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

LPL and endothelial lipase (EL) are associated with macrophages in human atherosclerotic lesions, and overexpression of LPL in mouse macrophages is associated with a greater extent of atherosclerosis. To investigate potential mechanisms by which macrophage-derived lipase expression may mediate proatherogenic effects, we used lentivirus-mediated RNA interference to suppress the expression of either LPL or EL within THP-1 macrophages. After suppression of either LPL or EL, significant decreases in the concentration of interleukin-1beta, interleukin-6, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha were observed. Incubation of THP-1 macrophages with either mildly or extensively oxidized LDL consistently decreased cytokine expression, which was additive to that contributed by lipase suppression. Decreased lipase expression was also associated with an altered lipid composition, with reduced percentages of cholesterol (unesterified and esterified), triglycerides, and lysophosphatidylcholine. Microarray data indicated a decreased expression of proinflammatory genes, growth factors, and antiapoptotic genes. By contrast, there was an increased expression of lipoprotein receptors (scavenger receptor 1, low density lipoprotein receptor, scavenger receptor class B type I, and CD36). Thus, we conclude that the suppression of either LPL or EL decreases proinflammatory cytokine expression and influences the lipid composition of THP-1 macrophages. These results provide further insight into the specific metabolic and potential pathological roles of LPL and EL in human macrophages.
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PMID:Suppression of endothelial or lipoprotein lipase in THP-1 macrophages attenuates proinflammatory cytokine secretion. 1709 91

Proteins involved in cholesterol trafficking are known to contribute to the pathogenesis of atherosclerosis and Alzheimer's disease. Allelic variants in the cholesterol transporters apolipoprotein E and ATP-binding cassette protein A1 (ABCA1) have recently been associated with susceptibility to age-related macular degeneration (AMD). Histopathological analyses of eyes with AMD demonstrate the presence of cholesterol and cholesteryl ester deposits beneath the retinal pigment epithelium (RPE), implicating abnormal cholesterol trafficking in disease progression. Here, we show that A2E, a quaternary amine and retinoid by-product of the visual cycle, causes the accumulation of free and esterified cholesterol in RPE cells. The mechanism involves neither generalized alterations in late endosomal/lysosomal pH nor a direct inhibition of acid lipase activity. Rather, A2E prevents cholesterol efflux from these organelles, which in turn indirectly inhibits acid lipase, leading to a subsequent accumulation of cholesteryl esters. Transcriptional activation of the ABCA1 cholesterol transporter by agonists of the liver X receptor/peroxisome proliferator-activated receptor pathway relieves the A2E-induced block on cholesterol efflux and restores cholesterol homeostasis in RPE cells. Our data also demonstrate that A2E, which is a cone-shaped lipid, increases the chemical activity and displacement of cholesterol from model membranes, providing a biophysical mechanism for cholesterol sequestration in A2E-loaded cells. Although endogenously produced A2E in the RPE has been associated with macular degeneration, the precise mechanisms are unclear. Our results provide direct evidence that A2E causes aberrant cholesterol metabolism in RPE cells which could likely contribute to AMD progression.
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PMID:The lipofuscin fluorophore A2E perturbs cholesterol metabolism in retinal pigment epithelial cells. 1757 16

Hypertriglyceridemia is a hallmark of many disorders, including metabolic syndrome, diabetes, atherosclerosis and obesity. A well-known cause is the deficiency of lipoprotein lipase (LPL), a key enzyme in plasma triglyceride hydrolysis. Mice carrying the combined lipase deficiency (cld) mutation show severe hypertriglyceridemia owing to a decrease in the activity of LPL and a related enzyme, hepatic lipase (HL), caused by impaired maturation of nascent LPL and hepatic lipase polypeptides in the endoplasmic reticulum (ER). Here we identify the gene containing the cld mutation as Tmem112 and rename it Lmf1 (Lipase maturation factor 1). Lmf1 encodes a transmembrane protein with an evolutionarily conserved domain of unknown function that localizes to the ER. A human subject homozygous for a deleterious mutation in LMF1 also shows combined lipase deficiency with concomitant hypertriglyceridemia and associated disorders. Thus, through its profound effect on lipase activity, LMF1 emerges as an important candidate gene in hypertriglyceridemia.
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PMID:Mutations in LMF1 cause combined lipase deficiency and severe hypertriglyceridemia. 1804 26

