Deregulation of cholesterol homeostasis has been associated with multiple types of cancer. All mice were maintained under pathogenfree conditions in our facilities. Abca1 gene expression, we examined the activity of the. Reverse cholesterol transport is a mechanism whereby the body can eliminate excess cholesterol. Mar 21, 2014 differential regulation of abca1 and abcg1 gene expressions in the remodeling mouse hippocampus after entorhinal cortex lesion and liverx receptor agonist treatment. Pdf protein kinase d regulates the adiponectin gene. Transcriptional regulation of the abca1 gene, upregulatory. Abca1 gene deletion protects against cerebral malaria. In the context of diabetes, regression of atherosclerosis is impaired. Regulation of abca1 protein expression and function in hepatic. Srebp2 positively regulates transcription of the cholesterol. A new era to alleviate atherosclerotic cardiovascular disease article pdf available may 2018 with 31 reads. Furthermore, abca1 was significantly induced by butyrate in vivo, ex vivo and in vitro and sp1 pathway was identified as a potential mechanism.
Promoterspecific roles for liver x receptorcorepressor. Transcriptional regulation of abca1 abca1mediated cholesterol ef. This study was aimed at evaluating and comparing abca1 and abcg1 genes expression in metabolic syndrome patients and healthy individuals. May 12, 2020 from ncbi gene alzheimer disease, type 9. Expression, regulation, and activity of abca1 in human. Abca1 mrna and protein distribution patterns predict multiple. Abca1 overexpression in endothelial cells in vitro. Recent gwas have implicated abca1 coding for atpbinding cassette, subfamily a abc1 member 1 in poag.
The ebox motif in the proximal abca1 promoter mediates. In view of the potential importance of abca1 in the regulation of hdl cholesterol, we studied the molecular mechanisms that regulate expression of the abca1 gene. Genetic evidence providing a causal link between elevated cholesterol and carcinogenesis, however, has been lacking. In this section, we will focus on the transcriptional regulation of the abca1 gene with emphasis on macrophages. Feb 08, 2019 in ecs stimulated with lipopolysaccharide, abca1 overexpression markedly decreased inflammatory gene expression. High cholesterol and diabetes are major risk factors for atherosclerosis. Relationship between abca1 gene polymorphism and lacunar. This protein moves cholesterol and certain fats called phospholipids across the cell. Wiggs, in progress in molecular biology and translational science, 2015. Ectopic abca1 reexpression in mp53ras cells to levels approximating those found in the parental yamc cells, i.
The abca1 transporter is one of the limiting steps in cellular cholesterol efflux. Regulation of abca1 and abcg1 transporter gene expression. Nov 28, 2006 an important facet of regulation of cholesterol efflux is via the ligandactivated transcription factor lxr liver x receptor. Gene regulation can occur at three possible places in the production of an active gene product. Jan 22, 2007 scavenger receptor type b class i srbi, abc transporter a1 abca1 and g1 abcg1 all play important roles in the reverse cholesterol transport. Abca1 plays a crucial role in active apolipoprotein ai apoai lipidation, a key step in reverse cholesterol transport. This response is mediated by the nuclear receptors lxra and lxrb, whose ligands are sterol metabolites.
The possiblity of controlling serum ldl cholesterol concentrations with statins is an outstanding pharmaceutical advance. The abca1 gene belongs to a group of genes called the atpbinding cassette family, which provides instructions for making proteins that transport molecules across cell membranes. This variant abca1 may confer a new level of regulation to the gene either at the transcriptional level, through the use of an alternate promoter, or the translational level, with the new 5. Regulation of the cholesterol efflux gene, abca1 the possiblity of controlling serum ldl cholesterol concentrations with statins is an outstanding pharmaceutical advance. The gene encoding atpbinding cassette transporter 1 is mutated in. Abca1 r219k gene polymorphism has been proved to have effects on the blood lipids, but effects of r219k gene polymorphism on human blood lipid profile remains unknown. A complex set of interactions between genes, rna molecules, proteins. Consistent with earlier reports 20, 21, we show that abca1 expression is effectively upregulated by 22 r hydroxycholesterol, a product of the mevalonate biosynthetic pathway. Abca1 gene promoter dna methylation is associated with hdl. Butyrate had metabolic effects on the liver by regulation of gene expression involved in lipidglucose metabolism. Expression, regulation, and activity of abca1 in human cell. Lxrs control the expression of a battery of genes involved in cholesterol, fatty acid and phospholipid metabolism through direct binding to lxr response elements lxres in their target promoters calkin and tontonoz, 2012.
