Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242339 (dyslipidemia)
 13,927 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The ATP cassette-binding (ABC) gene superfamily contains more than 40 members, many of which are involved in cellular lipid transport. The most prominent example is ABCA1, mutations in which affect plasma high-density lipoprotein (HDL) cholesterol concentration. ABCC6 is another member of the ABC gene family, and mutations in ABCC6 were recently shown to cause pseudoxanthoma elasticum (PXE). A Canadian patient with PXE was referred for assessment of moderately severe type IV hyperlipoproteinemia with hypoalphalipoproteinemia, which was refractory to pharmacological treatment. We identified intron-exon boundaries of ABCC6 to sequence genomic DNA from this patient to find the disease mutation. We report (1) identification of a set of amplification primers for the 31 exons of ABCC6; (2) identification of the ABCC6 R>X1164 nonsense mutation in the PXE subject with dyslipidemia; (3) identification of common amino acid variants and silent nucleotide variants in ABCC6, with a range of allele frequencies across ethnic groups; (4) evidence consistent with a possible pseudogene encoding 9 exons with sequence homology to ABCC6; and (5) association of the ABCC6 R>Q1268 variant with plasma triglyceride and HDL cholesterol. The results suggest that ABCC6 may be a determinant of plasma lipoproteins.
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PMID:ABCC6 gene polymorphism associated with variation in plasma lipoproteins. 1177 82

The loss of ABCA1 function leads to Tangier dyslipidemia in humans and to a Tangier-like phenotype in mice, by impairing the transformation of nascent apolipoproteins into mature HDL particles. Mechanistically this ensues from the inability of cells to release membrane lipids and cholesterol. Whereas the ability of ABCA1 to promote phospholipid effluxes, surface binding of apolipoproteins and outward flip of membrane lipids has been documented, the relationship between this series of ABCA1-dependent events is still elusive. Here we provide evidence that i) lipid effluxes require both flip of membrane lipids and binding of apolipoproteins to the cell surface, ii) apolipoprotein A-I binding depends on structural determinants on ABCA1, and iii) phospholipid effluxes can be modulated by engineered mutations on the structural determinants identified on ABCA1.
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PMID:Distinct sites on ABCA1 control distinct steps required for cellular release of phospholipids. 1245 69

The objective of this study was to determine the effect of two amino-terminal apolipoprotein A-I (apoA-I) deletions on high-density lipoprotein (HDL) biosynthesis and lipid homeostasis. Adenovirus-mediated gene transfer showed that the apoA-I[Delta(89-99)] deletion mutant caused hypercholesterolemia, characterized by increased plasma cholesterol and phospholipids, that were distributed in the very low density/intermediate density/low-density lipoprotein (VLDL/IDL/LDL) region, and normal triglycerides. The capacity of the mutant protein to promote ATP-binding cassette transporter A1- (ABCA1-) mediated cholesterol efflux and to activate lecithin:cholesterol acyltranserase (LCAT) was approximately 70-80% of the wild-type (WT) control. The phospholipid transfer protein (PLTP) activity of plasma containing the apoA-I[Delta(89-99)] mutant was decreased to 32% of the WT control. Similar analysis showed that the apoA-I[Delta(62-78)] deletion mutant in apoA-I-deficient mice caused combined hyperlipidemia characterized by increased triglycerides, cholesterol, and phospholipids in the VLDL/IDL region. There was enrichment of the VLDL/IDL with mutant apoA-I that resulted in reduction of in vitro lipolysis. The capacity of this mutant to promote ABCA1-mediated cholesterol efflux was normal, and the capacity to activate LCAT in vitro was reduced by 53%. The WT apoA-I and the apoA-I[Delta(62-78)] mutant formed spherical HDL particles, whereas the apoA-I[Delta(89-99)] mutant formed discoidal HDL particles. We conclude that alterations in apoA-I not only may have adverse effects on HDL biosynthesis but also may promote dyslipidemia due to interference of the apoA-I mutants on the overall cholesterol and triglycerides homeostasis.
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PMID:Deletions of helices 2 and 3 of human apoA-I are associated with severe dyslipidemia following adenovirus-mediated gene transfer in apoA-I-deficient mice. 1575 88

