Macrophage ABCA2 deletion modulates intracellular cholesterol deposition, affects macrophage apoptosis, and decreases early atherosclerosis in LDL receptor knockout mice

Calpe-Berdiel, Laura; Zhao, Ying; Graauw, Marjo de; Ye, Dan; Santbrink, Peter J. van; Mommaas, A. Mieke; Foks, Amanda C.; Bot, Martine; Meurs, Illiana; Kuiper, Johan; Mack, Jody T.; Eck, Miranda Van; Tew, Kenneth D.; Berkel, Theo J.C. Van

doi:10.1016/j.atherosclerosis.2012.05.039

Cited by 19 publications

(11 citation statements)

References 46 publications

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“…Ongoing research using animals and cells has produced increasing evidence that cholesterol efflux pathways are mediated by ABC transporters and that HDL suppresses atherosclerosis ( 25 ). In addition, the specific knockout of macrophage transporters has confirmed their role in the suppression of inflammatory responses in the arterial wall ( 26 , 27 ). Thus, the activation of cholesterol efflux pathways targeting ABCA1 and ABCG1 may prove to be novel therapeutic approaches to the treatment of atherosclerosis ( 9 ).…”

Section: Discussionmentioning

confidence: 92%

Purple perilla extracts with α-asarone enhance cholesterol efflux from oxidized LDL-exposed macrophages

Park

Paek

Shin

et al. 2015

International Journal of Molecular Medicine

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The cellular accumulation of cholesterol is critical in the development and progression of atherosclerosis. ATP-binding cassette (ABC) transporters play an essential role in mediating the efflux of excess cholesterol. In the current study, we investigated whether purple Perilla frutescens extracts (PPE) at a non-toxic concentration of 1–10 μg/ml stimulate the induction of the ABC transporters, ABCA1 and ABCG1, and cholesterol efflux from lipid-laden J774A.1 murine macrophages exposed to 50 ng/ml oxidized low-density lipoprotein (LDL). Purple perilla, an annual herb in the mint family and its constituents, have been reported to exhibit antioxidant and cytostatic activity, as well as to exert anti-allergic effects. Our results revealed that treatment with oxidized LDL for 24 h led to the accumulation of lipid droplets in the macrophages. PPE suppressed the oxidized LDL-induced foam cell formation by blocking the induction of scavenger receptor B1. However, PPE promoted the induction of the ABC transporters, ABCA1 and ABCG1, and subsequently accelerated cholesterol efflux from the lipid-loaded macrophages. The liver X receptor (LXR) agonist, TO-091317, and the peroxisome proliferator-activated receptor (PPAR) agonist, pioglitazone, increased ABCA1 expression and treatment with 10 μg/ml PPE further enhanced this effect. PPE did not induce LXRα and PPARγ expression per se, but enhanced their expression in the macrophages exposed to oxidized LDL. α-asarone was isolated from PPE and characterized as a major component enhancing the induction of ABCA1 and ABCG1 in macrophages exposed to oxidized LDL. α-asarone, but not β-asarone was effective in attenuating foam cell formation and enhancing cholesterol efflux, revealing an isomeric difference in their activity. The results from the present study demonstrate that PPE promotes cholesterol efflux from macrophages by activating the interaction of PPARγ-LXRα-ABC transporters.

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Section: Discussionmentioning

confidence: 92%

Purple perilla extracts with α-asarone enhance cholesterol efflux from oxidized LDL-exposed macrophages

Park

Paek

Shin

et al. 2015

International Journal of Molecular Medicine

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“…These findings were supported in studies of ABCA2 knockout macrophages [15]. In N2a mouse neuroblastoma cells, the Davis group determined that overexpression of human ABCA2 or reduction of endogenous ABCA2 levels in N2a cells and in primary rat neurons by RNAi modulated LDL receptor level.…”

Section: Introductionmentioning

confidence: 80%

“…A possible mechanistic role for ABCA2 in cardiovascular disease was suggested by a study describing deletion of ABCA2 in macrophages of LDL receptor knockout mice [15]. …”

Section: Introductionmentioning

confidence: 99%

The ATP-binding cassette transporter-2 (ABCA2) regulates esterification of plasma membrane cholesterol by modulation of sphingolipid metabolism

