Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: UMLS:C0020473 (hyperlipidemia)
15,891 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Although the concept that inflammation plays a role in the biology of atherosclerosis is now well accepted, the basic feature of the arterial lesion remains the accumulation of clusters of foam cells. These clusters are the consequence of the enhanced recruitment of monocytes in the vessel wall induced by the hyperlipidemia and of the disproportionate accumulation of lipids in the cytoplasm of macrophages deriving from monocytes. Ultimately, every molecular force and pathway with modulating activity over the developing lesion will have to act on a convergence point with factors regulating cholesterol balance in the macrophage. Consistent with this view is the recent report that cytokines, such as tumor necrosis factor-alpha, can influence the expression of the scavenger receptor, whereas interferon-gamma can inhibit adenosine triphosphate-binding cassette transporter-1, the main effector of cholesterol efflux in the peripheral cell. Conversely, recent data have shown that primary alterations in macrophage cholesterol balance, such as those produced by the total absence of acylcoenzyme A:cholesterol acyltransferase-1, may determine local changes compatible with the activation of inflammatory pathways. In this brief review, we discuss some of the convergence points between inflammation and cholesterol balance, and we highlight the additional therapeutic targets suggested by these new developments in vascular biology.
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PMID:The inflamed plaque: cytokine production and cellular cholesterol balance in the vessel wall. 1147 38

The acyl-CoA:cholesterol acyltransferase (ACAT) enzyme is thought to be responsible for foam cell formation and the subsequent progression of atherosclerosis. The apolipoprotein E and low density lipoprotein receptor double knockout (apoE/LDLr-DKO) mouse is an animal model that develops severe hyperlipidaemia and atherosclerosis. Here we have examined the effect of oral administration of an ACAT inhibitor, F-1394, on atherosclerosis in apoE/LDLr-DKO mice fed a regular chow diet. In en face analysis, a dose of 10, 30, or 100 mg kg(-1) day(-1) F-1394 for 10 weeks reduced the extent of lesions visible in the aorta by 24, 28 and 38%, respectively, as detected by staining with oil red O, without affecting serum cholesterol level in these mice. At the highest dose 100 mg kg(-1) day(-1) of F-1394, the reduction was statistically significant. For quantitative analysis of the cellular and non-cellular components comprising the lesions at the aortic sinus, the effects of an oral dose of 100 mg kg(-1) day(-1) F-1394 for 15 weeks were studied. There was a significant reduction (31.9%) in the oil-red O-stained area in cross-sections of the aortic sinus. In addition, the neointimal area, as well as levels of ACAT-1 protein tended to be decreased (15.2 and 25.8%, respectively, not significant). However, the areas containing macrophages, smooth muscle cells, and collagen were not affected by F-1394. In vitro, F-1394 attenuated foam cell formation in mouse peritoneal macrophages. These results indicate that ACAT may be primarily responsible for lipid accumulation in atherosclerotic lesions, and that its inhibition diminishes the lipid deposition via a direct effect on macrophages in the arterial wall.
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PMID:Direct effect of an acyl-CoA:cholesterol acyltransferase inhibitor, F-1394, on atherosclerosis in apolipoprotein E and low density lipoprotein receptor double knockout mice. 1148 9

Accumulating evidences in recent major clinical studies have shown the importance of anti-hyperlipidemic treatment in preventing atherosclerotic cardiovascular diseases. Lipid-lowering drugs can be divided into HMG-CoA reductase inhibitors (statins), bile-acid sequestrants (resins), nicotinic acid, fibrates and probucol. Among them, statins had revolutionary impact on the treatment of hyperlipidemia since pravastatin, which was developed in Japan, was launched in 1989. Several lipid-lowering drugs are now under development in Japan, including pitavastatin, rosuvastatin, F-1394 (ACAT inhibitor), CS-505 (ACAT inhibitor) and NO-1886 (LPL activator). In this review, characteristics of these new lipid-lowering drugs will be discussed.
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PMID:[Lipid-lowering drugs]. 1177 57