The concentration, composition, shape, and size of plasma high-density lipoprotein (HDL) are determined by numerous proteins that influence its biogenesis, remodeling, and catabolism. The discoveries of the HDL receptor (scavenger receptor class B type I, SR-BI) and the ABCA1 (ATP-binding cassette transporter A1) lipid transporter provided two missing links that were necessary to understand the biogenesis and some of the functions of HDL. Existing data indicate that functional interactions between apoA-I and ABCA1 are necessary for the initial lipidation of apoA-I. Through a series of intermediate steps, lipidated apoA-I proceeds to form discoidal HDL particles that can be converted to spherical particles by the action of lecithin:cholesterol acyltransferase (LCAT). Discoidal and spherical HDL can interact functionally with SR-BI and these interactions lead to selective lipid uptake and net efflux of cholesterol and thus remodel HDL. Defective apoA-I/ABCA1 interactions prevent lipidation of apoA-I that is necessary for the formation of HDL particles. In the same way, specific mutations in apoA-I or LCAT prevent the conversion of discoidal to spherical HDL particles. The interactions of lipid-bound apoA-I with SR-BI are affected in vitro by specific mutations in apoA-I or SR-BI. Furthermore, deficiency of SR-BI affects the lipid and apolipoprotein composition of HDL and is associated with increased susceptibility to atherosclerosis. Here we review the current status of the pathway of HDL biogenesis and mutations in apoA-I, ABCA1, and SR-BI that disrupt different steps of the pathway and may lead to dyslipidemia and atherosclerosis in mouse models. The phenotypes generated in experimental mouse models for apoA-I, ABCA1, LCAT, SR-BI, and other proteins of the HDL pathway may facilitate early diagnosis of similar phenotypes in the human population and provide guidance for proper treatment.
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PMID:Role of apoA-I, ABCA1, LCAT, and SR-BI in the biogenesis of HDL. 1650 36

Macrophages are central to the initiation and progression of atherosclerosis and thus can be very appropriate targets for therapy. Cell adhesion molecules mediating monocytes recruitment to the endothelium are attractive therapy targets and their inhibitors are in clinical trials. Macrophage scavenger receptors like SR-A and CD-36 mediate foam cell formation by facilitating the uptake of modified lipids. Peroxisome proliferator-activated receptors (PPAR), liver X receptor (LXR)-mediated signaling, mitogen-activated protein kinase (MAPK) induced phosphorylation events seem to play an important role in this phenomenon. Proteins affecting macrophage cholesterol metabolism and transport, including ATP-binding cassette (ABC) A1, ABCG1, acyl-CoA:cholesterol acyltransferase (ACAT), apolipoprotein A-1 (ApoA-1), neutral cholesteryl ester hydrolase (NCEH) also regulate foam cell formation and are being developed as therapeutic targets by many pharmaceutical companies. Macrophage proliferation and apoptosis are important events controlling inflammatory response, plaque vulnerability, and destabilization. Free cholesterol (FC) activates the macrophage endoplasmic reticulum (ER) stress pathway and apoptosis. Free radicals and nitric oxide also modulate macrophage foam cell formation and apoptosis. Various antioxidants like AGI-1067 and BO-653 are in clinical trials for atherosclerosis treatment. Macrophage matrix metalloproteinase's (MMP's) play a significant role in weakening and rupture of plaques. Efforts are on to develop isoform specific MMP inhibitor. CD-14, MMP-3, ABCA1, Toll-like receptor-4 (TLR-4), lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), arachidonate lipoxygenase-15 (ALOX-15), and Connexin37 polymorphisms and macrophage dysfunction signify their importance in atherosclerosis. Deciphering the role of macrophages in regulating dyslipidemia and inflammation during atherosclerosis is important for developing them as therapeutic targets.
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PMID:Macrophages: an elusive yet emerging therapeutic target of atherosclerosis. 1800 Sep 63