Lipoprotein lipase, hepatic lipase, and endothelial lipase are sn-1 lipases that play important roles in the metabolism of plasma lipoproteins. In vitro and in vivo studies suggest that these lipases exhibit both pro- and anti-atherogenic properties, which are dependent primarily on their tissue localization. The following chapter reviews the physiology of these lipases, and the consequences of the loss or gain of function for each lipase in modulating atherosclerosis, with emphasis on murine models.
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PMID:Lipases as modulators of atherosclerosis in murine models. 1822 Jul 7

Enteric drainage and intraperitoneal graft position is the preferred technique for pancreas transplantation at most transplant centers. The technique of retroperitoneal pancreas transplantation was first described by Boggi et al. [Transplantation,79 (2005), 1137]. In this case report, a modified model of retroperitoneal pancreas transplantation with systemic-enteric drainage is presented. A 48-yr-old patient underwent combined retroperitoneal pancreas and kidney transplantation because of type-I-diabetes, and diabetic nephropathy. At the time of transplantation, the patient had a body mass index of 31 and severe atherosclerosis of the iliac vessels. After mobilization of the colon and mesocolon ascendens, the vessels of the pancreas graft were anastomosed end-to-side to the aorta and to the inferior caval vein of the recipient. For exocrinous drainage, a side-to-side duodenojejunostomy was performed after bringing a jejunal loop through a window in the right colon mesentery. The graft was in a retroperitoneal position. The patient was insulin-independent after 48 h, the lipase and amylase levels were within the normal range. The first experience with retroperitoneal pancreas transplantation with systemic-enteric drainage showed that the technique was safe and had technical advantages when compared with the classic method.
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PMID:Retroperitoneal pancreas transplantation with systemic-enteric drainage--case report. 1843 82

Lysosomal acid lipase (LAL) deficiency results in Wolman disease and cholesteryl ester storage disease (CESD), a more benign form. CESD is a recessive disorder characterized by hypercholesterolaemia, hypertriglyceridaemia, low blood HDL and variable phenotype, while hepatomegaly is usually evident during childhood or adolescence. An 11-year-old girl was referred to our department for combined hyperlipidaemia (total cholesterol 323, triglycerides 259 mg/dl). All family members had normal lipid profile and liver function tests. At 8 years she was admitted for acute Epstein-Barr virus infection, with hepatosplenomegaly and elevation of liver enzymes. Liver-spleen enlargement resolved, but serum alanine aminotransferase and aspartate aminotransferase were persistently twice the upper limits, with other liver function tests within the normal range. Ultrasonography showed normal liver and spleen size and minimal hepatic steatosis. Infectious, autoimmune and metabolic causes of elevated liver enzymes were ruled out, including glycogen storage disease. Dysbetalipoproteinaemia was also ruled out (ApoE phenotype: E3E3). In the following 2 years the girl was symptom-free, BMI was at the 50th-75th centile for age and lipid profile was unchanged despite a low-fat diet. At 13 years of age, low acid lipase activity was demonstrated in leukocytes (10 nmol/h/ per mg protein, normal 140-380) and cultured skin fibroblasts (181 nmol/h per mg protein, normal 1100-2400), leading to diagnosis of CESD. CESD usually progresses to hepatic fibrosis, with high risk of premature atherosclerosis. CESD prevalence may be underestimated in the general population. The diagnosis may be considered in all subjects with atypical combined hyperlipidaemia (usually dominant in transmission or related to metabolic syndrome) and atypical 'fatty liver disease', in the absence of overweight.
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PMID:Combined hyperlipidaemia as a presenting sign of cholesteryl ester storage disease. 1921 73

