Retinoic Acid Receptor-Mediated Induction of ABCA1 in Macrophages

Costet, Philippe; Lalanne, Florent; Gerbod-Giannone, Marie Christine; Molina, Jennifer R.; Fu, Xuan; Lund, Erik; Gudas, Lorraine J.; Tall, Alan R.

doi:10.1128/mcb.23.21.7756-7766.2003

Cited by 128 publications

(103 citation statements)

References 49 publications

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“…Electrophoretic Mobility Shift Assays (EMSA)-EMSA were performed as described elsewhere (39). SREBP-1c expression vector was translated in vitro using TNT Coupled Reticulocyte Lysate Systems (Promega).…”

Section: Methodsmentioning

confidence: 99%

Hepatic PCSK9 Expression Is Regulated by Nutritional Status via Insulin and Sterol Regulatory Element-binding Protein 1c

Costet

Cariou

Lambert

et al. 2006

Journal of Biological Chemistry

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276

224

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Familial autosomal dominant hypercholesterolemia is associated with high risk for cardiovascular accidents and is related to mutations in the low density lipoprotein receptor or its ligand apolipoprotein B (apoB). Mutations in a third gene, proprotein convertase subtilisin kexin 9 (PCSK9), were recently associated to this disease. PCSK9 acts as a natural inhibitor of the low density lipoprotein receptor pathway, and both genes are regulated by depletion of cholesterol cell content and statins, via sterol regulatory elementbinding protein (SREBP). Here we investigated the regulation of PCSK9 gene expression during nutritional changes. We showed that PCSK9 mRNA quantity is decreased by 73% in mice after 24 h of fasting, leading to a 2-fold decrease in protein level. In contrast PCSK9 expression was restored upon high carbohydrate refeeding. PCSK9 mRNA increased by 4 -5-fold in presence of insulin in rodent primary hepatocytes, whereas glucose had no effect. Moreover, insulin up-regulated hepatic PCSK9 expression in vivo during a hyperinsulinemic-euglycemic clamp in mice. Adenoviral mediated overexpression of a dominant or negative form of SREBP-1c confirmed the implication of this transcription factor in insulinmediated stimulation of PCSK9 expression. Liver X receptor agonist T0901317 also regulated PCSK9 expression via this same pathway (a 2-fold increase in PCSK9 mRNA of primary hepatocytes cultured for 24 h in presence of 1 M T0901317). As our last investigation, we isolated PCSK9 proximal promoter and verified the functionality of a SREBP-1c responsive element located from 335 bp to 355 bp upstream of the ATG. Together, these results show that PCSK9 expression is regulated by nutritional status and insulinemia.Autosomal dominant hypercholesterolemia is associated with mutations in genes involved in the regulation of LDL 2 homeostasis. The most common and severe form of monogenic hypercholesterolemia is familial hypercholesterolemia, caused by mutations in the LDL receptor (LDLr) (1). Familial hypercholesterolemia is characterized by elevated plasma LDL-cholesterol levels and premature cardiovascular disease.Another form of this disease, familial defective apolipoprotein (apo)B100, is caused by mutations in the LDLr binding domain of ApoB100 (1). ApoB100 is synthesized by the liver and is the major protein component of very low density lipoprotein and LDL. Recently, proprotein convertase subtilisin kexin 9 (PCSK9) has been identified as the third gene involved in autosomal dominant hypercholesterolemia (5). Proprotein convertases are proteolytic enzymes that cleave their substrate, producing a biologically active molecule (2). We showed that patients mutated in PCSK9 prodomain (mutation S127R) have decreased LDL catabolism and increased very low density lipoprotein, intermediary density lipoprotein, and LDL production (3). Studies on knock-out mice and plasma lipid profiles of patients with nonsense mutations, showed that PCSK9 deficiency results in low circulating LDL-cholesterol concentrations (4 -6). Althou...

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Section: Methodsmentioning

confidence: 99%

Hepatic PCSK9 Expression Is Regulated by Nutritional Status via Insulin and Sterol Regulatory Element-binding Protein 1c

Costet

Cariou

Lambert

et al. 2006

Journal of Biological Chemistry

Self Cite

276

224

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“…Real-time quantitative PCR assays were performed as described in ref. 52. All samples were analyzed for ␤-actin, 36B4 expression, or 18S RNA in the same run as ABCA1, ABCG1, ABCA7, or MMP-9.…”

Section: Methodsmentioning

confidence: 99%

“…Protein extracts were prepared in modified radioimmunoprecipitation assay buffer as described in ref. 52. Equal amounts of protein (15 g) were fractioned on a 4-15% gradient SDS͞polyacrylamide gel, then transferred to a nitrocellulose membrane, incubated with anti-ABCA1 and anti-␤-actin Abs, and processed with horseradish peroxidaseconjugated secondary Ab using SuperSignal West Pico Chemiluminescent substrate (Pierce).…”

Section: Methodsmentioning

confidence: 99%

TNFα induces ABCA1 through NF-κB in macrophages and in phagocytes ingesting apoptotic cells