Currently, statin therapy is the first-line treatment for patients with hypercholesterolemia, although their effects on plasma triglyceride(TG) levels are modest and variable. Inhibition of microsomal triglyceride transfer protein(MTP), a key protein involved in the assembly of the apoB-containing lipoproteins, is an attractive lipid-lowering strategy. In animal models, MTP inhibitors have dramatic effects not only on plasma cholesterol and LDL levels but on TG levels as well, offering the potential for greater efficacy and plasma lipid control in both hypertriglyceridemia and mixed hyperlipidemia. Inhibitors of acyl-CoA: cholesterol acyltransferase(ACAT) present another strategy in treating atherosclerosis through direct inhibition of ACAT in macrophages of the arterial wall. Recent studies in mouse models of atherosclerosis lacking ACAT1, however, may argue against the selective inhibition of macrophage ACAT1.
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PMID:[MTP inhibitors and ACAT inhibitors. An update]. 1203 2

Two partially inbred strains of laboratory opossums exhibit extremely high or low levels of VLDL+LDL cholesterol concentrations, respectively, when challenged with a high cholesterol and high fat diet. The present studies were conducted to determine whether the high and low responding strains differ in activities of important enzymes that have been shown to affect lipemic responsiveness to diet. We measured plasma 27-hydroxycholesterol and hepatic activities of 27-hydroxylase and 7alpha-hydroxylase in high and low responding opossums while consuming the basal diet and cholesterol-enriched diets. Plasma 27-hydroxycholesterol concentration and 27-hydroxylase activity in liver did not differ between groups on the basal diet, but both were significantly higher in low responders than in high responders on the cholesterol-enriched diet with unsaturated fat (10.79 +/- 0.56 in low vs. 7.31 +/- 0.50 &mgr;g/dl in high responders for 27-hydroxycholesterol and 14.14 +/- 0.79 in low vs. 10.07 +/- 0.80 pmol/mg protein/min in high responders for 27-hydroxylase activity). On the other hand, 7alpha-hydroxylase activity was significantly higher in high responding opossums (75.72 +/- 6.81 pmol/mg protein/min) than in low responding opossums (51.39 +/- 6.18 pmol/mg protein/min) on the basal diet, but it did not differ on the high cholesterol and high fat diet. We measured hepatic ACAT and extrahepatic hepatic 27-hydroxylase activities in high and low responding opossums on the cholesterol enriched diet. Hepatic ACAT activity was significantly higher in high responding opossums (137.00 +/- 18.33 pmol/mg protein/min) than in low responding opossums (47.67 +/- 2.71 pmol/mg protein/min), whereas extrahepatic 27-hydroxylase activity was higher in low responding opossums (33.00 +/- 2.10 pmol/mg protein/min in lungs and 3.69 +/- 0.20 in kidneys) than in high responding opossums (21.17 +/- 1.54 pmol/mg protein/min in lungs and 2.82 +/- 0.31 in kidneys). We also compared the composition of bile between high and low responders. The concentration of taurine conjugates of cholic acid in bile of both groups was similar, but concentration of taurine conjugates of chenodeoxycholic acid in bile of low responding animals was higher than in high responding animals (124.9 +/- 17.3 in low vs. 59.2 +/- 13.2 &mgr;mol/ml in high responders). The results of these studies suggest two enzymes may affect the lipemic response to diet in laboratory opossums: sterol 27-hydroxylase and ACAT. Each of these enzymes may influence diet-induced hyperlipidemia at a different step of lipoprotein metabolism.
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PMID:High and low responding strains of laboratory opossums differ in sterol 27-hydroxylase and acyl-coenzyme A:cholesterol acyltransferase activities on a high cholesterol diet. 1203 Dec 49