To study the expression and activity of the human abca1 gene. In peripheral cells, such as macrophages and fibroblasts, abca1 gene expression is enhanced by loading cholesterol. The abca1 gene encodes for a member of subfamily a of the atpbinding cassette transporters that plays an important role in cellular export of cholesterol and phospholipids. Liver x receptors lxrs regulate the expression of genes involved in cholesterol. Rapid quantification of human abca1 mrna in various cell. Moreover, abca1 gene expression was positively associated with synthesis of 24s,25epoxycholesterol in these cell lines. Aug 29, 20 cholesterol is a lipid component of cell membranes that regulates membrane fluidity and is a part of membrane signaling systems. Regulation and activity of the human abca1 gene in. Transcriptional regulation of the atpbinding cassette transporter abca1 gene is complex. This casecontrol study was performed on 36 patients with metabolic syndrome and the same number of healthy individuals in. The most important function of high density lipoprotein hdl is its ability to remove cholesterol from cells and tissues involved in the early stages of atherosclerosis back to the liver for excretion.
Regulation and activity of the human abca1 gene in transgenic. Regulation of abca1 protein expression and function in. Abca1 gene expression has been reported in many tissues including placenta, lung, adrenal. Relationship between single nucleotide polymorphism of abca1.
Growing evidence suggests that posttranscriptional regulation of hdl. We provide evidence here that in addition to lipid uptake, ppar. Schematic representation of proposed scenarios for the mechanisms by which abca1 gene expression is regulated. Pdf complete genomic sequence of the human abca1 gene. The abca1 protein is produced in many tissues, with high amounts found in the liver and in immune system cells called macrophages. Stephanie belanger jasmin department of neurology and neurosurgery, mcgill university, montreal, quebec, canada h4a 2b4. Douglas mental health university institute, 6875 lasalle. Our studies demonstrate that mir145 regulates abca1 expression and. The membraneassociated protein encoded by this gene is a member of the superfamily of atpbinding cassette abc transporters. Hence, drugs that raise serum hdl or impair dietary cholesterol. Genetic analysis of abca1 gene of primary glaucoma in.
A direct correlation between the content of abca1 and abcg1 proteins and the ror. But statins are not so effective at reducing ldl if dietary cholesterol intake is excessive, and they do not rectify low hdl concentrations, a risk factor as important as raised ldl for coronary artery disease. We proposed that changes in glucose levels modulate lxrdependent gene expression. In addition, we report that the fragment spanning 2200 to 80 bp of the abca1 gene promoter contain a cholesterol regu. Regulation of the cholesterol efflux gene,abca1 the possiblity of controlling serum ldl cholesterol concentrations with statins is an outstanding pharmaceutical advance. Abca1 overexpression in endothelial cells in vitro enhances. But statins are not so effective at reducing ldl if dietary cholesterol intake is excessive, and they do not rectify low hdl. Abc genes are divided into seven distinct subfamilies abc1, mdrtap, mrp, ald, oabp, gcn20, white.
Proapoptotic mirna1282 modulates abca1, abcg1 and rxr. Must regulate or control which genes are turned on in which cells. We report the complete human abca1 gene sequence, including 1,453 bp of the promoter. Abca1 gene is 149 kb long and contains 50 exons, one more than previously described 21. The abca1 gene, a member of the atpbinding cassette a abca1 transporter superfamily, encodes a membrane protein that facilitates the cellular efflux of cholesterol and phospholipids. To fully understand the role that abca1 plays in regulating cellular cholesterol metabolism and the process of reverse cholesterol transport, we have determined the complete gene. Mutations in abca1 lead to familial high density lipoprotein deficiency and tangier disease. Furthermore, research has suggested that the expression of genes involved. Lxr forms a heterodimer with the retinoid x receptor, which together bind to a variation of a consensus sequence dr4 tgaccg nnnn taacct in the promoter of abca1 atpbindingcassette transportera1 and other genes, causing upregulated expression 4,5. All these genes are expressed within human retina, optic nerve, and trabecular meshwork. First, the transcription of the gene can be regulated. Lxrs link metabolism to inflammation through abca1dependent.
