An analysis of the role of a retroendocytosis pathway in ABCA1-mediated cholesterol efflux from macrophages

Faulkner, Loren E.; Panagotopulos, Stacey E.; Johnson, Jacob; Woollett, Laura A.; Hui, David Y.; Witting, Scott R.; Maiorano, J. Nicholas; Davidson, W. Sean

doi:10.1194/jlr.m800048-jlr200

Cited by 55 publications

(59 citation statements)

References 38 publications

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“…The fact that apoA-I lipidation and HDL release was fully recovered after WGA removal from the plasma membrane supports this notion. Our conclusion is also consistent with recent reports that HDL is primarily generated on the plasma membrane (44,45).…”

Section: A937vsupporting

confidence: 83%

ABCA1-mediated cholesterol efflux generates microparticles in addition to HDL through processes governed by membrane rigidity

Nandi

Denis

et al. 2009

Journal of Lipid Research

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ATP-binding cassette transporter A1 (ABCA1) mediates cholesterol efflux to lipid-poor apolipoprotein A-I (apoA-I) and generates HDL. Here, we demonstrate that ABCA1 also directly mediates the production of apoA-I free microparticles. In baby hamster kidney (BHK) cells and RAW macrophages, ABCA1 expression led to lipid efflux in the absence of apoA-I and released large microparticles devoid of apoB and apoE. We provide evidence that these microparticles are an integral component of the classical cholesterol efflux pathway when apoA-I is present and accounted for approximately 30% of the total cholesterol released to the medium. Furthermore, microparticle release required similar ABCA1 activities as was required for HDL production. For instance, a nucleotide binding domain mutation in ABCA1 (A937V) that impaired HDL generation also abolished microparticle release. Similarly, inhibition of protein kinase A (PKA) prevented the release of both types of particles. Interestingly, physical modulation of membrane dynamics affected HDL and microparticle production, rigidifying the plasma membrane with wheat germ agglutinin inhibited HDL and microparticle release, whereas increasing the fluidity promoted the production of these particles. Given the established role of ABCA1 in expending nonraft or more fluid-like membrane domains, our results suggest that both HDL and microparticle release is favored by a more fluid plasma membrane. We speculate that ABCA1 enhances the dynamic movement of the plasma membrane, which is required for apoA-I lipidation and microparticle formation.-Nandi, S

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Section: A937vsupporting

confidence: 83%

ABCA1-mediated cholesterol efflux generates microparticles in addition to HDL through processes governed by membrane rigidity

Nandi

Denis

et al. 2009

Journal of Lipid Research

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“…Cell surface expression of ABCA1 permits the transporter to transfer cholesterol and phospholipid to apoA-I, which is present in the extracellular environment (23,24). β1-Syntrophin binds ABCA1 through the PDZ motif in the ABCA1 C-terminal domain, and the positive effect that β 1-syntrophin has on the trafficking of ABCA1 likely is mediated by the ability of β 1-syntrophin to recruit utrophin, a cytoskeletal binding protein, to the ABCA1 complex (12,25,26).…”

Section: Discussionmentioning

confidence: 99%

SPTLC1 Binds ABCA1 To Negatively Regulate Trafficking and Cholesterol Efflux Activity of the Transporter

