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)

The objective of this study was to examine the effect of dietary Chol supplementation on SM metabolism in rat liver plasma membranes, as well as on membrane leaflet fluidity characteristics. The membrane Chol content increased significantly during the first 20 days of dietary feeding, but returned to the level of the control group when the diet was continued for another ten days. The initially more fluid outer leaflet of the membrane rigidified as a result of the diet, obliterating the natural asymmetry in the fluidity of the membrane bilayer. Changes in the neutral SMase activity were also observed. These changes were in strong negative correlation (r = -0.978) with the Chol/Pr ratio and are consistent with the in vitro inhibition of SMase activity reported earlier. In contrast, the SM synthesizing enzymes, PC:Cer-PCh and PE:Cer-PEt transferase, were stimulated in course of the dietary Chol feeding. The activity of PC:Cer-PCh transferase was more strongly affected. Our results support the concept that SM metabolism is regulated coordinately with that of Chol. The present work could contribute to the better understanding of the parallel accumulation of SM and Chol observed in a variety of pathological conditions such as atherosclerosis and Niemann-Pick disease.
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PMID:Influence of cholesterol on sphingomyelin metabolism and hemileaflet fluidity of rat liver plasma membranes. 158 91

This review article attempts to present an overview of the occurrence and function of lipid storage and secretory organelles: the lamellar bodies. Morphologically these organelles vary considerably in size (100 nm to 2400 nm); they are surrounded by a membrane and contain multilamellar lipid membranes. Lamellar bodies may also contain apolipoproteins and lytic enzymes and have an acidic pH, which confers on them a lysosomal character. Under normal physiological conditions, the main function of lamellar bodies is the supply of extracellular domains with specialized lipid components related to a specialized function. The lamellar bodies of the lung epithelium are best investigated in their functional and structural features and are the storage form of the lung surfactant. They provide a monomolecular lipid film of dipalmitoyl phosphatidylcholine (DPPC) on the surface of lung alveoli to lower surface tension necessary for optimal gas exchange and a hydrophobic protective lining against environmental influences. Additional cells of the respiratory system such as the mucosa of the human nose and the bronchi contain lamellar bodies. Lamellar bodies are also found in the gastrointestinal tract, in tongue papillae, oral epithelium, and mucosa cells of the stomach. The major phospholipid of lamellar bodies in mucosa cells of the stomach is DPPC, providing a hydrophobic protective lipid film against the tissue-damaging activities of gastric juice. The hydrophobic water-protective barrier of the skin, which consists mainly of neutral lipids, however, also originates from lamellar bodies secreted by epithelial cells. Lamellar bodies, mainly consisting of DPPC, also occur in mesodermal cell layers of sliding surfaces to provide the lubrication of joints, of the peritoneum, pericardium, and pleural mesothelium. In certain pathological conditions, such as atherosclerosis, Niemann-Pick disease, lecithin:cholesterol acyltransferase (LCAT) deficiency, cholestasis, degeneration of nerves and brain, and regeneration of nerves and wound healing, lipid-containing lamellar bodies have been observed in various cells, the function of which still remains to be elucidated. In early and late lesions of atherosclerotic plaques, lamellar bodies, consisting of unesterified cholesterol and phospholipids, are associated with the extracellular matrix of the intima. During regression of fatty streaks, lamellar bodies are seen intracellularly in macrophages and smooth muscle cells. Inherited metabolic disorders, such as Niemann-Pick disease type I and type II, result in the excessive accumulation of lamellar body-containing cells, for example in bone marrow, spleen, and lymphoid tissue. Type I is a deficiency in sphingomyelinase and type II is a defect in intracellular trafficking of lipoprotein-derived cholesterol.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Structure and function of lamellar bodies, lipid-protein complexes involved in storage and secretion of cellular lipids. 179 38

Sphingomyelin is found in plasma membranes and related organelles (such as endocytic vesicles and lysosomes) of all tissues, as well as in lipoproteins. Abnormalities in sphingomyelin metabolism have been associated with atherosclerosis, cancer and genetically transmitted diseases; however, except for Niemann-Pick disease, little is known about the mechanism for these disorders. Sphingomyelin biosynthesis de novo involves ceramide formation from serine and two mol of fatty acyl-CoA followed by addition of the phosphocholine headgroup. The headgroup appears to come from phosphatidylcholine, but other sources have not been ruled out. Factors that influence the rate of sphingomyelin synthesis include the availability of serine and palmitic acid, plus the relative activities of key enzymes of this pathway. Sphingomyelin turnover involves removal of the headgroup and amide-linked fatty acid by sphingomyelinases and ceramidases, respectively, which have been found in both lysosomes (with acidic pH optima) and plasma membranes (with neutral to alkaline pH optima). The enzymes of sphingomyelin turnover release ceramide and free sphingosine from endogenous substrates, which may have implications for the participation of a sphingomyelin/sphingosine cycle as another 'lipid second messenger' system.
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PMID:An update of the enzymology and regulation of sphingomyelin metabolism. 218 37

