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)

Elevated plasma intermediate density lipoprotein (IDL) is one of the features of uremic dyslipidemia which is potentially atherogenic. We examined the effects of pravastatin, an HMG-CoA reductase inhibitor, on IDL levels as well as other lipoprotein parameters in 19 uremic patients treated with hemodialysis (HD, n = 11) or continuous ambulatory peritoneal dialysis (CAPD, n = 8). The patients were administered 5 mg/day pravastatin for the initial 4 weeks and 10 mg/day for the subsequent 12 weeks. In the analysis of the total subjects, IDL-cholesterol was reduced by 31% as well as low density lipoprotein (LDL)-cholesterol. Cholesterol in very low density lipoprotein (VLDL) also decreased whereas that in high density lipoprotein (HDL) did not. Significant decrease of serum triglycerides was due mainly to reduced IDL- and LDL-triglycerides. Apolipoprotein (apo) A-I did not change, whereas apo A-II, B, C-II, C-III, E, and B/A-I ratio were significantly lowered. Pravastatin did not affect measured activity of lecithin: cholesterol acyltransferase, post-heparin plasma lipoprotein lipase or hepatic triglyceride lipase. HD and CAPD patients responded almost equally to the treatment. IDL elevation was present independent of serum total cholesterol, and it was lowered by pravastatin even in non-hypercholesterolemic subjects. There was no critical adverse effect besides transient and asymptomatic increase of serum creatine kinase level. We conclude that pravastatin can be a safe and effective approach to the management of dyslipidemia in uremic patients who have an elevated level of IDL.
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PMID:Reduction of intermediate density lipoprotein by pravastatin in hemo- and peritoneal dialysis patients. 760 82

We recently described our initial structure-activity relationship (SAR) studies on a series of N-phenyl-N'-aralkyl- and N-phenyl-N'-(1-phenylcycloalkyl)ureas as inhibitors of acyl-CoA: cholesterol acyltransferase (ACAT). From this series of analogs, compound 1 (PD 129337) was identified as a potent inhibitor of ACAT with an IC50 value of 17 nM. It was also shown to dose-dependently lower plasma cholesterol in cholesterol-fed rats. However, further investigation led to the suggestion that this compound was poorly absorbed, due to a lack of efficacy when administered by gavage in an aqueous vehicle. To overcome this deficiency, we continued our SAR study on this novel series of ACAT inhibitors using an acute in vivo screen in which the compounds are administered to rats in an aqueous, CMC/Tween suspension vehicle. Modification of the N'-phenyl moiety by incorporating functional groups which were amenable to forming salts and/or polar groups to reduce lipophilicity led to the identification of several inhibitors which displayed excellent efficacy employing this protocol. Overall, substitution on the phenyl ring in the ortho, meta, or para positions led to inhibitors with only a slight decrease in potency in vitro compared to the parent unsubstituted compound. Bulkier groups in the para position tended to lower the ACAT inhibitory activity in vitro. Polar groups, such as carboxyl (33,34), lowered in vitro activity significantly, suggesting that polar-ionic interactions are disfavored for the enzyme activity. From this series, compound 28 was evaluated further in secondary in vivo screens. In a chronic cholesterol-fed rat model of hypercholesterolemia, compound 28 dose-dependently reduced nonHDL cholesterol and significantly elevated HDL cholesterol. It showed significantly greater aqueous solubility than the parent compound 1. However, it was shown to cause adrenal toxicity in guinea pigs. This led us to design a series of homologs (44-51) with increased basicity and lower lipophilicity. Some of these compounds were more potent ACAT inhibitors in vitro and demonstrated excellent hypocholesterolemic activity in vivo. Interestingly, compound 45, unlike 28, did not produce adrenal toxicity in guinea pigs and demonstrated excellent lipid-modulating activity in the chronic model of preestablished dyslipidemia in rats.
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PMID:Inhibitors of acyl-CoA:cholesterol acyltransferase (ACAT). 7. Development of a series of substituted N-phenyl-N'-[(1-phenylcyclopentyl)methyl]ureas with enhanced hypocholesterolemic activity. 820 99

