Abstract 462: Activation of Akt2 by Apolipoprotein E Protects ATP-binding Cassette A1 From Degradation

2016 ◽  
Vol 119 (suppl_1) ◽  
Author(s):  
Hong Yang ◽  
Emmanuel U Okoro ◽  
Zhongmao Guo
Keyword(s):  
Apolipoprotein E ◽  
Protein Level ◽  
Low Density Lipoprotein ◽  
Mrna Level ◽  
Density Lipoprotein ◽  
Atp Binding ◽  
Mrna Levels ◽  
Akt Phosphorylation ◽  
Abca1 Protein ◽  
Atp Binding Cassette

We previously reported that lipid-free apolipoprotein E (apoE) is able to increase ATP-binding cassette transporter A1 (ABCA1) transcription by activation of a signaling cascade involving very low-density lipoprotein receptor, apoE receptor 2, disabled-1, phosphatidylinositol 3-kinase (PI3K), protein kinase Cζ, and specificity protein 1 (Sp1). Here we demonstrated that treatment of RAW 264.7 murine macrophages with human apoE3 enhanced Akt phosphorylation, and upregulated ABCA1 protein and mRNA expression. Inhibition of PI3K weakened apoE3-induced Akt phosphorylation, and reduced ABCA1 protein and mRNA levels. In contrast, inhibition of Akt only diminished apoE-induced ABCA1 protein but not significantly alter ABCA1 mRNA level. Inhibition of protein synthesis did not erase the ability of apoE3 to increase ABCA1 protein level. Further, apoE3 increased the resistance of ABCA1 protein to calpain-mediated degradation without affecting calpain activity. Treatment of 264.7 cells with apoE3 selectively enhanced the phosphorylation of Akt1 and Akt2 but not Akt3. Knockdown of Akt1 enhanced the phosphorylation of Akt2. Vice versa, knockdown of Akt2 enhanced Akt1 phosphorylation. Underexpression of Akt1 or Akt2, respectively, increased and decreased ABCA1 protein level; while overexpression of these Akt isoenzymes caused changes in ABCA1 protein level opposite to those induced by knockdown of the corresponding Akt. These data imply that apoE3 guards against calpain-mediated ABCA1 degradation through Akt2. PI3K might be a step in the signaling pathway for apoE3 to trigger Akt2. [This study was supported by NIH grants SC1HL101431].

scholarly journals ATP-Binding Cassette Transporter A1: A Cell Cholesterol Exporter That Protects Against Cardiovascular Disease

2005 ◽  
Vol 85 (4) ◽  
pp. 1343-1372 ◽  
Author(s):  
John F. Oram ◽  
Jay W. Heinecke
Keyword(s):  
Cardiovascular Disease ◽  
Density Lipoprotein ◽  
Deficiency Syndrome ◽  
Atp Binding ◽  
The Metabolic Syndrome ◽  
Atp Binding Cassette Transporter ◽  
A Cell ◽  
Cell Membrane Protein ◽  
Abca1 Protein ◽  
Atp Binding Cassette

Blood high-density lipoprotein (HDL) levels are inversely related to risk for cardiovascular disease, implying that factors associated with HDL metabolism are atheroprotective. One of these factors is ATP-binding cassette transporter A1 (ABCA1), a cell membrane protein that mediates the transport of cholesterol, phospholipids, and other metabolites from cells to lipid-depleted HDL apolipoproteins. ABCA1 transcription is highly induced by sterols, a major substrate for cellular export, and its expression and activity are regulated posttranscriptionally by diverse processes. Liver ABCA1 initiates formation of HDL particles, and macrophage ABCA1 protects arteries from developing atherosclerotic lesions. ABCA1 mutations can cause a severe HDL deficiency syndrome characterized by cholesterol deposition in tissue macrophages and prevalent atherosclerosis. Genetic manipulations of ABCA1 expression in mice also affect plasma HDL levels and atherogenesis. Metabolites elevated in individuals with the metabolic syndrome and diabetes destabilize ABCA1 protein and decrease cholesterol export from macrophages. Moreover, oxidative modifications of HDL found in patients with cardiovascular disease reduce the ability of apolipoproteins to remove cellular cholesterol by the ABCA1 pathway. These observations raise the possibility that an impaired ABCA1 pathway contributes to the enhanced atherogenesis associated with common inflammatory and metabolic disorders. The ABCA1 pathway has therefore become an important new therapeutic target for treating cardiovascular disease.

