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)

Inhibitors of acyl CoA:cholesterol acyltransferase (ACAT) have attracted considerable interest as a potential treatment for atherosclerosis. Currently available inhibitors probably act nonselectively against the two known ACATs. One of these enzymes, ACAT1, is highly expressed in macrophages in atherosclerotic lesions, where it contributes to foam-cell formation. In this study, we examined the effects of selective ACAT1 deficiency in two mouse models of atherosclerosis. In the setting of severe hypercholesterolemia caused by deficiency in apoE or the LDL receptor (LDLR), total ACAT1 deficiency led to marked alterations in cholesterol homeostasis and extensive deposition of unesterified cholesterol in the skin and brain. Bone marrow transplantation experiments demonstrated that ACAT1 deficiency in macrophages was sufficient to cause dermal xanthomas in hyperlipidemic LDLR-deficient mice. ACAT1 deficiency did not prevent the development of atherosclerotic lesions in either apoE-deficient or LDLR-deficient mice, despite causing relatively lower serum cholesterol levels. However, the lesions in ACAT1-deficient mice were atypical in composition, with reduced amounts of neutral lipids and a paucity of macrophages in advanced lesions. Although the latter findings may be associated with increased lesion stability, the marked alterations in cholesterol homeostasis indicate that selectively inhibiting ACAT1 in the setting of severe hyperlipidemia may have detrimental consequences.
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PMID:Massive xanthomatosis and altered composition of atherosclerotic lesions in hyperlipidemic mice lacking acyl CoA:cholesterol acyltransferase 1. 1072 36

During atherogenesis, circulating macrophages migrate into the subendothelial space, internalize cholesterol-rich lipoproteins, and become foam cells by progressively accumulating cholesterol esters. The inhibition of macrophage acyl coenzyme A:cholesterol acyltransferase (ACAT), which catalyzes the formation of cholesterol esters, has been proposed as a strategy to reduce foam cell formation and to treat atherosclerosis. We show here, however, that hypercholesterolemic LDL receptor-deficient (LDLR(-/-)) mice reconstituted with ACAT1-deficient macrophages unexpectedly develop larger atherosclerotic lesions than control LDLR(-/-) mice. The ACAT1-deficient lesions have reduced macrophage immunostaining and more free cholesterol than control lesions. Our findings suggest that selective inhibition of ACAT1 in lesion macrophages in the setting of hyperlipidemia can lead to the accumulation of free cholesterol in the artery wall, and that this promotes, rather than inhibits, lesion development.
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PMID:Increased atherosclerosis in LDL receptor-null mice lacking ACAT1 in macrophages. 1116 Jan 32

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

Acyl-coenzyme A:cholesterol acyltransferase (ACAT) 1 and ACAT2 play an important role in cellular cholesterol esterification and thus modulate intestinal cholesterol absorption and hepatic lipoprotein secretion. The relative expression levels of ACAT1 and ACAT2 in human tissues differ from those in other animals, including nonhuman primates. The present study compared the relative expression levels of ACAT1 and ACAT2 in baboons with high and low lipemic responses to dietary lipids. We isolated RNA and prepared cDNA from frozen liver and small intestine from high- and low-responding pedigreed baboons necropsied after consuming a high-cholesterol and high-fat diet for 18 months. The expression of ACAT1 and ACAT2 was measured by TaqMan real-time quantitative PCR normalized to 18s ribosomal RNA. The expression of ACAT1 was higher than that of ACAT2 in the liver, whereas the expression of ACAT2 was higher than that of ACAT1 in the duodenum and jejunum. There was no difference in the expression of ACAT1 or ACAT2 in the liver and intestine between high- and low-responding baboons except that the expression of ACAT1 was higher in the duodenum of high responders than in that of low responders. Western blot analysis also showed a higher level of ACAT1 protein in the duodenum of high responders than in that of low responders. There was a significant correlation between duodenal ACAT expression levels and total plasma cholesterol concentration in baboons. These results suggest that differences in ACAT1 expression may affect plasma cholesterol concentration and partly affect diet-induced hyperlipidemia.
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PMID:Expression levels of ACAT1 and ACAT2 genes in the liver and intestine of baboons with high and low lipemic responses to dietary lipids. 1608 Dec 63