Cavalier-Smith (1981) has identified 22 characters that are universally present in eukaryotes but absent in prokaryotes. Of these, he argues that one, exocytosis, might have been the driving force behind the evolution of modern eukaryotic cells. Bloom and Mouritsen (1988) further argue that sterols may have removed an evolutionary bottleneck to cytosis. Therefore, the advent of sterols in membranes might have been the single feature that led to eukaryote evolution. The evolutionary advantage conferred by cholesterol is associated primarily with plasma membrane function, since the majority of cellular free cholesterol resides in that membrane. However, sterol synthesis occurs in the ER; therefore, the cell must have a mechanism for transporting sterol to the plasma membrane and its regulation. As has been pointed out in this review, much remains to be elucidated in the study of intracellular sterol trafficking. To date, neither diffusion nor vesicle-mediated transport can be fully confirmed or ruled out. Microtubule and microfilament involvement appears important in some routes (e.g., mitochondria) but not in others. In addition, trafficking roles of cytoplasmic lipoproteinlike particles have not been addressed. Finally, although some "sterol carrier proteins" demonstrate the ability to mediate intervesicular transfer of cholesterol in vitro, the true physiological role of these proteins remains obscure. Future research in this field awaits the refinement of available techniques. Particularly valuable would be cytochemical methods for detection of sterol at the ultrastructural level. Possibly, direct microscopic visualization of radiolabeled components in cells represents the necessary approach. Purification of elements carrying newly synthesized sterols would allow the proteins mediating transport to be identified. Continued analysis of mutants defective in transport, such as in type C Niemann-Pick disease, will shed light on this complex problem. The importance of extracellular trafficking of cholesterol owing to its involvement in the progression of atherosclerosis, has been emphasized in recent years. Little emphasis has been placed on intracellular trafficking of sterol; however, it can be argued that such transport also plays a major role in atherosclerosis, possibly by fueling retrotransport of cholesterol to the liver and secretion in the bile. Therefore, we hope this review will serve to stimulate research interest in this area.
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PMID:Intracellular trafficking of sterols. 223 7

Cellular cholesterol homeostasis is a balance of influx, catabolism and synthesis, and efflux. Unlike vascular lipoprotein cholesterol transport, intracellular cholesterol trafficking is only beginning to be resolved. Exogenous cholesterol and cholesterol ester enter cells via the low-density lipoprotein (LDL) receptor/lysosomal and less so by nonvesicular, high-density lipoprotein (HDL) receptor/caveolar pathways. However, the mechanism(s) whereby cholesterol enters the lysosomal membrane, translocates, and transfers out of the lysosome to the cell interior are unknown. Likewise, the steps whereby cholesterol enters the cytofacial leaflet of the plasma membrane caveolae, rapidly translocates, leaves the exofacial leaflet, and transfers to extracellular HDL are unclear. Increasing evidence obtained with model and isolated cell membranes, transfected cells, genetic mutants, and gene-ablated mice suggests that proteins such as caveolin, sterol carrier protein-2 (SCP-2), Niemann-Pick C1 protein, steroidogenic acute regulatory protein (StAR), and other intracellular proteins mediate intracellular cholesterol transfer. While these proteins bind cholesterol and/or interact with cholesterol-rich membrane microdomains (e.g., caveolae, rafts, and annuli), their relative contributions to direct molecular versus vesicular cholesterol transfer remain to be resolved. The formation, regulation, and role of membrane microdomains in regulating cholesterol uptake/efflux and trafficking are unclear. Some cholesterol-binding proteins exert opposing effects on cellular cholesterol uptake/efflux, transfer of cholesterol out of the lysosomal membrane, and/or intracellular cholesterol trafficking to select membranous organelles. Resolving these cholesterol pathways and the role of membrane cholesterol microdomains is essential to our understanding not only of processes that affect cholesterol metabolism, but also of the abnormal regulation that may lead to disease (diabetes, obesity, atherosclerosis, neutral lipid storage, Niemann-Pick C, congenital lipoid adrenal hyperplasia, etc.).
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PMID:Recent advances in membrane microdomains: rafts, caveolae, and intracellular cholesterol trafficking. 1168 93