scholarly journals Sortilin promotes macrophage cholesterol accumulation and aortic atherosclerosis through lysosomal degradation of ATP-binding cassette transporter A1 protein

2019 ◽  
Vol 51 (5) ◽  
pp. 471-483 ◽  
Author(s):  
Yuncheng Lv ◽  
Jing Yang ◽  
Anbo Gao ◽  
Sha Sun ◽  
Xilong Zheng ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Atp Binding ◽  
Low Density ◽  
Lysosomal Degradation ◽  
Atp Binding Cassette Transporter ◽  
Abca1 Expression ◽  
Abca1 Protein ◽  
Atp Binding Cassette

Abstract Sortilin is closely associated with hyperlipidemia and the risk of atherosclerosis (AS). The role of sortilin and the underlying mechanism in peripheral macrophage are not fully understood. In this study, we investigated the effect of macrophage sortilin on ATP-binding cassette transporter A1 (ABCA1) expression, ABCA1-mediated cholesterol efflux, and aortic AS. Macrophage sortilin expression was upregulated by oxidized low-density lipoproteins (ox-LDLs) in both concentration- and time-dependent manners. Its expression reached the peak level when cells were incubated with 50 μg/ml ox-LDL for 24 h. Overexpression of sortilin in macrophage reduced cholesterol efflux, leading to an increase in intracellular total cholesterol, free cholesterol, and cholesterol ester. Sortilin was found to bind with ABCA1 protein and suppress macrophage ABCA1 expression, resulting in a decrease in cholesterol efflux from macrophages. The inhibitory effect of sortilin in cholesterol efflux was partially reversed by treatment with chloroquine, a lysosomal inhibitor. On the contrary, the ABCA1 protein level and ABCA1-mediated cholesterol efflux is increased by sortilin short hairpin RNA transfection. The fecal and biliary cholesterol 3H-sterol from cholesterol-laden mouse peritoneal macrophage was reduced by sortilin overexpression through lentivirus vector (LV)-sortilin in low-density lipoprotein receptor knockout mice, which was prevented by co-treatment with chloroquine. Treatment with LV-sortilin reduced plasma high-density lipoprotein and increased plasma ox-LDL levels. Accordingly, aortic lipid deposition and plaque area were exacerbated, and ABCA1 expression was reduced in mice in response to infection with LV-sortilin alone. These effects of LV-sortilin were partially reversed by chloroquine. Sortilin enhances lysosomal degradation of ABCA1 protein and suppresses ABCA1-mediated cholesterol efflux from macrophages, leading to foam cell formation and AS development.

scholarly journals Deficiency of ATP-Binding Cassette Transporter B6 in Megakaryocyte Progenitors Accelerates Atherosclerosis in Mice

2014 ◽  
Vol 34 (4) ◽  
pp. 751-758 ◽  
Author(s):  
Andrew J. Murphy ◽  
Vincent Sarrazy ◽  
Nan Wang ◽  
Nora Bijl ◽  
Sandra Abramowicz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Atp Binding ◽  
Platelet Activity ◽  
Platelet Production ◽  
Expression Of Genes ◽  
Density Lipoprotein Receptor ◽  
Megakaryocyte Progenitors ◽  
Atp Binding Cassette

Objective— The ATP-binding cassette (ABC) transporter B6 (ABCB6) is highly expressed in megakaryocyte progenitors, but its role in platelet production and disease has not been elucidated. Approach and Results— Among various ABC transporters, ABCB6 was highly expressed in megakaryocyte progenitors, exhibiting the same pattern of expression of genes involved in heme synthesis pathway. Transplantation of Abcb6 deficient ( Abcb6 −/− ) bone marrow into low density lipoprotein receptor deficient recipient mice resulted in expansion and proliferation of megakaryocyte progenitors, attributable to increased reactive oxygen species production in response to porphyrin loading. The enhanced megakaryopoiesis in Abcb6 −/− bone marrow–transplanted mice was further illustrated by increased platelet counts, mean platelet volume, and platelet activity. Platelets from Abcb6 −/− bone marrow–transplanted mice had higher levels of chemokine (C-C motif) ligand 5, which was associated with increased plasma chemokine (C-C motif) ligand 5 levels. There were also increased platelet–leukocyte aggregates, which resulted in leukocyte activation. Abcb6 −/− bone marrow–transplanted mice had accelerated atherosclerosis which was associated with deposition of the chemotactic agent, chemokine (C-C motif) ligand 5 in atherosclerotic plaques, resulting in increased macrophage accumulation. Conclusions— Our findings identify a new role of ABCB6 in preventing atherosclerosis development by dampening platelet production, reactivity, and chemokine (C-C motif) ligand 5 deposition in atherosclerotic lesions.