Avasimibe is a novel orally bioavailable ACAT inhibitor, currently under clinical development (phase III trials). It was safe when administered to rats, dogs, and humans. In vitro studies in human macrophages demonstrated that avasimibe reduces foam cell formation not only by enhancing free cholesterol efflux, but also by inhibiting the uptake of modified LDL. The concentration-dependent reduction in cellular cholesteryl ester content in these cells was not accompanied by an increase in intracellular free cholesterol, which is in agreement with a good safety profile for avasimibe. In the liver, avasimibe caused a significant reduction in the secretion of apo B and apo B-containing lipoproteins into plasma. Avasimibe induced cholesterol 7alpha-hydroxylase and increased bile acid synthesis in cultured rat hepatocytes, and its administration to rats did not produce an increase in lithogenicity index of the bile. The hypolipidemic efficacy of the compound was demonstrated in cholesterol-fed as well as in non-cholesterol-fed animals. In these models, plasma cholesterol levels were reduced, mainly due to the decrease in the non-HDL cholesterol fraction. Clinical data are scarce, but in a study performed in 130 men and women with combined hyperlipidemia and hypoalphalipoproteinemia, avasimibe, 50-500 mg/day, significantly reduced plasma total triglyceride and VLDL-cholesterol. Although total cholesterol, LDL-cholesterol, and HDL-cholesterol were unchanged, it must be stressed that animal data suggest that avasimibe may have direct antiatherosclerotic activity in addition to its cholesterol-lowering effect. Avasimibe treatment can also contribute to increase plaque stability, as it reduces the accumulation of lipids in the arterial wall, inhibits macrophage infiltration into the media and reduces matrix metalloproteinase expression and activity. Moreover, avasimibe and statins have been shown to have synergistic effects, and the combination therapy may not only inhibit atherosclerotic lesion progression but also induce lesion regression, independently of changes in plasma cholesterol.
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PMID:Pharmacology of the ACAT inhibitor avasimibe (CI-1011). 1259 16

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 protein is ubiquitously expressed in tissues, including macrophages, hepatocytes, adrenal glands, and intestines. In contrast, ACAT-2 is expressed mainly in the intestine in humans. However, the roles of ACAT-1 and ACAT-2 in lipoprotein metabolism in humans have not yet been reported. This study was carried out to clarify the relationship between ACAT-2 gene mutations and hyperlipidemia in humans. To identify gene mutations, we screened 30 subjects with hyperlipidemia (TC > 220 mg/dl or TG >150 mg/dl) by direct sequencing. As a result, we found a new single-nucleotide polymorphism (SNP; a point mutation in intron 1, IVS1 -8 G-->C) in the ACAT-2 gene. To investigate the relationship between this SNP and both plasma lipids and apolipoproteins, 91 unrelated hyperlipidemic subjects (40 males and 51 females), and 92 unrelated normolipidemic subjects (46 males and 46 females) were screened by direct sequencing. The frequencies of the IVS1 - 8G-->C allele in normolipidemic and hyperlipidemic subjects were 0.131 and 0.125, respectively. IVS1 -8 G-->C did not affect plasma concentrations of lipids or apolipoproteins in either normolipidemic or hyperlipidemic subjects. Although further studies are needed, our data suggest that the ACAT-2 gene may not affect lipid levels in humans.
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PMID:Effects of a new single-nucleotide polymorphism in the Acyl-CoA:cholesterol acyltransferase-2 gene on plasma lipids and apolipoproteins in patients with hyperlipidemia. 1262 Nov 62

The field of new lipid-lowering drug research is very active, with researchers, looking to make the currently available drugs more powerful and safer, and to develop new classes of drugs. Among the statins, development has gone the farthest for rosuvastatin and pitavastatin. Colesevelam is a new bile acid sequestrant with a better digestive tolerance. Among the new classes of drugs, the most promising molecules are the cholesterol absorption inhibitors--with ezetimibe as the first in line--and the PPAR-alpha and PPAR-gamma activators. Among the other classes, the acyl-CoA:cholesterol acyltransferase (ACAT) inhibitors, microsomal triglyceride transfer protein (MTP) inhibitors, cholesteryl ester transfer protein (CETP) inhibitors, and ileal bile acid transporter inhibitors, have to be mentioned. In most of the cases, those new compounds are being developed mainly as a combined treatment with statins. However, these combination therapies differ depending on the lipid abnormalities of the patient. The statin-ezitimibe and the statin-bile acid sequestrant combinations have been the most studied treatments in pure hypercholesterolaemia. On another hand, the statin-PPAR-alpha and -gamma activator combination were the first to be developed for patients with combined hyperlipidaemia or type 2 diabetes mellitus. However, the clinical benefit of ACAT or CETP inhibitors remains to be determined and the development of MTP inhibitors has been restricted so far, because of problems of digestive intolerance and hepatic steatosis. Finally, the discovery of new specific lipoprotein receptors, such as the ABCA1 and SRB1 receptors, means that we can work towards developing new potential targets for pharmacological intervention.
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PMID:[New antilipemics: prospects]. 1282 7