Cholesterol is an important sterol in mammals. Defects in cholesterol synthesis or intracellular routing have devastating consequences already in utero: the Smith-Lemli-Opitz syndrome, desmosterolosis and Niemann-Pick C1 disease provide examples of severe human inherited diseases caused by mutations in cholesterol metabolism genes. On the other hand, elevated plasma cholesterol concentrations are associated with the development of atherosclerosis which represents a major health risk in Western societies. Moreover, several studies indicate that development of atherosclerosis may already start during fetal life. Hence, a carefully balanced regulation of cholesterol metabolism appears of critical importance for both the development of the fetus and health of the adult. In the adult, the liver X receptor is a key regulator of cholesterol metabolism. Its target genes regulate cellular cholesterol efflux and thereby modulate whole-body cholesterol fluxes. LXR and several of its target genes have recently been demonstrated to be expressed in the placenta, which would provide a means to control delivery of maternal cholesterol to the fetus. Here we discuss the potential role of the placenta in the regulation of fetal cholesterol homeostasis and strategies to influence maternal-fetal cholesterol transfer.
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PMID:Cholesterol transport by the placenta: placental liver X receptor activity as a modulator of fetal cholesterol metabolism? 1714 66

Although a range of studies indicated Liver X receptor (LXR) activation inhibited the development of atherosclerosis in animal models, the mechanism of this effect for LXR agonists has not been fully understood. A recent study has suggested LXR activators increased the amount of free cholesterol in the plasma membrane of human macrophages by inducing Niemann-Pick type C1 (NPC1) gene expression. Therefore, we hypothesize that LXRs may also promote NPC1 expression in vivo. Here we investigated the effect of a synthetic LXR agonist T0901317 on ATP-binding cassette transporter A1 (ABCA1) and NPC1 in apolipoprotein E knockout (apoE-/-) mice. Male apoE-/- mice were randomized into four groups: baseline group (n = 10), vehicle group (n = 14), prevention group (n = 14), and treatment group (n = 14). En face analysis and Oil red O staining were used to examine the aortic atherosclerotic lesions. Macrophage content of aortic root atherosclerotic lesions and cholesterol efflux form peritoneal macrophages were measured. Gene and protein expression was analyzed by real-time quantitative polymerase chain reaction and Western blotting, respectively. T0901317 treatment reduced aortic atherosclerotic lesion area by 64.2% in prevention group (P < 0.001) and 58.3% in treatment group (P < 0.001) and resulted in a reduction in macrophage content. Plasma triglyceride, total cholesterol, high-density lipoprotein cholesterol, and apoA-I concentrations were markedly increased in T0901317-treated groups. T0901317 also promoted ABCA1 and NPC1 gene and protein levels in the aorta, liver, and small intestine of apoE-/- mice and significantly increased cholesterol efflux from peritoneal macrophages. T0901317 upregulates ABCA1 and NPC1. This study gives us a new insight into the mechanism for antiatherogenic effect of LXR synthetic agonists.
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PMID:The effect of T0901317 on ATP-binding cassette transporter A1 and Niemann-Pick type C1 in apoE-/- mice. 1843 96

Niemann-Pick C1 (NPC1) is a key participant in cellular cholesterol trafficking. Loss of NPC1 function leads to defective suppression of SREBP-dependent gene expression and failure to appropriately activate liver X receptor-mediated (LXR-mediated) pathways, ultimately resulting in intracellular cholesterol accumulation. To determine whether NPC1 contributes to regulation of macrophage sterol homeostasis in vivo, we examined the effect of NPC1 deletion in BM-derived cells on atherosclerotic lesion development in the Ldlr-/- mouse model of atherosclerosis. High-fat diet-fed chimeric Npc1-/- mice reconstituted with Ldlr-/-Npc1-/- macrophages exhibited accelerated atherosclerosis despite lower serum cholesterol compared with mice reconstituted with wild-type macrophages. The discordance between the low serum lipoprotein levels and the presence of aortic atherosclerosis suggested that intrinsic alterations in macrophage sterol metabolism in the chimeric Npc1-/- mice played a greater role in atherosclerotic lesion formation than did serum lipoprotein levels. Macrophages from chimeric Npc1-/- mice showed decreased synthesis of 27-hydroxycholesterol (27-HC), an endogenous LXR ligand; decreased expression of LXR-regulated cholesterol transporters; and impaired cholesterol efflux. Lower 27-HC levels were associated with elevated cholesterol oxidation products in macrophages and plasma of chimeric Npc1-/- mice and with increased oxidative stress. Our results demonstrate that NPC1 serves an atheroprotective role in mice through regulation of LXR-dependent cholesterol efflux and mitigation of cholesterol-induced oxidative stress in macrophages.
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PMID:Niemann-Pick C1 protects against atherosclerosis in mice via regulation of macrophage intracellular cholesterol trafficking. 1848 20