scholarly journals Effect of ATP-binding Cassette Transporter A1 (ABCA1) Gene Polymorphisms on Plasma Lipid Variables and Common Demographic Parameters in Greek Nurses

2016 ◽  
Vol 10 (1) ◽  
pp. 233-239 ◽  
Author(s):  
Vana Kolovou ◽  
Apostolia Marvaki ◽  
Maria Boutsikou ◽  
Georgios Vasilopoulos ◽  
Dimitrios Degiannis ◽  
...  
Keyword(s):  
Gene Polymorphism ◽  
Gene Polymorphisms ◽  
Low Density Lipoprotein ◽  
Plasma Lipid ◽  
Density Lipoprotein ◽  
Lipoprotein Cholesterol ◽  
Demographic Parameters ◽  
Atp Binding ◽  
Atp Binding Cassette Transporter ◽  
Atp Binding Cassette

Objective: The present study is on line with our previous studies evaluating the influence of ATP-binding cassette transporter A1 (ABCA1) gene polymorphisms on the lipid variables of Greek student-nurses. The current study was undertaken to (1) estimate the influence of variant(s) such as rs2066715 (V825I), R219K, R1587K, I883M of ABCA1 gene on lipid variables and (2) evaluate the effect of all four ABCA1 polymorphisms on common demographic parameters. Methods: The study population involved 432 unrelated nurses (86 men) who were genotyped for ABCA1 polymorphisms and correlated according to lipid variables [total cholesterol (TC), triglycerides (TGs), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) and apolipoprotein (apo) A] and demographic parameters (age, gender, BMI, waist circumference). Results: According to lipid variables concentration there was no difference between genotypes and alleles of V825I, R219K and I883M polymorphisms. The LDL-C concentration was 13% lower in RR compared with RK genotype (100.7 vs. 113.9 mg/dl, p=0.013) of R1587K gene polymorphism. In regression analysis the effects of age, gender and only R1587K gene polymorphism on LDL-C concentrations were proved significant. Additionally, LDL-C was increased (by 1.29 mg/dl on average) by every year of increase of age. Moreover, females had lower LDL-C concentrations as compared with males. Conclusion: Findings suggested that only R1587K polymorphism of ABCA1 gene was associated with lipid variables, age, and gender of Greek nurses. These findings may be helpful in assessing the risk factors for premature coronary heart disease and distinct individuals with lower/higher atherosclerotic burden.

scholarly journals Role of Cholesterol Pathways in Norovirus Replication

2009 ◽  
Vol 83 (17) ◽  
pp. 8587-8595 ◽  
Author(s):  
Kyeong-Ok Chang
Keyword(s):  
Virus Replication ◽  
Fluorescent Protein ◽  
Cholesterol Biosynthesis ◽  
Low Density Lipoprotein ◽  
Mrna Level ◽  
Density Lipoprotein ◽  
Prototype Strain ◽  
Squalene Epoxidase ◽  
Mrna Levels ◽  
Norwalk Virus

ABSTRACT Norwalk virus (NV) is a prototype strain of the noroviruses (family Caliciviridae) that have emerged as major causes of acute gastroenteritis worldwide. I have developed NV replicon systems using reporter proteins such as a neomycin-resistant protein (NV replicon-bearing cells) and a green fluorescent protein (pNV-GFP) and demonstrated that these systems were excellent tools to study virus replication in cell culture. In the present study, I first performed DNA microarray analysis of the replicon-bearing cells to identify cellular factors associated with NV replication. The analysis demonstrated that genes in lipid (cholesterol) or carbohydrate metabolic pathways were significantly (P < 0.001) changed by the gene ontology analysis. Among genes in the cholesterol pathways, I found that mRNA levels of hydroxymethylglutaryl-coenzyme A (HMG-CoA) synthase, squalene epoxidase, and acyl-CoA:cholesterol acyltransferase (ACAT), ACAT2, small heterodimer partner, and low-density lipoprotein receptor (LDLR)-related proteins were significantly changed in the cells. I also found that the inhibition of cholesterol biosynthesis using statins (an HMG-CoA reductase inhibitor) significantly increased the levels of NV proteins and RNA, whereas inhibitors of ACAT significantly reduced the replication of NV in replicon-bearing cells. Up- or downregulation of virus replication with these agents significantly correlated with the mRNA level of LDLR in replicon-bearing cells. Finally, I found that the expression of LDLR promoted NV replication in trans by transfection study with pNV-GFP. I conclude that the cholesterol pathways such as LDLR expression and ACAT activity may be crucial in the replication of noroviruses in cells, which may provide potential therapeutic targets for viral infection.