Shosaikoto, a Kampo medicine used clinically to treat patients with chronic hepatitis or cirrhosis in Japan, displays immunoregulatory effects, especially on macrophage functions. Oral administration of shosaikoto influences the synthesis of humoral factors such as the interleukins, nitric oxide and prostaglandins in macrophages. In addition, phagocytic activity is enhanced by treatment with shosaikoto, resulting in an antigen that is effectively presented to T lymphocytes to produce more antibodies. The role of macrophages in the pathogenesis of atherosclerosis is well recognized, although a therapeutic agent targeted at macrophages has not yet been developed. When shosaikoto was administered to atherosclerotic rabbits, it did not exhibit antihyperlipidemic effects but did reduce the formation of atherosclerotic lesions. In addition, treatment with shosaikoto suppressed intimal hyperplasia in apoE-deficient mice fed a cholesterol-enriched diet for nine weeks. Biochemical studies demonstrated that the mechanism of the antiatherosclerotic effect was partly due to the increase of oxidized low-density lipoprotein (oxLDL) elimination by macrophages, resulting from stimulation of oxLDL uptake through scavenger receptors, activation of acyl-CoA:cholesterol acyltransferase and neutral cholesteryl ester hydrolase, and increase of cholesterol elimination by high-density lipoprotein. Furthermore, shosaikoto is able to reverse the depression of macrophage functions caused by hyperlipidemia. These results indicate the potential of this medicine as a new type of preventive or therapeutic agent for atherosclerosis.
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PMID:Shosaikoto as a potential antiatherosclerotic agent. 1293 13

We are continuing to both elucidate underlying mechanisms and identify clinical applications for a chemically induced murine model of dose-controlled hyperlipidemia and atherosclerosis. This murine model neither utilizes genetically modified mice nor a high-fat, cholate-containing diet, although simultaneous ingestion of a high-fat, cholate-enriched diet potentiates the hyperlipidemic response and the number and size of aortic atherosclerotic lesions formed in C57BL/6 mice. The chemical agent used to induce hyperlipidemia is poloxamer 407 (P-407), a nonionic surface-active-agent. To date, we have investigated the effect of P-407 on the biologic activity of a variety of key enzymes involved with lipid metabolism and transport. These enzymes include 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, lipoprotein lipase (LPL), cholesterol 7alpha-hydoxylase (C7alphaH), sterol 27-hydroxylase (S27H), lecithin cholesterol acyltransferase (LCAT), cholesteryl-ester-transfer-protein (CETP), hepatic lipase (HL), and endothelial lipase (EL). P-407 directly inhibits the heparin-releasable fraction of LPL and HL and indirectly increases the biologic activity of CETP and LCAT. Long-term (> 4 months) administration of P-407 to C57BL/6 mice appears to have no effect on the biologic activity of S27H and HMG-CoA reductase, but decreases the activity of C7alphaH. This would suggest that hypertriglyceridemia and hypercholesterolemia result from inhibition of LPL and C7alphaH, respectively, while the biologic activity of CETP and LCAT are indirectly increased to compensate for the increased cholesterol burden. The above model has proven useful for predicting the therapeutic efficacy of existing and possibly newer statin drugs, as well as evaluating the potential of one statin drug (atorvastatin calcium) to cause the regression of P-407-induced atherosclerotic lesions in mice. The P-407-induced murine model of atherogenesis represents an alternative to the use of either genetically modified or diet-induced models and may also prove beneficial for the evaluation of newer classes of antihyperlipidemic agents such as antioxidants, CETP inhibitors, and liver X receptor (LXR) agonists.
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PMID:The P-407-induced murine model of dose-controlled hyperlipidemia and atherosclerosis: a review of findings to date. 1508 72


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