Coronary heart disease is mainly caused by atherosclerosis, which is a multifactorial and systemic disease. Lipid metabolism disorder and chronic inflammation are two well accepted mechanisms leading to atherosclerosis. The key initiating process in athrogenesis is lipid retention in subendothelium. Inflammatory activity plays an important role in the whole pathogenesis of atherosclerosis. Recent investigations have demonstrated that rapamycin reduces lipid retention by increasing adipose-tissue lipase activity and decreasing lipoprotein lipase activity. Rapamycin also reduce intracellular lipid accumulation in smooth muscle cells and macrophages. Since rapamycin is a definite immunosuppressive agent, and inflammatory process has been involved in atherosclerosis, the compound would have effect on the progression of atherosclerosis through reducing inflammatory activity. Moreover, rapamycin would protect plaque from rupture by selectively clearing macrophages without affecting vascular smooth muscle cells. Even some in vivo studies demonstrate that rapamycin can notably inhibit the development of atherosclerosis. Rapamycin, especially its analog, everolimus, is a non-toxic, well-tolerated drug suitable for long term use. Clinical experiments demonstrate that everolimus can reduce graft vasculopathy in heart transplant patients. Therefore, we propose that everolimus administered systemically is a promising medical therapy to attenuate atherosclerosis and prevent further adverse events. In addition, rapamycin is a selective and effective mammalian target of rapamycin (mTOR) inhibitor. mTOR acts as a hub for cell metabolism, cell growth and cell survival. Based on previous evidences, we hypotheses that mTOR signaling pathway could play a significant role in the pathogenesis of atherosclerosis.
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PMID:Everolimus, a promising medical therapy for coronary heart disease? 1937 41

Cholesterol ester (CE)-laden macrophage foam cells are the hallmark of atherosclerosis, and the hydrolysis of intracellular CE is one of the key steps in foam cell formation. Although hormone-sensitive lipase (LIPE) and cholesterol ester hydrolase (CEH), which is identical to carboxylsterase 1 (CES1, hCE1), were proposed to mediate the neutral CE hydrolase (nCEH) activity in macrophages, recent evidences have suggested the involvement of other enzymes. We have recently reported the identification of a candidate, neutral cholesterol ester hydrolase 1(Nceh1). Here we demonstrate that genetic ablation of Nceh1 promotes foam cell formation and the development of atherosclerosis in mice. We further demonstrate that Nceh1 and Lipe mediate a comparable degree of nCEH activity in macrophages and together account for most of the activity. Mice lacking both Nceh1 and Lipe aggravated atherosclerosis in an additive manner. Thus, Nceh1 is a promising target for the treatment of atherosclerosis.
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PMID:Ablation of neutral cholesterol ester hydrolase 1 accelerates atherosclerosis. 1972 98

Molecular disruption of the lipid carrier AFABP/aP2 in mice results in improved insulin sensitivity and protection from atherosclerosis. Because small molecule inhibitors may be efficacious in defining the mechanism(s) of AFABP/aP2 action, a chemical library was screened and identified 1 (HTS01037) as a pharmacologic ligand capable of displacing the fluorophore 1-anilinonaphthalene 8-sulfonic acid from the lipid binding cavity. The X-ray crystal structure of 1 bound to AFABP/aP2 revealed that the ligand binds at a structurally similar position to a long-chain fatty acid. Similar to AFABP/aP2 knockout mice, 1 inhibits lipolysis in 3T3-L1 adipocytes and reduces LPS-stimulated inflammation in cultured macrophages. 1 acts as an antagonist of the protein-protein interaction between AFABP/aP2 and hormone sensitive lipase but does not activate PPARgamma in macrophage or CV-1 cells. These results identify 1 as an inhibitor of fatty acid binding and a competitive antagonist of protein-protein interactions mediated by AFABP/aP2.
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PMID:Identification and characterization of a small molecule inhibitor of Fatty Acid binding proteins. 1975 98

Eicosanoids, including epoxyeicosatrienoic acids, hydroxyeicosatetraenoic acids, and other oxylipins derived from polyunsaturated fatty acids, have emerging roles in endothelial inflammation and subsequent atherosclerosis. Unlike eicosanoids in the prostanoid series, they are known to be esterified in cell lipids such as phospholipids and triglycerides; however, our understanding of these reservoirs is in its infancy. This review focuses on recent work identifying circulating oxylipins, primarily esterified with lipoprotein lipids, and their effects on markers of endothelial dysfunction. These oxylipins are known to be released by at least one lipase (lipoprotein lipase) and to mediate increased expression of inflammatory markers in endothelial cells, which coincides with the known roles of lipoproteins in endothelial dysfunction. The implications of the lipolytic release of lipoprotein-bound oxylipins for the inflammatory response, challenges to analysis of this oxylipin compartment, and the potential importance of non-arachidonate-derived oxylipins are discussed.
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PMID:Impact of circulating esterified eicosanoids and other oxylipins on endothelial function. 1985 80


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