Activation of Phosphatidylinositol-Specific Phospholipase C in Response to HDL
            <sub>3</sub>
            and LDL Is Markedly Reduced in Cultured Fibroblasts From Tangier Patients

Drobnik, Wolfgang; Möllers, Christoph; Resink, Thérèse J.; Schmitz, Gerd

doi:10.1161/01.atv.15.9.1369

Cited by 27 publications

(15 citation statements)

References 37 publications

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“…This result was later confirmed by Li, Tsujita, and Yokoyama (32) and Drobnik et al (28). Activation of PKC by phorbol esters resulted in activation of efflux to apoA-I or HDL (27,32,(64)(65)(66).…”

Section: Discussionmentioning

confidence: 54%

“…Phosphorylation of a PEST sequence in ABCA1 promotes calpain-mediated degradation of ABCA1 (25). Protein kinase C (PKC) stimulators promoted cholesterol efflux in a dose-dependent fashion in normal and Tangier disease [(TD) ABCA1-defective] fibroblasts (26,27), and deficient PKC activation was detected in TD fibroblasts (28). It was proposed that apolipoprotein A-I (apoA-I)-containing lipoproteins stimulate removal of sphingomyelin, which, in turn, stimulates phosphatidylcholine-specific phospholipase C (PC-PLC) and phospholipase D (PC-PLD) (29).…”

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confidence: 99%

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Lipid efflux in human and mouse macrophagic cells: evidence for differential regulation of phospholipid and cholesterol efflux

Kiss

Maric

Marcel

2005

Journal of Lipid Research

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With the recent discovery of the role of ABCA1 in lipid efflux, and the potential regulation of ABCA1 as a means to regulate plasma HDL levels, much research has focused on the transcriptional and posttranslational regulation of ABCA1. There are multiple elements in the proximal promoter of ABCA1 that may regulate its expression (1). Cholesterol loading strongly stimulates ABCA1 expression in macrophages, where it evidently increases ABCA1 mRNA abundance and protein levels, although the mechanism is not understood (2). ABCA1 gene regulation is also mediated by the nuclear liver X receptors (LXR ␣ and ␤ ) and retinoid X receptors (RXRs) (3, 4), and their respective ligands, oxysterols and 9-cis -retinoic acid (9cRA). Cavelier et al. (5) showed, in mice carrying a human ABCA1 transgene under the control of its natural flanking sequences, that the human and mouse ABCA1 genes responded differently to cyclic AMP (cAMP), and that novel, as-yet-unreported promoters may exist that regulate ABCA1 expression and activity. As such, cAMP significantly stimulates efflux in J774, mouse peritoneal macrophages (MPMs), and RAW 264 cells (6-10) and not in THP-1 cells or human monocyte-derived macrophages (MDMs) (11, 12). cAMP's primary effect may be on transcription and protein expression, because efflux is not stimulated before 6 h, and protein synthesis inhibitors prevent stimulation (13). At the other end, efflux was reduced to near baseline levels within 6 h upon removal of cAMP, indicating that ABCA1 is highly regulated at the protein level (8,(14)(15)(16). ABCA1 can be phosphorylated in vitro (17,18), and this can be regulated by protein kinase A (PKA) (18,19). Activators of PKA, including cAMP, are known to stimulate specific efflux and ABCA1 phosphorylation, whereas inhibitors of PKA cause decreased efflux and reduced phosphorylation (18,(20)(21)(22)(23). Therefore, cAMP promotes lipid efflux by both stimulating expression of ABCA1 and activation of ABCA1 by phosphorylation.It is known that many other signaling pathways can also affect lipid efflux. Janus kinase 2 appears to selectively modulate apolipoprotein interactions with ABCA1 without di-

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Section: Discussionmentioning

confidence: 54%

mentioning

confidence: 99%

Lipid efflux in human and mouse macrophagic cells: evidence for differential regulation of phospholipid and cholesterol efflux

Kiss

Maric

Marcel

2005

Journal of Lipid Research

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“…7,11,13 Because PLD is also thought to participate in mitogenic signaling, 43 the question arises as to whether defective G i -protein-mediated signaling is involved in the growth and cell cycle abnormalities of TD fibroblasts. We have demonstrated that neither the blockade of G i protein function with PTX 33 nor the inhibition of phosphatidic acid generation by butanol 34 was able to induce a G 2 /M-phase arrest or to elevate cellular ceramide levels in control cells.…”