In industrialized societies with excess food supply, obesity is an expanding problem. As a result of metabolic overload, besides obesity, insulin resistance, type-2 diabetes, dyslipidemia, hypertension, and atherosclerosis develop, which together make up the metabolic syndrome. The imbalance of lipid uptake, metabolism, and removal in many organs such as the liver, muscle, adipose tissue, vessel wall, and macrophages triggers organ transdifferentiation toward lipid storage phenotypes. Macrophages, foam cells, and osteoclasts in calcifying lesions are a hallmark of atherosclerosis and the metabolic syndrome, and must be regarded as an important therapeutic target. In this review, pathways regulating lipid homeostasis in macrophages are updated. These include lipid influx through different receptor entry pathways, the role of membrane microdomains, endolysosomal and cytosolic lipid storage leading to phospholipidosis, and lipid droplet accumulation or activation of lipid efflux either through the Golgi system or bypassing this organelle on the way to the plasma membrane. The interdependence of these pathways and pharmacological modifications are described. The monocyte innate immunity receptor complex in defining monocyte subpopulations and their role in cardiovascular disease is taken into account. The composition of certain molecular lipid species in membrane microdomains and other organelles is essential for cellular functions affecting raft dynamics, signal transduction, and membrane and organelle trafficking. It is very likely that the underlying defects in lipid-associated rare genetic diseases such as ABCA1 deficiency, Niemann-Pick disease type C, as well as the more frequent complex disorders associated with atherosclerosis and phospholipidosis are related to disturbances in membrane homeostasis, signal transduction, and cellular lipid metabolism.
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PMID:Lipid homeostasis in macrophages - implications for atherosclerosis. 1842 39

Homozygous staggerer mice (sg/sg) display decreased and dysfunctional retinoic acid receptor-related orphan receptor alpha (RORalpha) expression. We observed decreases in serum (and liver) triglycerides and total and high density lipoprotein serum cholesterol in sg/sg mice. Moreover, the sg/sg mice were characterized by reduced adiposity (associated with decreased fat pad mass and adipocyte size). Candidate-based expression profiling demonstrated that the dyslipidemia in sg/sg mice is associated with decreased hepatic expression of SREBP-1c, and the reverse cholesterol transporters, ABCA1 and ABCG1. This is consistent with the reduced serum lipids. The molecular mechanism did not involve aberrant expression of LXR and/or ChREBP. However, ChIP and transfection analyses revealed that RORalpha is recruited to and regulates the activity of the SREBP-1c promoter. Furthermore, the lean phenotype in sg/sg mice is also characterized by significantly increased expression of PGC-1alpha, PGC-1beta, and lipin1 mRNA in liver and white and brown adipose tissue from sg/sg mice. In addition, we observed a significant 4-fold increase in beta(2)-adrenergic receptor mRNA in brown adipose tissue. Finally, dysfunctional RORalpha expression protects against diet-induced obesity. Following a 10-week high fat diet, wild-type but not sg/sg mice exhibited a approximately 20% weight gain, increased hepatic triglycerides, and notable white and brown adipose tissue accumulation. In summary, these changes in gene expression (that modulate lipid homeostasis) in metabolic tissues are involved in decreased adiposity and resistance to diet-induced obesity in the sg/sg mice, despite hyperphagia. In conclusion, we suggest this orphan nuclear receptor is a key modulator of fat accumulation and that selective ROR modulators may have utility in the treatment of obesity.
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PMID:The orphan nuclear receptor, RORalpha, regulates gene expression that controls lipid metabolism: staggerer (SG/SG) mice are resistant to diet-induced obesity. 1844 Oct 15