Essential hypertension is, at least in many subjects, associated with a decrease in insulin sensitivity, whereas glycemic control is (still) normal. Metaanalyses of hypertension intervention studies revealed different efficacy of treatment on cerebral (cerebrovascular accidents [CVA]) and cardiac (coronary heart disease [CHD]) morbidity and mortality. Although CVA were reduced to an extent similar to that anticipated, the decrease in CHD was less than expected. These differences are likely to be caused by the different impact of concomitant cardiovascular risk factors, such as dyslipidemia, impaired glucose tolerance, and non-insulin-dependent diabetes mellitus on CHD and CVA. Frequently these cardiovascular risk factors are ineffectively controlled in hypertensive patients, and moreover, some of the widely used antihypertensive agents have unfavorable side effects and further deteriorate these particular metabolic risk factors. Therefore, the metabolic side effects of antihypertensive treatment have received more attention. During the past few years, studies demonstrated that most antihypertensive agents modify insulin sensitivity in parallel with alterations in the atherogenic lipid profile. Alpha1-blockers and angiotensin converting enzyme inhibitors were shown to either have no impact on or even improve insulin resistance and the profile of atherogenic lipids, whereas most of the calcium channel blockers were found to be metabolically inert. The diuretics and beta-adrenoreceptor antagonists further decrease insulin sensitivity and worsen dyslipidemia. The mechanisms by which beta-adrenoreceptor antagonist treatment exert its disadvantageous effects are not fully understood, but several possibilities exist: significant body weight gain, reduction in enzyme activities (muscle lipoprotein lipase and lecithin cholesterol acyltransferase), alterations in insulin clearance and insulin secretion, and, probably most important, reduced peripheral blood flow due to increase in total peripheral vascular resistance. Recent metabolic studies found beneficial effects of the newer vasodilating beta-blockers, such as dilevalol, carvedilol and celiprolol, on insulin sensitivity and the atherogenic risk factors. In many hypertensive patients, elevated sympathetic nerve activity and insulin resistance are a deleterious combination. Although conventional beta-blocker treatment was able to take care of the former, the latter got worse; the newer vasodilating beta-blocker generation seems to be capable of successfully treating both of them.
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PMID:Antihypertensive therapy and insulin sensitivity: do we have to redefine the role of beta-blocking agents? 979 45

Acyl-CoA:cholesterol acyltransferase (ACAT) catalyzes cholesterol esterification in mammalian cells. Two isoforms of ACAT have been reported to date (ACAT-1 and ACAT-2). ACAT-1 is ubiquitously expressed in tissues except the intestine. In contrast, ACAT-2 is expressed mainly in the intestine in humans. To investigate the relationship between ACAT-2 and dyslipidemia, we determined the structure of the human ACAT-2 gene and then studied the relationship between mutations of the ACAT-2 gene and dyslipidemia. To isolate human ACAT-2 genomic DNA, we designed primers based on the human ACAT-2 cDNA sequence: forward primer 5'-ACACCTCGATCTTGGTCCTGCCATA-3' and reverse primer 5'-GGAATGCAGACAGGGAGTCCT-3'. Using these primers, a human P1-derived artificial chromosome (PAC) library was screened by PCR-based procedures. Isolated PAC clones were completely digested with BamHI and subcloned into plasmid vector. Subclones that contained exons were screened by dot-blot hybridization using partial ACAT-2 cDNA fragments. The coding region of the ACAT-2 gene was encoded in 15 exons from 51 to 265 base pairs on a 21 kilobase span of genomic DNA. The exonic sequences coincided completely with that of ACAT-2 cDNA, and each exon-intron junction conserved splicing consensus sequences. Next, 187 (91 dyslipidemic and 96 normolipidemic) subjects were screened by PCR single-strand conformational polymorphism analysis of the ACAT-2 gene. Three mutations were identified by DNA sequencing: two missense mutations (E14G in exon 1 and T254I in exon 7) and a point mutation in intron 7 (-35G-->A). Mutations in exon 1 and intron 7 were not associated with plasma concentrations of lipids and apolipoproteins (apo). However, plasma apoC-III levels in T254I heterozygotes were significantly higher than those in subjects without mutation. Plasma triglyceride (TG) levels in T254I heterozygotes were similar to those in subjects without mutation. Although further studies are needed, our data suggest that ACAT-2 may contribute to apoC-III gene expression and the assembly of apoC-III and TG, possibly in the intestine.
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PMID:Structure of the human acyl-CoA:cholesterol acyltransferase-2 (ACAT-2) gene and its relation to dyslipidemia. 1132 14

