Efflux of sphingomyelin, cholesterol, and phosphatidylcholine by ABCG1

Kobayashi, Aya; Takanezawa, Yasukazu; Hirata, Takashi; Shimizu, Yūji; Misasa, Keiko; Kioka, Noriyuki; Arai, Hiroyuki; Ueda, Kazumitsu; Matsuo, Masaru

doi:10.1194/jlr.m500546-jlr200

Cited by 188 publications

(167 citation statements)

References 42 publications

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“…Alternatively, PC may be the more favorable substrate for ABCA1 to transport with cholesterol. Indeed, the medium of ABCA1-expressing cells contains more PC species than SM species in the presence of apoA-I (23).…”

Section: Discussionmentioning

confidence: 99%

Enhanced ApoA-I-dependent Cholesterol Efflux by ABCA1 from Sphingomyelin-deficient Chinese Hamster Ovary Cells

Nagao

Takahashi

Hanada

et al. 2007

Journal of Biological Chemistry

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ATP binding cassette protein A1 (ABCA1) plays a major role in cholesterol homeostasis and high density lipoprotein (HDL) metabolism. It is proposed that ABCA1 reorganizes the plasma membrane and generates more loosely packed domains that facilitate apoA-I-dependent cholesterol efflux. In this study, we examined the effects of the cellular sphingomyelin level on HDL formation by ABCA1 by using a Chinese hamster ovary-K1 mutant cell line, LY-A, which has a missense mutation in the ceramide transfer protein CERT. When LY-A cells were cultured in Nutridoma-BO medium and sphingomyelin content was reduced, apoA-I-dependent cholesterol efflux by ABCA1 from LY-A cells increased 1.65-fold compared with that from LY-A/CERT cells stably transfected with human CERT cDNA. Exogenously added sphingomyelin significantly reduced the apoA-I-dependent efflux of cholesterol from LY-A cells, confirming that the decrease in sphingomyelin content in the plasma membrane stimulates cholesterol efflux by ABCA1. The amount of cholesterol available to cold methyl-␤-cyclodextrin (M␤CD) extraction from LY-A cells was increased by 40% by the expression of ABCA1 and was 1.6-fold higher than that from LY-A/CERT cells. This step in ABCA1 function, making cholesterol available to cold M␤CD, was independent of apoA-I. These results suggest that the function of ABCA1 could be divided into two steps: (i) a flopping step to move phosphatidylcholine and cholesterol from the inner to outer leaflet of the plasma membrane, where cholesterol becomes available to cold M␤CD extraction, and (ii) a loading step to load phosphatidylcholine and cholesterol onto apoA-I to generate HDL. ATP binding cassette protein A1 (ABCA1)2 plays a major role in cholesterol homeostasis and high density lipoprotein (HDL) metabolism (1). It has been reported that apolipoprotein A-I (apoA-I) binds to ABCA1 and cellular-free cholesterol (FC) and phospholipids (PL) are loaded onto apoA-I to form pre-␤ HDL. It is clear that ABCA1 is involved in PL-rich HDL generation in plasma, because plasma PL concentration of Abca1 Ϫ/Ϫ mice was decreased by more than 75%, mostly due to a reduction of HDL (2); however, the molecular mechanism behind ABCA1-mediated pre-␤HDL formation is still poorly understood.Several models have been proposed for the mechanism of ABCA1-mediated pre-␤ HDL formation: (a) A two-step process model proposed by Fielding et al. (3) and Wang et al. (4) that ABCA1 first mediates PL efflux to apoA-I and this apolipoprotein-PL complex accepts FC in an ABCA1-independent manner; (b) a concurrent process model that FC and PL efflux by ABCA1 to apoA-I are tightly coupled to each other (5); and (c) a phosphatidylserine flopping model that ABCA1 mediates the translocation of phosphatidylserine to the outer leaflet and extracellular exposure of phosphatidylserine promotes apoA-I binding to the cell surface and subsequent translocation of phosphatidylcholine (PC) and cholesterol to apoA-I (6). To explore the mechanism of ABCA1-mediated pre-␤ HDL formation, we purified human ABCA1 a...

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Section: Discussionmentioning

confidence: 99%

Enhanced ApoA-I-dependent Cholesterol Efflux by ABCA1 from Sphingomyelin-deficient Chinese Hamster Ovary Cells

Nagao

Takahashi

Hanada

et al. 2007

Journal of Biological Chemistry

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“…36 In this case, BSA most likely works as an acceptor for lipids secreted from the cells expressing ABCG1. However, no lipid efflux by ABCB4 was observed in the presence of BSA (Fig.…”

Section: Discussionmentioning

confidence: 99%

Bile salt–dependent efflux of cellular phospholipids mediated by ATP binding cassette protein B4

et al. 2007

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“…Control and Abcg1 stable KD (SKD) adipocytes (day 10) were incubated for 16 h at 37°C with 0.2% BSA (free of endotoxins and free fatty acids) as an efficient acceptor for Abcg1-mediated SM efflux (15). Media were collected and cells were washed extensively with cold PBS.…”

Section: Quantification Of Sm Massmentioning

confidence: 99%

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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Efflux of sphingomyelin, cholesterol, and phosphatidylcholine by ABCG1

Cited by 188 publications

References 42 publications

Enhanced ApoA-I-dependent Cholesterol Efflux by ABCA1 from Sphingomyelin-deficient Chinese Hamster Ovary Cells

Enhanced ApoA-I-dependent Cholesterol Efflux by ABCA1 from Sphingomyelin-deficient Chinese Hamster Ovary Cells

Bile salt–dependent efflux of cellular phospholipids mediated by ATP binding cassette protein B4

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

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