Davis

2014

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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The ATP-binding cassette transporters are a large family (~ 48 genes divided into seven families A–G) of proteins that utilize the energy of ATP-hydrolysis to pump substrates across lipid bilayers against a concentration gradient. The ABC “A” subfamily is comprised of 13 members and transport sterols, phospholipids and bile acids. ABCA2 is the most abundant ABC transporter in human and rodent brain with highest expression in oligodendrocytes, although it is also expressed in neurons. Several groups have studied a possible connection between ABCA2 and Alzheimer’s disease as well as early atherosclerosis. ABCA2 expression levels have been associated with changes in cholesterol and sphingolipid metabolism. In this paper, we hypothesized that ABCA2 expression level may regulate esterification of plasma membrane-derived cholesterol by modulation of sphingolipid metabolism. ABCA2 overexpression in N2a neuroblastoma cells was associated with an altered bilayer distribution of the sphingolipid ceramide that inhibited acylCoA:cholesterol acyltransferase (ACAT) activity and cholesterol esterification. In contrast, depletion of endogenous ABCA2 in the rat schwannoma cell line D6P2T increased esterification of plasma membrane cholesterol following treatment with exogenous bacterial sphingomyelinase. These findings suggest that control of ABCA2 expression level may be a key locus of regulation for esterification of plasma membrane-derived cholesterol through modulation of sphingolipid metabolism.

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“…Examples of such a beneficial effect of macrophage apoptosis on lesion burden are as follows: ABCG1 −/− LDLr −/− animals, 65 ABCA2 deletion in mouse macrophages, 66 and ATGL deficiency in mouse macrophages. 67 Consistently, deficiency of the proapoptotic key regulator p53 tended to reduce apoptosis, whereas it increased lesion area, lesion macrophage area, and necrotic core area.…”

Section: Discussionmentioning

confidence: 99%

ORP4L Facilitates Macrophage Survival via G-Protein–Coupled Signaling

Wang¹,

Pan²,

Wang³

et al. 2016

Circulation Research

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Rationale: Macrophage survival within the arterial wall is a central factor contributing to atherogenesis. Oxysterols, major components of oxidized low-density lipoprotein, exert cytotoxic effects on macrophages. Objective: To determine whether oxysterol-binding protein–related protein 4 L (ORP4L), an oxysterol-binding protein, affects macrophage survival and the pathogenesis of atherosclerosis. Methods and Results: By hiring cell biological approaches and ORP4L − /− mice, we show that ORP4L coexpresses with and forms a complex with Gα q/11 and phospholipase C (PLC)-β3 in macrophages. ORP4L facilitates G-protein–coupled ligand-induced PLCβ3 activation, IP 3 production, and Ca 2+ release from the endoplasmic reticulum. Through this mechanism, ORP4L sustains antiapoptotic Bcl-XL expression through Ca 2+ -mediated c-AMP responsive element binding protein transcriptional regulation and thus protects macrophages from apoptosis. Excessive stimulation with the oxysterol 25-hydroxycholesterol disassembles the ORP4L/Gα q/11 /PLCβ3 complexes, resulting in reduced PLCβ3 activity, IP 3 production, and Ca 2+ release, as well as decreased Bcl-XL expression and increased apoptosis. Overexpression of ORP4L counteracts these oxysterol-induced defects. Mice lacking ORP4L exhibit increased apoptosis of macrophages in atherosclerotic lesions and a reduced lesion size. Conclusions: ORP4L is crucial for macrophage survival. It counteracts the cytotoxicity of oxysterols/oxidized low-density lipoprotein to protect macrophage from apoptosis, thus playing an important role in the development of atherosclerosis.

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Macrophage ABCA2 deletion modulates intracellular cholesterol deposition, affects macrophage apoptosis, and decreases early atherosclerosis in LDL receptor knockout mice

Cited by 19 publications

References 46 publications

Purple perilla extracts with α-asarone enhance cholesterol efflux from oxidized LDL-exposed macrophages

Purple perilla extracts with α-asarone enhance cholesterol efflux from oxidized LDL-exposed macrophages

The ATP-binding cassette transporter-2 (ABCA2) regulates esterification of plasma membrane cholesterol by modulation of sphingolipid metabolism

ORP4L Facilitates Macrophage Survival via G-Protein–Coupled Signaling

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