Cholesterol management to reduce the burden of cardiovascular disease is a major public health concern. Despite widespread recognition of lipid abnormalities as cardiovascular risk factors, significant cardiovascular event reductions with cholesterol-lowering therapies, and dissemination of treatment guidelines, most high-risk patients are not at target lipid levels. In addition to lifestyle changes, four major drug classes are available to modify lipid levels: fibrates, niacin, resins, and statins. High efficacy and tolerability in clinical trials make statins the most widely prescribed of these agents. Newer, more potent members of this class and novel formulations of niacin and resins may provide more effective therapy for dyslipidemia with fewer side effects. Several agents in development (cholesterol-absorption inhibitors and ACAT inhibitors) exploit mechanisms of action complementary to those of current treatments and combined with statins may produce greater improvements in lipid profiles than are now possible. These innovations should enable a greater number of patients to achieve more aggressive cholesterol goals, thereby reducing the risk of cardiovascular events.
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PMID:Future directions in lipid therapies. 1206 69

Coronary atherosclerotic heart disease (CAD) is a multifactorial disorder resulting from numerous gene-gene and gene-environment interactions. Lecithin:cholesterol acyltransferase (LCAT), a key enzyme in reverse cholesterol transport and the metabolism of high-density lipoprotein (HDL), is thought to be a candidate gene related to dyslipidemia and CAD. Variations in the LCAT gene were investigated in 190 CAD patients and 209 age- and gender-matched controls by denaturing high-performance liquid chromatography, and confirmed by sequencing and RFLP assay. In CAD patients, a novel single-nucleotide polymorphism (P143L) in exon 4 of the LCAT gene was discovered in nine males and two females (frequency of 5.79%), which was found in none of 209 controls. The genotype and allele distribution of P143L is significantly (P<0.04 ) higher in the low HDL-C subgroup than in the normal HDL-C subgroup in both male patients and all CAD patients. P143L was also found to be significantly (P<0.01) associated with the low HDL-C phenotype in both male patients and all CAD patients, with odds-ratios of 7.003 (95% CI 2.243-21.859) and 5.754 (95% CI 1.893-13.785), respectively. Thus, the P143L polymorphism may play a role in causing decreased HDL-C levels, leading to increased risk of dyslipidemia and CAD in Chinese.
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PMID:Novel P143L polymorphism of the LCAT gene is associated with dyslipidemia in Chinese patients who have coronary atherosclerotic heart disease. 1511 Jul 45

Chronic renal failure (CRF) is associated with increased risk of arteriosclerotic cardiovascular disease and profound alteration of plasma lipid profile. Uremic dyslipidemia is marked by increased plasma concentration of ApoB-containing lipoproteins and impaired high-density lipoprotein (HDL)-mediated reverse cholesterol transport. These abnormalities are, in part, due to acquired LCAT deficiency and upregulation of hepatic acyl-CoA:cholesterol acyltransferase (ACAT). ACAT catalyzes intracellular esterification of cholesterol, thereby promoting hepatic production of ApoB-containing lipoproteins and constraining HDL-mediated cholesterol uptake in the peripheral tissues. In view of the above considerations, we tested the hypothesis that pharmacological inhibition of ACAT may ameliorate CRF-induced dyslipidemia. 5/6 Nephrectomized rats were treated with either ACAT inhibitor IC-976 (30 mg.kg(-1).day(-1)) or placebo for 6 wk. Sham-operated rats served as controls. Key cholesterol-regulating enzymes, plasma lipids, and creatinine clearance were measured. The untreated CRF rats exhibited increased plasma low-density lipoprotein (LDL) and very LDL (VLDL) cholesterol, unchanged plasma HDL cholesterol, elevated total cholesterol-to-HDL cholesterol ratio, reduced liver microsomal free cholesterol, and diminished creatinine clearance. This was accompanied by reduced plasma LCAT, increased hepatic ACAT-2 mRNA, ACAT-2 protein and ACAT activity, and unchanged hepatic HMG-CoA reductase and cholesterol 7alpha-hydroxylase. ACAT inhibitor raised plasma HDL cholesterol, lowered LDL and VLDL cholesterol, and normalized total cholesterol-to-HDL cholesterol ratio without changing total cholesterol concentration (hence, a shift from ApoB-containing lipoproteins to HDL). This was accompanied by normalizations of hepatic ACAT activity and plasma LCAT. In conclusion, inhibition of ACAT reversed LCAT deficiency and improved plasma HDL level in CRF rats. Future studies are needed to explore the efficacy of ACAT inhibition in humans with CRF.
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PMID:ACAT inhibition reverses LCAT deficiency and improves plasma HDL in chronic renal failure. 1528 Jan 62