Section: Discussionmentioning

confidence: 99%

Growth and Cell Cycle Abnormalities of Fibroblasts From Tangier Disease Patients

Drobnik

Liebisch

Biederer

et al. 1999

ATVB

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Abstract-We have investigated the abnormal proliferation and morphology of fibroblasts from patients with Tangier disease (TD), a high density lipoprotein (HDL) deficiency syndrome that is characterized by impairment of HDL 3 -mediated lipid efflux and G i -protein-mediated signaling via phosphatidylinositol-specific phospholipase C (PI-PLC) and phospholipase D (PLD). TD fibroblasts displayed a 30% to 50% reduced in vitro growth rate and a 1.6-fold increased cell surface area. The response to different mitogens was diminished, and asynchronously growing TD fibroblasts showed 4.4Ϯ0.3% S-phase and 19.1Ϯ0.5% G 2 /M-phase cells compared with 9.7Ϯ0.6% and 7.8Ϯ0.5%, respectively, in controls. Monensin, but not brefeldin A, induced an S-and G 2 /M-phase distribution in control cells similar to that found in TD fibroblasts. This effect of monensin was accompanied by an increase of ceramide levels in controls, whereas TD fibroblasts already had a 2.5-fold increased basal ceramide concentration. Incubation of control cells with C2 ceramide and threo-1-phenyl-2-decanoylamino-3-morpholino-1-propanol (PDMP) mimicked the effect of monensin on the cell cycle. The inhibition of neither G i protein function by pertussis toxin nor PLD by butanol resulted in a G 2 /M-phase arrest. Propranolol, known to increase phosphatidic acid levels, was ineffective in reversing the G 2 /M-phase arrest in TD fibroblasts. In addition, cDNA sequences and mRNA expression of the participants of PI-PLC or PLD signaling, ie, G-protein subunits ␣ i 1, ␣ i 2, and ␣ i 3; phosphatidylinositol transfer proteins-␣ and -␤; and ADP ribosylation factors 1 and 3 were found to be normal. Thus, growth and cell cycle abnormalities in TD fibroblasts are likely to be related to impaired Golgi function and sphingolipid signaling rather than inoperative G-protein signal transduction. Because PDMP was also found to decrease HDL 3 -mediated lipid efflux in control but not TD fibroblasts, similar pathways seem to be involved in the disturbances of lipid transport and growth retardation.

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“…The cholesterol export kinetics during incubation of macrophages with HDL 3 was assessed for HDL 3 -dependent and -independent cholesterol efflux. For this, macrophages were loaded with acLDL for 2 days in the presence of 14 C-cholesterol as described (25)(26)(27). Cells were then washed and deloaded in the presence of HDL 3 for 12, 24, and 48 h, respectively.…”

Section: Kinetics Of Cholesterol Loading and Deloading In Human Macromentioning

confidence: 99%

ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport

Klucken

Büchler

Orsó

et al. 2000

Proc. Natl. Acad. Sci. U.S.A.

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438

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Excessive uptake of atherogenic lipoproteins such as modified lowdensity lipoprotein complexes by vascular macrophages leads to foam cell formation, a critical step in atherogenesis. Cholesterol efflux mediated by high-density lipoproteins (HDL) constitutes a protective mechanism against macrophage lipid overloading. The molecular mechanisms underlying this reverse cholesterol transport process are currently not fully understood. To identify effector proteins that are involved in macrophage lipid uptake and release, we searched for genes that are regulated during lipid influx and efflux in human macrophages using a differential display approach. We report here that the ATP-binding cassette (ABC) transporter ABCG1 (ABC8) is induced in monocyte-derived macrophages during cholesterol influx mediated by acetylated low-density lipoprotein. Conversely, lipid efflux in cholesterol-laden macrophages, mediated by the cholesterol acceptor HDL 3, suppresses the expression of ABCG1. Immunocytochemical and flow cytometric analyses revealed that ABCG1 is expressed on the cell surface and in intracellular compartments of cholesterol-laden macrophages. Inhibition of ABCG1 protein expression using an antisense strategy resulted in reduced HDL 3-dependent efflux of cholesterol and choline-phospholipids. In a comprehensive analysis of the expression and regulation of all currently known human ABC transporters, we identified an additional set of ABC genes whose expression is regulated by cholesterol uptake or HDL 3-mediated lipid release, suggesting a potential function for these transporters in macrophage lipid homeostasis. Our results demonstrating a regulator function for ABCG1 in cholesterol and phospholipid transport define a biologic activity for ABC transporters in macrophages.

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Activation of Phosphatidylinositol-Specific Phospholipase C in Response to HDL ₃ and LDL Is Markedly Reduced in Cultured Fibroblasts From Tangier Patients

Cited by 27 publications

References 37 publications

Lipid efflux in human and mouse macrophagic cells: evidence for differential regulation of phospholipid and cholesterol efflux

Lipid efflux in human and mouse macrophagic cells: evidence for differential regulation of phospholipid and cholesterol efflux

Growth and Cell Cycle Abnormalities of Fibroblasts From Tangier Disease Patients

ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport

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Activation of Phosphatidylinositol-Specific Phospholipase C in Response to HDL 3 and LDL Is Markedly Reduced in Cultured Fibroblasts From Tangier Patients

Cited by 27 publications

References 37 publications

Lipid efflux in human and mouse macrophagic cells: evidence for differential regulation of phospholipid and cholesterol efflux

Lipid efflux in human and mouse macrophagic cells: evidence for differential regulation of phospholipid and cholesterol efflux

Growth and Cell Cycle Abnormalities of Fibroblasts From Tangier Disease Patients

ABCG1 (ABC8), the human homolog of the Drosophila white gene, is a regulator of macrophage cholesterol and phospholipid transport

Contact Info

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Activation of Phosphatidylinositol-Specific Phospholipase C in Response to HDL ₃ and LDL Is Markedly Reduced in Cultured Fibroblasts From Tangier Patients