et al. 2008

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ABCA1 transport of cholesterol and phospholipids to nascent HDL particles plays a central role in lipoprotein metabolism and macrophage cholesterol homeostasis. ABCA1 activity is regulated both at the transcriptional level and at the post-translational level. To explore mechanisms involved in the post-translational regulation of the transporter, we have used affinity purification and mass spectrometry to identify proteins that bind ABCA1 and influence its activity. Previously, we demonstrated that an interaction between β 1-syntrophin stimulated ABCA1 activity, at least in part, be slowing the degradation of the transporter. This work demonstrates that one subunit of the serine palmitoyltransferase enzyme, SPTLC1, but not subunit 2 (SPTLC2), is copurified with ABCA1 and negatively regulates its function. In human THP-I macrophages and in mouse liver, the ABCA1-SPTLC1 complex was detected by co-immunoprecipitation, demonstrating that the interaction occurs in cellular settings where ABCA1 activity is critical for HDL genesis. Pharmacologic inhibition of SPTLC1 with myriocin, which resulted in the disruption of the SPTLC1-ABCA1 complex, and siRNA knockdown of SPTLC1 expression both stimulated ABCA1 efflux by nearly 60% (p < 0.05). In contrast, dominant-negative mutants of SPTLC1 inhibited ABCA1 efflux, indicating that a reduced level of sphingomyelin synthesis could not explain the effect of myriocin on ABCA1 activity. In 293 cells, the SPTLC1 inhibition of ABCA1 activity led to the blockade of the exit of ABCA1 from the endoplasmic reticulum. In contrast, myriocin treatment of macrophages increased the level of cell surface ABCA1. In composite, these results indicate that the physical interaction of ABCA1 and SPTLC1 results in reduction of ABCA1 activity and that inhibition of this interaction produces enhanced cholesterol efflux.Disruption of cellular cholesterol homeostasis leads to a variety of pathological conditions, including cardiovascular disease (1). Active efflux of cholesterol to extracellular

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“…It is also interesting that only these two tissues quantitatively produce apoA-I (56). There is also mounting evidence that assembly of most HDL particles occurs at the cell surface (45,(58)(59)(60)(61)(62)(63)(64) or in a recycling endosomal compartment by ABCA1 (65)(66)(67)(68)(69)(70) and not in the secretory pathway of the endoplasmic reticulum and Golgi apparatus (71). Because we have shown that poorly lipidated apoA-I (i.e., pre-b1 HDL) is rapidly catabolized by the kidney, whereas lipid-free apoA-I rapidly and quantitatively transfers to plasma HDLs (17,51), newly synthesized apoA-I from hepatocytes or intestinal epithelial cells has several metabolic fates.…”

Section: Discussionmentioning

confidence: 99%

Initial interaction of apoA-I with ABCA1 impacts in vivo metabolic fate of nascent HDL

Mulya

Lee

Gebre

et al. 2008

Journal of Lipid Research

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We investigated the in vivo metabolic fate of preb HDL particles in human apolipoprotein A-I transgenic (hA-I Tg ) mice. Pre-b HDL tracers were assembled by incubation of [125 I]tyramine cellobiose-labeled apolipoprotein A-I (apoA-I) with HEK293 cells expressing ABCA1. Radiolabeled pre-b HDLs of increasing size (pre-b1, -2, -3, and -4 HDLs) were isolated by fast-protein liquid chromatography and injected into hA-I Tg -recipient mice, after which plasma decay, in vivo remodeling, and tissue uptake were monitored. Pre-b2, -3, and -4 had similar plasma die-away rates, whereas pre-b1 HDL was removed 7-fold more rapidly. Radiolabel recovered in liver and kidney 24 h after tracer injection suggested increased (P , 0.001) liver and decreased kidney catabolism as pre-b HDL size increased. In plasma, pre-b1 and -2 were rapidly (,5 min) remodeled into larger HDLs, whereas pre-b3 and -4 were remodeled into smaller HDLs. Pre-b HDLs were similarly remodeled in vitro with control or LCAT-immunodepleted plasma, but not when incubated with phospholipid transfer protein knockout plasma. Our results suggest that initial interaction of apoA-I with ABCA1 imparts a unique conformation that partially determines the in vivo metabolic fate of apoA-I, resulting in increased liver and decreased kidney catabolism as pre-b HDL particle size

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An analysis of the role of a retroendocytosis pathway in ABCA1-mediated cholesterol efflux from macrophages

Cited by 55 publications

References 38 publications

ABCA1-mediated cholesterol efflux generates microparticles in addition to HDL through processes governed by membrane rigidity

ABCA1-mediated cholesterol efflux generates microparticles in addition to HDL through processes governed by membrane rigidity

SPTLC1 Binds ABCA1 To Negatively Regulate Trafficking and Cholesterol Efflux Activity of the Transporter

Initial interaction of apoA-I with ABCA1 impacts in vivo metabolic fate of nascent HDL

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