Dyslipidemia is a prominent feature of chronic renal failure (CRF) and a major risk factor for atherosclerosis and the progression of renal disease. CRF-induced dyslipidemia is marked by hypertriglyceridemia and a shift in plasma cholesterol from HDL to the ApoB-containing lipoproteins. Several studies have demonstrated a favorable response to administration of 3-hydroxy-3-methylglutaryl (HMG)-CoA reductase inhibitors (statins) in CRF. This study was intended to explore the effect of statin therapy on key enzymes and receptors involved in cholesterol metabolism. Accordingly, CRF (5/6 nephrectomized) and sham-operated rats were randomized to untreated and statin-treated (rosuvastatin 20 mg x kg(-1) x day(-1)) groups and observed for 6 wk. The untreated CRF rats exhibited increased total cholesterol-to-HDL cholesterol ratio, diminished plasma lecithin:cholesterol acyltransferase (LCAT) and the hepatic LDL receptor, elevated hepatic acyl-CoA:cholesterol acyltransferase (ACAT), and no change in hepatic HMG-CoA reductase, cholesterol 7alpha-hydroxylase, or HDL receptor (SRB-1). Statin administration lowered HMG-CoA reductase activity, normalized plasma LCAT, total cholesterol-to-HDL cholesterol ratio, and hepatic LDL receptor but did not significantly change either plasma total cholesterol, hepatic cholesterol 7alpha-hydroxylase, total ACAT activity, or SRB-1 in the CRF animals. Statin administration to the normal control rats led to significant increases in plasma LCAT and hepatic LDL receptor, significant reductions of total cholesterol-to-HDL cholesterol ratio, hepatic HMG-CoA reductase activity, and cholesterol 7alpha-hydroxylase abundance with virtually no change in plasma cholesterol concentration. Thus administration of rosuvastatin reversed LCAT and LDL receptor deficiencies and promoted a shift in plasma cholesterol from ApoB-containing lipoproteins to HDL in CRF rats.
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PMID:HMG-CoA reductase inhibition reverses LCAT and LDL receptor deficiencies and improves HDL in rats with chronic renal failure. 1550 47

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

Atherosclerotic cardiovascular disease (CVD) is the leading cause of morbidity and mortality worldwide. Dyslipidemia is one of the main risk factors leading to atherosclerosis. Moreover, there is evidence for a role of oxidation in linking lipids and inflammation to development and progression of atherosclerosis. Current therapeutic approaches with lipid-lowering agents, such as statins, fail to protect more than half of patients from cardiovascular events. Therefore, there is a need for additional and alternative treatment options. There are several novel molecules undergoing preclinical or clinical development for the treatment of dyslipidemia or against distinct pathways which contribute to the development of atherosclerosis. Novel squalene synthase inhibitors with significant cholesterol-lowering and antiatherosclerotic properties are under development. Targeting the production of apolipoprotein B-100 with an antisense oligonucleotide is another interesting approach for lowering low density lipoprotein(LDL)-cholesterol levels. Raising high density lipoprotein(HDL)-cholesterol levels or improving its antiatherosclerotic properties constitute additional attractive targets for protection against CVD. Such compounds include the cholesteryl ester transfer protein inhibitors, HDL-derived proteins, and mimetic peptides/lipids. Direct targeting of atherosclerosis remains a challenge. Molecules against oxidation and/or inflammation could be beneficial in reducing atherosclerosis. Other targets involved in distinct pathways of atherosclerosis include the lipoprotein-associated phospholipase A(2), 5-lipoxygenase-activating protein, acyl-CoA:cholesterol acyltransferase, chemokine receptors, and protein kinases. In conclusion, there are several promising novel therapeutic approaches for dyslipidemia and atherosclerosis under development which are expected to be of great benefit for patients at risk of CVD.
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PMID:Novel molecules targeting dyslipidemia and atherosclerosis. 1839 49


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