Ezetimibe is a selective cholesterol absorption inhibitor, which potently inhibits the uptake and absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides or bile acids. Identification and characterization of Niemann-Pick C1 Like 1 (NPC1L1) has established NPC1L1 as an essential protein in the intestinal cholesterol absorption process. While otherwise phenotypically normal, Npc1l1 null mice exhibit a significant reduction in the intestinal uptake and absorption of cholesterol and phytosterols. Characterization of the NPC1L1 pathway revealed that ezetimibe specifically binds to NPC1L1 and inhibits its sterol transport function. Npc1l1 null mice were resistant to diet-induced hypercholesterolemia, and when crossed with apoE null mice, were completely resistant to the development of atherosclerosis. In Npc1l1/apoE null mice or apoE null mice treated with ezetimibe plasma cholesterol levels were reduced primarily in the apoB48 containing chylomicron remnant lipoproteins relative to untreated apoE null mice. SR-B1 has been proposed to play a role in intestinal cholesterol uptake, but in Npc1l1/SR-B1 double null mice intestinal cholesterol absorption was not different than Npc1l1 null alone mice. Therefore, NPC1L1 is the critical intestinal sterol transporter which influences whole body cholesterol homeostasis, and is the molecular target of ezetimibe.
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PMID:Cholesterol homeostasis by the intestine: lessons from Niemann-Pick C1 Like 1 [NPC1L1). 1858 81

Deregulated lipid metabolism may be of particular importance for CNS injuries and disorders, as this organ has the highest lipid concentration next to adipose tissue. Atherosclerosis (a risk factor for ischemic stroke) results from accumulation of LDL-derived lipids in the arterial wall. Pro-inflammatory cytokines (TNF-alpha and IL-1), secretory phospholipase A2 IIA and lipoprotein-PLA2 are implicated in vascular inflammation. These inflammatory responses promote atherosclerotic plaques, formation and release of the blood clot that can induce ischemic stroke. TNF-alpha and IL-1 alter lipid metabolism and stimulate production of eicosanoids, ceramide, and reactive oxygen species that potentiate CNS injuries and certain neurological disorders. Cholesterol is an important regulator of lipid organization and the precursor for neurosteroid biosynthesis. Low levels of neurosteroids were related to poor outcome in many brain pathologies. Apolipoprotein E is the principal cholesterol carrier protein in the brain, and the gene encoding the variant Apolipoprotein E4 is a significant risk factor for Alzheimer's disease. Parkinson's disease is to some degree caused by lipid peroxidation due to phospholipases activation. Niemann-Pick diseases A and B are due to acidic sphingomyelinase deficiency, resulting in sphingomyelin accumulation, while Niemann-Pick disease C is due to mutations in either the NPC1 or NPC2 genes, resulting in defective cholesterol transport and cholesterol accumulation. Multiple sclerosis is an autoimmune inflammatory demyelinating condition of the CNS. Inhibiting phospholipase A2 attenuated the onset and progression of experimental autoimmune encephalomyelitis. The endocannabinoid system is hypoactive in Huntington's disease. Ethyl-eicosapetaenoate showed promise in clinical trials. Amyotrophic lateral sclerosis causes loss of motorneurons. Cyclooxygenase-2 inhibition reduced spinal neurodegeneration in amyotrophic lateral sclerosis transgenic mice. Eicosapentaenoic acid supplementation provided improvement in schizophrenia patients, while the combination of (eicosapentaenoic acid + docosahexaenoic acid) provided benefit in bipolar disorders. The ketogenic diet where >90% of calories are derived from fat is an effective treatment for epilepsy. Understanding cytokine-induced changes in lipid metabolism will promote novel concepts and steer towards bench-to-bedside transition for therapies.
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PMID:Altered lipid metabolism in brain injury and disorders. 1875 14


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