Nuclear hormone receptors liver X receptor (LXRalpha and LXRbeta) ligands are attractive approaches for the treatment of dyslipidemia and atherosclerosis. To further elucidate the function of LXRalpha in liver lipid metabolism in a disease-relevant animal model, the KKAy mouse, we used adenoviral vectors to selectively knock down LXRalpha gene expression. Out of five different short hairpin RNAs (shRNAs) that were tested in vitro, one construct was selected for detailed analysis of LXRalpha knockdown in vivo. Reduction of LXRalpha transcript levels to 48 +/- 13% compared with control virus transduction resulted in a significant downregulation of the LXRalpha-regulated lipogenic genes sterol-regulatory element binding protein-1c (SREBP1c) and stearoyl CoA desaturase 1 in vivo. Interestingly, ABCA1 and phoshoenolpyruvate carboxykinase 1 expression was not affected, whereas lipoprotein lipase (LPL) expression was found to be increased. In addition, 8 days after virus transduction, both plasma and liver triglycerides (TGs) were reduced by about 50%. Changes in TG levels were not due to reduced food intake in virus-treated animals, because pair-fed mice showed unchanged TG levels. Taken together, liver-specific knockdown of LXRalpha in vivo by shRNA reduced expression of lipogenic master genes, like SREBP1c, and improved the lipid profile of hypertriglyceridemic KKAy mice.
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PMID:Improved lipid profile through liver-specific knockdown of liver X receptor alpha in KKAy diabetic mice. 1876 20

Liver X receptors (LXRs) are ligand-activated transcription factors that coordinate regulation of gene expression involved in several cellular functions but most notably cholesterol homeostasis encompassing cholesterol transport, catabolism, and absorption. WAY-252623 (LXR-623) is a highly selective and orally bioavailable synthetic modulator of LXR, which demonstrated efficacy for reducing lesion progression in the murine LDLR(-/-) atherosclerosis model with no associated increase in hepatic lipogenesis either in this model or Syrian hamsters. In nonhuman primates with normal lipid levels, WAY-252623 significantly reduced total (50-55%) and LDL-cholesterol (LDLc) (70-77%) in a time- and dose-dependent manner as well as increased expression of the target genes ABCA1/G1 in peripheral blood cells. Statistically significant decreases in LDLc were noted as early as day 7, reached a maximum by day 28, and exceeded reductions observed for simvastatin alone (20 mg/kg). Transient increases in circulating triglycerides and liver enzymes reverted to baseline levels over the course of the study. Complementary microarray analysis of duodenum and liver gene expression revealed differential activation of LXR target genes and suggested no direct activation of hepatic lipogenesis. WAY-252623 displays a unique and favorable pharmacological profile suggesting synthetic LXR ligands with these characteristics may be suitable for evaluation in patients with atherosclerotic dyslipidemia.
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PMID:LXR ligand lowers LDL cholesterol in primates, is lipid neutral in hamster, and reduces atherosclerosis in mouse. 1931 84

Serine palmitoyltransferase (SPT) is the key enzyme for the biosynthesis of sphingolipids. It has been reported that oral administration of myriocin (an SPT inhibitor) decreases plasma sphingomyelin (SM) and cholesterol levels, and reduces atherosclerosis in apoE knockout (KO) mice. We studied cholesterol absorption in myriocin-treated WT or apoE KO animals and found that, after myriocin treatment, the mice absorbed significantly less cholesterol than controls, with no observable pathological changes in the small intestine. More importantly, we found that heterozygous Sptlc1 (a subunit of SPT) KO mice also absorbed significantly less cholesterol than controls. To understand the mechanism, we measured protein levels of Niemann-Pick C1-like 1 (NPC1L1), ABCG5, and ABCA1, three key factors involved in intestinal cholesterol absorption. We found that NPC1L1 and ABCA1 were decreased, whereas ABCG5 was increased in the SPT deficient small intestine. SM levels on the apical membrane were also measured and they were significantly decreased in SPT deficient mice, compared with controls. In conclusion, SPT deficiency might reduce intestinal cholesterol absorption by altering NPC1L1 and ABCG5 protein levels in the apical membranes of enterocytes through lowering apical membrane SM levels. This may be also true for ABCA1 which locates on basal membrane of enterocytes. Manipulation of SPT activity could thus provide a novel alternative treatment for dyslipidemia.
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PMID:Serine palmitoyltransferase (SPT) deficient mice absorb less cholesterol. 1941 52


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