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)

Familial hypercholesterolemia (FH) can cause early disability and death from premature atherosclerotic cardiovascular disease. Patients homozygous for the disease have very high plasma cholesterol, extensive xanthomatosis, and die from atherosclerosis in childhood or early adulthood. Past attempts to improve the prognosis included removal of cholesterol from the circulation by ileal bypass or biliary diversion. Neither treatment was successful. Direct removal by plasmapheresis of low-density lipoprotein (LDL), the primary carrier of cholesterol in plasma, was first performed on an FH homozygous patient in 1966. The treatment was well tolerated and led to rapid diminution of xanthomas. Other experimental treatments included selective LDL apheresis with monoclonal or polyclonal antibody affinity columns. A method for selective LDL apheresis was developed in 1983 by Armstrong, Seidel, and colleagues based on heparin precipitation of LDL at low pH. This method, called HELP, removes all apolipoprotein B-containing lipoproteins including LDL and lipoprotein (a), as well as some fibrinogen. LDL apheresis by HELP is well tolerated; the incidence of side effects is low, and the treatment has been associated with regression of cardiovascular disease. LDL apheresis, rather than liver transplantation, is the treatment of choice for patients with severe, life-threatening hypercholesterolemia which does not respond to diet and drug therapy.
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PMID:Treatment of hypercholesterolemia with heparin-induced extracorporeal low-density lipoprotein precipitation (HELP). 891 17

We investigated the effects of a "tall oil"-derived phytosterol mixture (TODPM) on the formation of atherosclerotic lesions in apoE-deficient mice. TODPM was added at 2% (wt/wt) to the chow of nine mice; the control group had six animals. The diet of all animals contained 9% (wt/wt) fat and 0.15% (wt/wt) cholesterol. After 4 weeks, plasma total cholesterol levels were significantly reduced in the TODPM-treated mice (26.6 versus 42.0 mmol/L, P < .0001). The mean body weight of the TODPM-supplemented group was significantly higher at week 5 and throughout the study (29.4 versus 27.7 g, P < .05). The experiment was terminated at 18 weeks. Histological examination showed mature atherosclerotic lesions composed of foam cells underlying the endothelium, a mosaic of extracellular glycosaminoglycans, numerous apparently proliferative smooth muscle cells, and foci of cholesterol clefts in the control animals. By contrast, the TODPM-treated mice showed only early lesions containing mainly superficial foam cells. As assessed by morphometry, the lesion area in the aortic sinuses of TODPM-treated animals was less than half that of control animals (P < .0001). This reduced lesion area was accompanied by a substantial reduction in all lesional components, reflecting a delay in progression of atheromatous changes. A strong positive correlation (r = .69, P < .01) was found between plasma total cholesterol levels and lesion area in the aortic sinuses. TODPM also prevented the occurrence of xanthomatosis. We conclude that supplementation of a cholesterol-enriched diet with TODPM significantly lowers plasma cholesterol and retards development of atherosclerosis in apoE-deficient mice, suggesting a therapeutic potential for the mixture of phytosterols studied.
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PMID:"Tall oil"-derived phytosterols reduce atherosclerosis in ApoE-deficient mice. 901 46

We have identified a 44-year-old patient with symmetrically excessive xanthomatosis, called Erdheim-Chester disease (ECD), and simultaneously decreased levels of low-density lipoprotein (LDL) cholesterol. Clinically, this patient presents lipoidgranulomatosis of numerous long and flat bones with involvement of the liver, spleen, pericardium, pleura, thyroid, skin, conjunctiva, and gingiva. However, the patient does not have any signs of atherosclerosis. So far, the underlying defect has not been elucidated. We performed a LDL-apolipoprotein B (apoB) kinetic study in the ECD patient and a normal control to determine the etiology of the low LDL level in ECD. LDL was isolated from both subjects, radioiodinated with either 131I or 125I, and injected simultaneously into the ECD patient and the normal control. Normal and ECD LDL was catabolized at the same rate after injection into the control subject (fractional catabolic rate [FCR], 0.43/d and 0.46/d, respectively). Therefore, LDL isolated from an ECD subject is metabolically normal. In contrast, autologous LDL injected into the ECD subject showed a markedly increased catabolism (FCR, 0.69/d) compared with that in the control subject (FCR, 0.43/d). This is the first report about increased catabolism of LDL cholesterol in a patient.
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PMID:Erdheim-Chester disease: low low-density lipoprotein levels due to rapid catabolism. 932 10

