Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Disease genes may be identified through functional, positional, and candidate gene approaches. Although extensive and often labor-intensive studies such as family linkage analysis, functional investigation of gene products and genome database searches are usually involved, thousands of human disease genes, especially for monogenic diseases with Mendelian transmission, have been identified. However, in diseases caused by more than one gene, or by a combination of genetic and environmental factors, identification of the genes is even more difficult. Common examples include atherosclerosis, cancer, Alzheimer's disease, asthma, diabetes, glaucoma, and age-related macular degeneration. There have been conflicting reports on the roles of associated genes. Even with population-based case-control studies and new statistical methods such as the sib-ship disequilibrium test and the discordant alleles test, there is no agreement on whether alpha2-macroglobulin (A2M) is a gene for Alzheimer's disease. Another example is the inconsistent association between age-related macular degeneration and ATP-binding cassette transporter (ABCR). Ethnic variation causes further complications. In our investigation of LDL-receptor variants in familial hypercholesterolemia, and the trabecular meshwork inducible glucocorticoid response protein, or myocillin (TIGR-MYOC) mutation pattern in primary open angle glaucoma, we did find dissimilar results in Chinese compared to Caucasians. New information from the Human Genome Project and advancements in technologies will aid the search for and confirm identification of disease genes despite such challenges.
 ...
PMID:Hunting for disease genes in multi-functional diseases. 1109 34

It is widely believed that HDL functions to transport cholesterol from peripheral cells to the liver by reverse cholesterol transport, a pathway that may protect against atherosclerosis by clearing excess cholesterol from arterial cells. A cellular ATP-binding cassette transporter (ABC) called ABCA1 mediates the first step of reverse cholesterol transport: the transfer of cellular cholesterol and phospholipids to lipid-poor apolipoproteins. Mutations in ABCA1 cause Tangier disease (TD), a severe HDL deficiency syndrome characterized by accumulation of cholesterol in tissue macrophages and prevalent atherosclerosis. Studies of TD heterozygotes revealed that ABCA1 activity is a major determinant of plasma HDL levels and susceptibility to CVD. Drugs that induce ABCA1 in mice increase clearance of cholesterol from tissues and inhibit intestinal absorption of dietary cholesterol. Multiple factors related to lipid metabolism and other processes modulate expression and tissue distribution of ABCA1.Therefore, as the primary gatekeeper for eliminating tissue cholesterol, ABCA1 has a major impact on cellular and whole body cholesterol metabolism and is likely to play an important role in protecting against cardiovascular disease.
 ...
PMID:ABCA1. The gatekeeper for eliminating excess tissue cholesterol. 1148 17

Abnormal high density lipoprotein metabolism may contribute to the increased atherosclerosis associated with diabetes and insulin resistance. The ATP-binding cassette transporter ABCA1 mediates cholesterol transport from tissue macrophages to apoA-I, the major high density lipoprotein protein component. Because fatty acids are elevated in diabetes, we examined the effects of fatty acids on ABCA1 activity in cultured macrophages. Results showed that unsaturated fatty acids markedly inhibited ABCA1-mediated cholesterol and phospholipid efflux from macrophages when ABCA1 was induced by a cAMP analog. This was accompanied by a reduction in the membrane content of ABCA1 and a decrease in apoA-I binding to whole cells and to ABCA1. In contrast, saturated fatty acids had no effect on these processes. Fatty acids did not alter ABCA1 mRNA abundance or incorporation of methionine into ABCA1, indicating that decreased ABCA1 transcription, enhanced mRNA decay, or impaired translation efficiency did not account for these inhibitory effects. Unsaturated fatty acids, however, increased ABCA1 turnover when protein synthesis was blocked by cycloheximide. We conclude that unsaturated fatty acids reduce the macrophage ABCA1 content by enhancing its degradation rate. These findings raise the possibility that an increased supply of unsaturated fatty acids in the artery wall promotes atherogenesis by impairing the ABCA1 cholesterol secretory pathway in macrophages.
 ...
PMID:Unsaturated fatty acids inhibit cholesterol efflux from macrophages by increasing degradation of ATP-binding cassette transporter A1. 1174 98

The disturbance of lipid metabolism is seen in some inherited diseases and also in patients with some kinds of underlying diseases. The presence of its disturbance can be detected by measuring the concentrations of cholesterol and triglyceride in serum. Although hyperlipidemia or hypolipidemia is the result of abnormal lipid metabolism, hyperlipidemia is of more concern to physicians because of the close association with atherosclerosis. Responsible genes for some primary (or hereditary) hyperlipidemic diseases have been confirmed as follows; LPL or apo C-II for primary chylomicronemia, LDL receptor for familial hypercholesterolemia and apo B-100 for familial defective apo B-100. However, the responsible gene remains controversial for familial combined hyperlipidemia, though AI/CIII/AIV cluster is one of the possible candidate genes. Secondary hyperlipidemia is caused by various diseases such as diabetes mellitus, renal diseases and cholestasis. This type of hyperlipidemia is improved by therapy for the underlying diseases. To date, the mechanism of lipid metabolism has been defined in a molecular basis. In fact, sterol regulatory element-binding protein (SREBP), peroxisome proliferator-activated receptor (PPAR) and ATP-binding cassette transporter subfamily A, member 1(ABCA1) were recently identified and it was demonstrated that these regulate lipid metabolism.
 ...
PMID:[Disturbance of lipid metabolism]. 1198 47