scholarly journals ATP-binding cassette transporter A7 enhances phagocytosis of apoptotic cells and associated ERK signaling in macrophages

2006 ◽  
Vol 174 (4) ◽  
pp. 547-556 ◽  
Author(s):  
Andreas W. Jehle ◽  
Shyra J. Gardai ◽  
Suzhao Li ◽  
Patrick Linsel-Nitschke ◽  
Konosuke Morimoto ◽  
...  
Keyword(s):  
Cell Surface ◽  
Sequence Similarity ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Erk Signaling ◽  
Atp Binding ◽  
Apoptotic Cells ◽  
Erk Phosphorylation ◽  
Density Lipoprotein Receptor ◽  
Atp Binding Cassette

The mammalian ATP-binding cassette transporters A1 and A7 (ABCA1 and -A7) show sequence similarity to CED-7, a Caenorhabditis elegans gene that mediates the clearance of apoptotic cells. Using RNA interference or gene targeting, we show that knock down of macrophage ABCA7 but not -A1 results in defective engulfment of apoptotic cells. In response to apoptotic cells, ABCA7 moves to the macrophage cell surface and colocalizes with the low-density lipoprotein receptor–related protein 1 (LRP1) in phagocytic cups. The cell surface localization of ABCA7 and LRP1 is defective in ABCA7-deficient cells. C1q is an opsonin of apoptotic cells that acts via phagocyte LRP1 to induce extracellular signal–regulated kinase (ERK) signaling. We show that ERK signaling is required for phagocytosis of apoptotic cells and that ERK phosphorylation in response to apoptotic cells or C1q is defective in ABCA7-deficient cells. These studies reveal a major role of ABCA7 and not -A1 in the clearance of apoptotic cells and therefore suggest that ABCA7 is an authentic orthologue of CED-7.

scholarly journals Genes Potentially Associated with Familial Hypercholesterolemia

Biomolecules ◽  
2019 ◽  
Vol 9 (12) ◽  
pp. 807 ◽  
Author(s):  
Svetlana Mikhailova ◽  
Dinara Ivanoshchuk ◽  
Olga Timoshchenko ◽  
Elena Shakhtshneider
Keyword(s):  
Familial Hypercholesterolemia ◽  
Low Density Lipoprotein ◽  
Density Lipoprotein ◽  
Adaptor Protein ◽  
Atp Binding ◽  
Low Density ◽  
Lipoprotein Receptor ◽  
Low Density Lipoprotein Receptor ◽  
Density Lipoprotein Receptor ◽  
Atp Binding Cassette

This review addresses the contribution of some genes to the phenotype of familial hypercholesterolemia. At present, it is known that the pathogenesis of this disease involves not only a pathological variant of low-density lipoprotein receptor and its ligands (apolipoprotein B, proprotein convertase subtilisin/kexin type 9 or low-density lipoprotein receptor adaptor protein 1), but also lipids, including sphingolipids, fatty acids, and sterols. The genetic cause of familial hypercholesterolemia is unknown in 20%–40% of the cases. The genes STAP1 (signal transducing adaptor family member 1), CYP7A1 (cytochrome P450 family 7 subfamily A member 1), LIPA (lipase A, lysosomal acid type), ABCG5 (ATP binding cassette subfamily G member 5), ABCG8 (ATP binding cassette subfamily G member 8), and PNPLA5 (patatin like phospholipase domain containing 5), which can cause aberrations of lipid metabolism, are being evaluated as new targets for the diagnosis and personalized management of familial hypercholesterolemia.

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