Familiar xanthomatosis hypercholesterolemia in homozygous or heterozygous (two or more defects in LDL receptors) forms are rare. The cholesterol levels are frequently above 700 mg/dL. The management of these patients includes odd procedures, such as ileal bypass to control of levels of cholesterol. We present a case of pregnancy in patient with familiar hypercholesterolemia (FH) and coronary and cerebral atherosclerosis who had undergone ileal bypass, five years prior. During pregnancy, there were no clinical signs or symptoms related to coronary or cerebral atherosclerosis and we did not observe obstetric complications. Nevertheless, the levels of cholesterol and triglyceride increased significantly to 1182 mg/dL and 807 mg/dL. Face the unknown prognosis of this clinical situation we decided to hospitalize the patient and to prescribe prolonged rest, dietary measures and specific therapy. This approach permitted her to reach the end of pregnancy without maternal and fetal complications. The patient was submitted to cesarean section by obstetric reasons. The newborn was healthy but his levels of cholesterol and triglycerides were respectively, 339 mg/dL and 301 mg/dL. The success of this case does not allow the change in the recommendation of avoiding pregnancy in patients with severe FH.
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PMID:[Pregnancy in patient with familial hypercholesterolemia and atherosclerosis disease]. 943 57

The idea of a fat transport system in the plasma of mammals evolved slowly over three centuries. At the turn of this century, it was discovered that plasma globulins contained lecithin and that the digestion of plasma proteins with pepsin liberated small amounts of fat and cholesterol. The high density lipoprotein (HDL) was first isolated from horse serum in 1929 and the low density lipoprotein (LDL) in 1950. It was then shown that flotation of plasma in the ultracentrifuge revealed an array of lipoproteins that included VLDL, LDL and HDL and permitted quantitation. Subsequently, it was discovered that the free fatty acids (FFA) in plasma were bound to albumin and varied with feeding and fasting. From further studies, it was concluded that lipoprotein-bound triglycerides were delivered to adipose cells for uptake after meals; during fasting, the fat cells secreted FFA, which provided fuel for many tissues. The protein components of the lipoproteins (apopeptides) were characterized in the period from 1960 to 1970 and the LDL-receptor was identified in 1974. Fat transport was then established as a receptor-mediated delivery system of lipoproteins to targeted tissues. Defects in this system due to genetically altered or absent receptors explained dyslipidemias, which promoted atherosclerosis, xanthomatosis and Alzheimer's disease.
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PMID:Discovery of the lipoproteins, their role in fat transport and their significance as risk factors. 947 44

Sterol 27-hydroxylase is important for the degradation of the steroid side chain in conversion of cholesterol into bile acids and has been ascribed a regulatory role in cholesterol homeostasis. Its deficiency causes the autosomal recessive disease cerebrotendinous xanthomatosis (CTX), characterized by progressive dementia, xanthomatosis, and accelerated atherosclerosis. Mice with a disrupted cyp27 (cyp27(-/-)) had normal plasma levels of cholesterol, retinol, tocopherol, and 1,25-dihydroxyvitamin D. Excretion of fecal bile acids was decreased (<20% of normal), and formation of bile acids from tritium-labeled 7alpha-hydroxycholesterol was less than 15% of normal. Compensatory up-regulation of hepatic cholesterol 7alpha-hydroxylase and hydroxymethylglutaryl-CoA reductase (9- and 2-3-fold increases in mRNA levels, respectively) was found. No CTX-related pathological abnormalities were observed. In CTX, there is an increased formation of 25-hydroxylated bile alcohols and cholestanol. In bile and feces of the cyp27(-/-) mice only traces of bile alcohols were found, and there was no cholestanol accumulation. It is evident that sterol 27-hydroxylase is more important for bile acid synthesis in mice than in humans. The results do not support the contention that 27-hydroxylated steroids are critical for maintenance of cholesterol homeostasis or levels of vitamin D metabolites in the circulation.
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PMID:Markedly reduced bile acid synthesis but maintained levels of cholesterol and vitamin D metabolites in mice with disrupted sterol 27-hydroxylase gene. 961 81

We have recently described an inherited over-expression of the macrophage scavenger receptor (SR) in blood monocytes from members of a kindred, only two of whom displayed extensive xanthomatosis. Using mRNA differential display we demonstrated abnormally high expression of the signal transducer and activator of transcription (STAT1alpha) in monocytes from the proband II-2. Expression of gamma-interferon inducible protein 10 (IP-10), a STAT1alpha-responsive gene and mediator of inflammatory response, was also abnormally expressed in the monocytes from II-2. Over-expression of both genes was restricted to monocytes from II-2 and was not observed in monocytes from the clinically unaffected family members, unlike that of SR. Gel retardation assays with THP-1 cell extracts identified gamma-IFN inducible DNA binding activity to three potential STATI DNA binding elements in the human IP-10 promoter region from nucleotides - 245 to - 188. Taken together these results suggest that gamma-interferon mediated cell activation is responsible for STAT1alpha-induced transcription of the IP-10 gene in THP-1 macrophages as well as in monocytes from II-2. Analysis of monocytes from familial hypercholesterolemic (FH) subjects, who frequently develop xanthomatosis, revealed a significant number of subjects with elevated STAT1alpha and IP-10 expression. Our data suggest that the inflammatory effects of gamma-IFN signaling could play a role in foam cell formation and xanthomatosis.
Atherosclerosis 1998 Jun
PMID:Expression of gamma-IFN responsive genes in scavenger receptor over-expressing monocytes is associated with xanthomatosis. 969 Sep 17