Gerbod-Giannone

Holleboom

et al. 2006

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

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101

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Recent evidence suggests that tumor necrosis factor ␣ (TNF␣) signaling in vascular cells can have antiatherogenic consequences, but the mechanisms are poorly understood. TNF␣ is released by free cholesterol-loaded apoptotic macrophages, and the clearance of these cells by phagocytic macrophages may help to limit plaque development. Macrophage cholesterol uptake induces ATP-binding cassette (ABC) transporter ABCA1 promoting cholesterol efflux to apolipoprotein A-I and reducing atherosclerosis. We show that TNF␣ induces ABCA1 mRNA and protein in control and cholesterolloaded macrophages and enhances cholesterol efflux to apolipoprotein A-I. The induction of ABCA1 by TNF␣ is reduced by 65% in I B kinase ␤-deficient macrophages and by 30% in p38␣-deficient macrophages, but not in jun kinase 1 (JNK1)-or JNK2-deficient macrophages. To evaluate the potential pathophysiological significance of these observations, we fed TNF␣-secreting free cholesterol-loaded apoptotic macrophages to a healthy macrophage monolayer (phagocytes). ABCA1 mRNA and protein were markedly induced in the phagocytes, a response that was mediated both by TNF␣ signaling and by liver X receptor activation. Thus, TNF␣ signals primarily through NF-B to induce ABCA1 expression in macrophages. In atherosclerotic plaques, this process may help phagocytic macrophages to efflux excess lipids derived from the ingestion of cholesterol-rich apoptotic corpses.atherosclerosis ͉ cytokine ͉ ATP-binding cassette transporter A BCA1 belongs to the ATP-binding cassette (ABC) transporter superfamily (1, 2) and promotes efflux of cholesterol and phospholipids from cellular membranes to apolipoprotein A-I (apoA-I) (3). In macrophages, oxysterol-activated liver X receptor (LXR) (4) and retinoid X receptor form a heterodimer that binds to a direct repeat 4 sequence (5, 6) located in the proximal promoter of the ABCA1 gene, resulting in increased gene transcription and increased cholesterol and phospholipid efflux to apoA-I (7). Bone marrow transplantation studies have shown that the expression of ABCA1 in macrophage foam cells has antiatherogenic consequences (8, 9).Atherosclerosis represents an inflammatory reaction in the arterial wall, initiated by the retention of lipoprotein lipids (10, 11). One of the most studied inflammatory cytokines is tumor necrosis factor ␣ (TNF␣), which is active in both human and rodent atherosclerotic plaques (10, 12). Many of the inflammatory properties of TNF␣ suggest that TNF␣ signaling is proatherogenic (13). Paradoxically, other studies have shown that signaling by means of the TNF␣ receptor I (p55) may have an overall atheroprotective effect (14) and moreover that TNF␣ signaling through NF-B in macrophages and vascular smooth muscle cells may be antiatherogenic (14-17). However, the mechanisms of atheroprotective effects of TNF␣ signaling in macrophages are not well understood. In this work, we show that TNF␣ induces ABCA1 through NF-B in macrophages and in phagocytes ingesting apoptotic cells, revealing a previously undescribed antiat...

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“…Two RXR agonists, 9-cis RA and methoprene acid, increased promoter activity 2.7-and 1.5-fold. The RAR agonist, [14] who showed that the livers of TTNPB-fed mice did not show any changes in FAS mRNA expression. Untreated, RXRa-expressing cells showed a slight induction of promoter activity, whereas cells cotransfected with RARb, but not RAtreated, had an approximately 50% decreased FAS promoter activity (Fig.…”

Section: Effect Of Retinoids On the Fas Promotermentioning

confidence: 99%

SREBP‐1c mediates the retinoid‐dependent increase in fatty acid synthase promoter activity in HepG2

2007

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Treatment of HepG2 with all-trans retinoic acid (RA) induces expression of fatty acid synthase (FAS) mRNA and protein. Transfections show that the FAS promoter positively responds to retinoid X receptor (RXR) but not to RA receptor (RAR) agonists. Since RXR alone is capable of mediating the RA response of FAS, the existence of a classical RA-responsive element in the FAS promoter may be ruled out. Binding sites for NF-Y and SREBP-1 proved to be essential for the RA response. Exposure to all-trans RA increased mRNA and protein levels of SREBP-1, a transcriptional activator for FAS. Overexpression of a dominant-negative form of SREBP-1c diminished the RAdependent increase in promoter activity. These data demonstrate that RXR ligands can stimulate the expression of a lipogenic gene solely by inducing transcription and cleavage of membrane-bound SREBP-1c.

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Retinoic Acid Receptor-Mediated Induction of ABCA1 in Macrophages

Abstract: ABCA1, the mutant molecule in Tangier

Cited by 128 publications

References 49 publications

Hepatic PCSK9 Expression Is Regulated by Nutritional Status via Insulin and Sterol Regulatory Element-binding Protein 1c

Hepatic PCSK9 Expression Is Regulated by Nutritional Status via Insulin and Sterol Regulatory Element-binding Protein 1c

TNFα induces ABCA1 through NF-κB in macrophages and in phagocytes ingesting apoptotic cells

SREBP‐1c mediates the retinoid‐dependent increase in fatty acid synthase promoter activity in HepG2

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