Section: Introductionmentioning

confidence: 99%

Betulin attenuates atherosclerosis in apoE−/− mice by up-regulating ABCA1 and ABCG1

et al. 2016

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Aim: Betulin is a pentacyclic triterpenoid isolated from the bark of yellow and white birch trees with anti-cancer and anti-malaria activities. In this study we examined the effects of betulin on atherosclerosis in apoE -/-mice and the underlying mechanisms. Methods: Murine macrophage RAW264.7 cells and human monocyte-derived THP-1 cells were tested. Foam cell formation was detected with Oil Red O staining. Cholesterol efflux was assessed using [3 H]-cholesterol efflux assay. The expression of ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1) was examined using RT-PCR and Western-blotting. The ABCA1 promoter activity was evaluated using luciferase activity assay. Male apoE -/-mice fed on a high-fat-diet (HFD), and received betulin (20 and 40 mg·kg -1 ·d -1, ig) for 12 weeks. The macrophage content and ABCA1 expression in the aortic sinuses were evaluated with immunofluorescence staining. The hepatic, intestinal and fecal cholesterol were also analyzed in the mice. Results: In RAW264.7 cells, betulin (0.1-2.5 μg/mL) dose-dependently ameliorated oxLDL-induced cholesterol accumulation and enhanced cholesterol efflux. In both RAW264.7 and THP-1 cells, betulin increased the expression of ABCA1 and ABCG1 via suppressing the transcriptional repressors sterol-responsive element-binding proteins (SREBPs) that bound to E-box motifs in ABCA1 promoter, whereas E-box binding site mutation markedly attenuated betulin-induced ABCA1 promoter activity. In HFD-fed apoE -/-mice, betulin administration significantly reduced lesions in en face aortas and aortic sinuses. Furthermore, betulin administration significantly increased ABCA1 expression and suppressed macrophage positive areas in the aortic sinuses. Moreover, betulin administration improved plasma lipid profiles and enhanced fecal cholesterol excretion in the mice. Conclusion: Betulin attenuates atherosclerosis in apoE -/-mice by promoting cholesterol efflux in macrophages.

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Combined deficiency of ABCA1 and ABCG1 promotes foam cell accumulation and accelerates atherosclerosis in mice

Cited by 348 publications

References 61 publications

Adipocyte ATP-Binding Cassette G1 Promotes Triglyceride Storage, Fat Mass Growth, and Human Obesity

Adipocyte ATP-Binding Cassette G1 Promotes Triglyceride Storage, Fat Mass Growth, and Human Obesity

Lipid homeostasis and the formation of macrophage-derived foam cells in atherosclerosis

Betulin attenuates atherosclerosis in apoE−/− mice by up-regulating ABCA1 and ABCG1

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