Japanese quail of a strain (SUS) susceptible to dietary cholesterol-induced atherosclerosis were fed a diet supplemented with cholesterol (0.5% w/w) for 4, 8 or 12 weeks. Plasma cholesterol increased significantly from 240-1550 mg/dl at 4 weeks and remained at that concentration for 8 and 12 weeks on the same diet. Plasma triglycerides (TGs) increased from 112-384 mg/dl after 4 weeks but showed no significant increases thereafter. Striking eruptive xanthomatous lesions were noticed on the feet of 50% of these birds at 4 weeks, and the percentage of birds affected increased to 85 after 12 weeks on the cholesterol-supplemented diet. This is the first report of xanthomatosis in birds. These birds had also developed atherosclerotic plaques in the aorta and brachiocephalic arteries by 4 weeks. There was no significant correlation between xanthoma scores and plasma cholesterol and TG concentrations at any of the three sampling periods (4, 8 and 12 weeks of cholesterol feeding). There was, however, a significant negative correlation (r = -0.61) between xanthoma scores and atherosclerotic plaque scores at 4 weeks. The correlation became non-significant at later stages of cholesterol exposure. Similarities between mammalian and SUS Japanese quail xanthomatosis may make the SUS quail a useful model for the study of this disorder.
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PMID:Dietary cholesterol-induced xanthomatosis in atherosclerosis-susceptible Japanese quail (Cotunix japonica). 983 3

Necrobiotic xanthogranuloma (NXG) is a rare histiocytic disease with generalized xanthomatosis. However, most cases with NXG are normolipidemic or hypolipidemic. The mechanism for the formation of xanthoma in NXG has not yet been clarified. We observed a case of NXG with severe hypocholesterolemia (total cholesterol: 1.69 mmol/l) and analyzed the function of monocytes in this case. Histological examinations by light microscopy revealed a large amount of lipid deposition in the patient's freshly isolated monocytes. The patient's monocytes showed a 3-fold increase in cholesteryl ester content and a 3-fold enhancement of acetyl low density lipoprotein (LDL) uptake compared with the control monocytes. However, no significant difference was noted in the expression of CD36 protein and the mRNA levels of scavenger receptor-class A (SR-A) between the monocytes of the patient and the control. The phagocytotic ability of the patient's monocytes was enhanced 1.5-fold compared with that of the control monocytes. These findings suggest that the activated monocytes may have degraded the modified LDL via a pathway other than CD36 or SR-A, and accumulated a great amount of lipids in vivo. In conclusion, the present study has demonstrated a possible pathogenesis of NXG that the activation of monocytes in vivo may contribute to the intracellular accumulation of lipoprotein-derived lipids leading to non-inherited xanthomatosis and the marked hypocholesterolemia.
Atherosclerosis 1999 Feb
PMID:Activation of monocytes in vivo causes intracellular accumulation of lipoprotein-derived lipids and marked hypocholesterolemia--a possible pathogenesis of necrobiotic xanthogranuloma. 1003 Mar 87

Acyl-CoA:cholesterol acyltransferase (ACAT) catalyzes esterification of cellular cholesterol. To investigate the role of ACAT-1 in atherosclerosis, we have generated ACAT-1 null (ACAT-1-/-) mice. ACAT activities were present in the liver and intestine but were completely absent in adrenal, testes, ovaries, and peritoneal macrophages in our ACAT-1-/- mice. The ACAT-1-/- mice had decreased openings of the eyes because of atrophy of the meibomian glands, a modified form of sebaceous glands normally expressing high ACAT activities. This phenotype is similar to dry eye syndrome in humans. To determine the role of ACAT-1 in atherogenesis, we crossed the ACAT-1-/- mice with mice lacking apolipoprotein (apo) E or the low density lipoprotein receptor (LDLR), hyperlipidemic models susceptible to atherosclerosis. High fat feeding resulted in extensive cutaneous xanthomatosis with loss of hair in both ACAT-1-/-:apo E-/- and ACAT-1-/-:LDLR-/- mice. Free cholesterol content was significantly increased in their skin. Aortic fatty streak lesion size as well as cholesteryl ester content were moderately reduced in both double mutant mice compared with their respective controls. These results indicate that the local inhibition of ACAT activity in tissue macrophages is protective against cholesteryl ester accumulation but causes cutaneous xanthomatosis in mice that lack apo E or LDLR.
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PMID:Absence of ACAT-1 attenuates atherosclerosis but causes dry eye and cutaneous xanthomatosis in mice with congenital hyperlipidemia. 1077 3


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