Gene perturbation experiments indicate that abca1 has strong antitumor activity. Lxrmediated abca1 expression and function are modulated by. In ecs stimulated with lipopolysaccharide, abca1 overexpression markedly decreased inflammatory gene expression. Request pdf regulation and activity of the human abca1 gene in transgenic mice the abca1 transporter is one of the limiting steps in cellular cholesterol efflux. This protein moves cholesterol and certain fats called phospholipids across. Epigenetic regulation of atpbinding cassette protein a1 abca1. The atpbinding cassette transporters abca1 and abcg1 are responsible for the major part of cholesterol efflux to hdl in macrophage foam cells. Here, the regulation of srbi, abca1, and abcg1 by dexamethasone a synthetic glucocorticoid and insulin were studied in order to gain more insight. Jul 05, 2000 the abca1 gene, a member of the atpbinding cassette a abca1 transporter superfamily, encodes a membrane protein that facilitates the cellular efflux of cholesterol and phospholipids. It involves multiple transcription start sites and the binding of several different transcription factors to the abca1 promoter region. Function and regulation of abca1 membrane mesodomain. Gene expression and regulation learning goal by the end of this learning material you would have learnt about.
We report the complete human abca1 gene sequence, including 1,453 bp of the promoter, 146,581 bp of introns and exons. Regression of atherosclerosis is mediated in part by the liver x receptor lxr through the induction of genes involved in cholesterol transport and efflux. Dual mechanisms of abca1 regulation by geranylgeranyl. Abc proteins transport various molecules across extra and intracellular membranes. Jul 14, 2015 the liver x receptors lxrs are members of the nuclear receptor superfamily that play pivotal roles in sterol homeostasis in mammals. Differential regulation of abca1 and abcg1 gene expressions. Peripheral blood mononuclear cell abca1 transcripts and protein. Regulation and activity of the human abca1 gene in transgenic mice. We compared abca1 transcriptional regulation and cholesterol efflux in human skin fibroblasts, monocytederived macrophages and hepatocytes hepg2. Their work supports a model in which increased cholesterol synthesis and abca1. Pdf the abca1 gene, a member of the atpbinding cassette a abca1 transporter. The process by which the genetic code directs protein synthesis to produce the structures of a cell the cellular processes that control the rate and manner of gene expression. These findings could change our understanding of the molecular mechanisms involved in the pathophysiological processes leading to cad.
Smith and land show that the efflux function of the cholesterol exporter abca1 gene has anticancer activity. The abca1 gene promoter contains a tata box localized 24 bp upstream of the transcription initiation site, essential for promoter activity in macrophages as well as in hepatocytes langmann et al. Regulation of the cholesterol efflux gene, abca1 the lancet. Protein kinase d regulates the adiponectin gene expression through phosphorylation of ap2. Loss of lxr leads to derepression of the abca1 gene in macrophages and the intestine.
Diseases free fulltext epigenetic regulation of atp. Various factors including nutrition, state diseases, stress and inflammation can alter epigenetic abca1 gene regulation in different cells mainly macrophages and hepatocytes 1. Posttranscriptional and posttranslational regulation of this gene will be discussed in later sections. Dba1 mice 12 to 14 weeks old were generated in our laboratory as previously described. Abca1 atp binding cassette subfamily a member 1 human. Cavelier lb, qiu y, bielicki jk, afzal v, cheng jf, and rubin em 2001. Researchers have identified two key regulatory sequences for a human gene that plays a role in transporting cholesterol and is associated with tangier disease, a lipid disorder involving the accumulation of cholesterol in certain tissues. We also identified an initiation methionine, which extends the protein an additional 60 aa 21. Alzheimer disease is a neurodegenerative disorder characterized by progressive dementia, loss of cognitive abilities, and deposition of fibrillar amyloid proteins as intraneuronal neurofibrillary tangles, extracellular amyloid plaques and vascular amyloid.
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