Since the identification of mutations in the ATP-binding cassette transporter (ABCA1), the relationship between ABCA1 expression, cholesterol efflux, high-density lipoprotein (HDL) biosynthesis and cholesterol homeostasis has been a subject of intense investigation. Several studies have provided significant new information with regards to pathways controlling ABCA1 expression and activity and established that this transporter facilitates the efflux of cholesterol and phospholipids to apoprotein acceptors, leading to the formation of nascent HDL particles. Although ABCA1 appears to play a critical role in cholesterol flux from tissues, and despite a considerable interest in developing pharmacological agents that increase ABCA1 activity, the role of ABCA1 in preventing atherosclerosis remains unclear.
 ...
PMID:ABCA1: regulation, function and relationship to atherosclerosis. 1205 89

The ATP-binding cassette transporter, ABCA1, is a member of the ABC superfamily of proteins involved in the active transport of substrates across cellular membranes. Recent studies have implicated mutations in ABCA1 as the cause of Tangier disease (TD) and familial hypoalphalipoproteinemia (FHA). To evaluate the molecular basis of low high density lipoprotein (HDL) in a family with premature coronary artery disease, single strand conformational polymorphism analysis was performed for all coding regions and splice site junctions of ABCA1 with the genomic DNA of the proband. The proband and affected individuals were heterozygotes for C254T with proline converted to leucine (P85L). This mutation was not identified in over 400 chromosomes of healthy subjects. In the FHA kindred, family members heterozygous for the ABCA1 variant also exhibited corresponding low levels of HDL cholesterol. These data confirm recent data that a single defective allele in ABCA1 may be associated with reduced HDL cholesterol and FHA.
Atherosclerosis 2002 Oct
PMID:ABCA1(Alabama): a novel variant associated with HDL deficiency and premature coronary artery disease. 1292 88

Low HDL-cholesterol (HDL-C) concentrations are inversely correlated with cardiovascular disease, and previous studies have demonstrated that variants in the ATP-binding cassette transporter, ABCA1, are responsible for a proportion of HDL-C deficiency states. We identified a novel variant in ABCA1 in a kindred with decreased HDL-C. This variant was not identified in >200 chromosomes of healthy individuals. The proband, a heterozygote for G2265T, developed premature coronary artery disease. In addition to low HDL-C, six biological family members heterozygous for the ABCA1 variant exhibited low HDL-C concentrations compared with unaffected family members (0.83 +/- 0.32 vs 1.33 +/- 0.36 mmol/L; P = 0.009). Despite the decreased HDL-C, carotid artery B-mode ultrasound studies failed to reveal increased intima-media thickening in affected individuals compared with age- and sex-matched controls. Although these data extend previous observations that a single defective ABCA1 allele may lead to decreased HDL-C, associated evidence of early atherosclerosis was not confirmed.
 ...
PMID:Lack of association between increased carotid intima-media thickening and decreased HDL-cholesterol in a family with a novel ABCA1 variant, G2265T. 1240 1

For three decades, low-density lipoprotein (LDL) dominated research into cholesterol metabolism and atherosclerosis, whereas scant attention was paid to high-density lipoprotein (HDL), an equally important risk factor for cardiovascular disease. This low interest reflected the lack of knowledge about physiological HDL receptors. As a result, our understanding of HDL-cell interactions failed to develop alongside that of LDL, and mechanisms through which atheroprotective HDL promoted clearance of cholesterol from peripheral cells remained poorly-defined. Interest was kindled with the recognition that scavenger receptor class B, type I is the cell-surface protein in hepatocytes and steroidogenic tissues which selectively extracts cholesteryl esters from HDL. Greater impetus still was given by the discovery that mutations in the gene encoding the ATP-binding cassette transporter, class A1 (ABCA1) are the cause of Tangier disease, a rare recessive disorder with near-absent plasma HDL. The ABCA1 transmembrane protein is crucial for efficient efflux of cellular cholesterol and HDL maturation and has emerged as a promising therapeutic target for cardiovascular disease. The hope is that new drugs, regulating ABCA1 activity and HDL homeostasis, will accelerate cholesterol efflux from lipid-laden foam cells and thus promote regression of atherosclerotic lesions.
 ...
PMID:ATP-binding cassette A1 protein and HDL homeostasis. 1257 59

Studies with ATP-binding cassette transporter (ABCA1)-deficient mice have been critical in demonstrating the relation between ABCA1 expression, cellular lipid efflux, and HDL metabolism. The phenotype of the ABCA1-deficient mouse parallels the phenotype observed in human Tangier disease, including substantial reductions in both apolipoprotein B and apolipoprotein AI with confounding affects on atherosclerosis.
 ...
PMID:ABCA1-deficient mice: insights into the role of monocyte lipid efflux in HDL formation and inflammation. 1261 79

The removal of excess free cholesterol from cells by HDL or its apolipoproteins is important for maintaining cellular cholesterol homeostasis. This process is most likely compromised in the atherosclerotic lesion because the development of atherosclerosis is associated with low HDL cholesterol. Multiple mechanisms for efflux of cell cholesterol exist. Efflux of free cholesterol via aqueous diffusion occurs with all cell types but is inefficient. Efflux of cholesterol is accelerated when scavenger receptor class-B type I (SR-BI) is present in the cell plasma membrane. Both diffusion-mediated and SR-BI-mediated efflux occur to phospholipid-containing acceptors (ie, HDL and lipidated apolipoproteins); in both cases, the flux of cholesterol is bidirectional, with the direction of net flux depending on the cholesterol gradient. The ATP-binding cassette transporter AI (ABCA1) mediates efflux of both cellular cholesterol and phospholipid. In contrast to SR-BI-mediated flux, efflux via ABCA1 is unidirectional, occurring to lipid-poor apolipoproteins. The relative importance of the SR-BI and ABCA1 efflux pathways in preventing the development of atherosclerotic plaque is not known but will depend on the expression levels of the two proteins and on the type of cholesterol acceptors available.
 ...
PMID:Importance of different pathways of cellular cholesterol efflux. 1261 88


1 2 3 4 5 Next >>