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)

Mouse models were used to determine whether Chlamydia pneumoniae establishes chronic infection of the aorta and contributes to atherogenesis. Persistent infection of the aorta occurred in 11 of 31 hyperlipidemic apolipoprotein E-deficient (apoE(-/-)) mice but not in C57BL/6J mice fed a normal diet after a single inoculation and in both models following repeated inoculation with C. pneumoniae. Repeated inoculation of C57BL/6J mice resulted in inflammatory changes in the heart and aorta in 8 of 40 of mice; however, no atherosclerotic lesion development was observed. Repeated inoculation of apoE(-/-) mice resulted in a statistically significant increase in lesion area (n=43; P=.05). Although Chlamydia trachomatis disseminated to the aorta, persistent infection was not established and no statistically significant increase in lesion area occurred. These studies suggest that persistent infection of the aorta can lead to inflammatory changes in the absence of hyperlipidemia and accelerate lesion progress in concert with hyperlipidemia.
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PMID:Mouse models of C. pneumoniae infection and atherosclerosis. 1083 49

The goal of this study was to compare the lipid lowering properties of maritime pine and fish oils in apolipoprotein E-deficient (KOE) mice, an animal model of hyperlipidemia. KOE mice were supplemented with either lard, fish or maritime pine oil (10% w/w) for one month. Compared to lard, fish and maritime pine oils decreased cholesterol (-31% and -52% respectively) and phospholipid (-41 and -52%) levels and increased triglyceride (+182% and +123%) levels. These lipid changes resulted in an enrichment in triglycerides and a depletion in cholesterol of VLDL+IDL plasma fraction as compared to lard-fed mice. These findings suggest that VLDL-triglyceride lipolysis is impaired in KOE mice fed fish or maritime pine oil.
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PMID:Comparison of maritime pine oil and fish oil effects on plasma lipoproteins in apolipoprotein E-deficient mice. 1088 62

The increased risk of hyperlipidemia on the development of complications of atherosclerosis is well established. Cholesterol-lowering therapies lead to a decrease in the incidence of vascular thrombotic events that is out of proportion to the reduction in plaque size. This suggests that the occurrence of acute thrombosis overlying a disrupted plaque is influenced by changes in lipid levels. The influence of acute hyperlipidemia on the development of thrombosis overlying an atherosclerotic plaque in vivo has not been extensively studied. We used a murine model of vascular injury induced by a photochemical reaction to elicit thrombus formation overlying an atherosclerotic plaque. Fifteen apolipoprotein E-deficient mice were maintained on normal chow until the age of 30 weeks. Five days before the induction of thrombosis, 6 mice were started on a high fat diet, and 9 mice were continued on normal chow. Mice then underwent photochemical injury to the common carotid artery immediately proximal to the carotid bifurcation, where an atherosclerotic plaque is consistently present. Mice maintained on normal chow developed occlusive thrombi, determined by cessation of blood flow, 44+/-5 minutes (mean+/-SEM) after photochemical injury, whereas mice fed a high fat chow developed occlusive thrombosis at 27+/-3 minutes (P<0.02). Histological analysis confirmed the presence of acute thrombus formation overlying an atherosclerotic plaque. These studies demonstrate a useful model for assessing the determinants of thrombosis in the setting of atherosclerosis and show that acute elevations in plasma cholesterol facilitate thrombus formation at sites of atherosclerosis after vascular injury.
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PMID:Hyperlipidemia promotes thrombosis after injury to atherosclerotic vessels in apolipoprotein E-deficient mice. 1089 25

Wild-type C57BL mice are known to be susceptible to diet-induced atherosclerosis, whilst C3H mice are resistant. We investigated the effect of these background strains on the hyperlipidaemia and atherosclerosis that develops in mice deficient in apolipoprotein E (apoE(-/-)). Male and female apoE(-/-) mice on C3H/HeNHsd (C3H) and C57BL/6J (C57) backgrounds were fed atherogenic Western diet for 12 weeks. Serum cholesterol and triglyceride concentrations were measured and atherosclerosis quantified in the aortic sinus. C3H apoE(-/-) mice fed normal diet had 1.5 2 fold higher serum cholesterol levels than C57 apoE(-/-) mice and 4-5 fold higher serum triglyceride concentrations. Feeding Western diet caused a 4-5 fold increase in serum cholesterol in all mice, but levels of triglyceride were either attenuated or were unaffected in C3H apoE(-/-) and C57 apoE(-/-) mice, respectively. C3H apoE(-/-) mice had approximately 2 fold higher serum cholesterol and 4 fold higher triglyceride concentrations than the C57 apoE(-/-) mice throughout the study. Serum triglyceride concentrations were 35-108% higher in male C3H apoE(-/-) than female C3H apoE(-/-) mice. Most of the lipids were present in the very low density lipoprotein (VLDL)/chylomicron fraction in both strains of mice whether they were fed normal or Western diet. Notwithstanding the lower plasma lipid concentrations, atherosclerotic lesion areas were more than 2-fold larger in C57 apoE(-/-) than in C3H apoE(-/-) mice (males 68 +/- 11 x 10(3) vs 30 +/- 6 x 10(3) females 102 +/- 12 x 10(3) vs 41 +/- 8 x 10(3) microm2. mean +/- SEM).
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PMID:C3H apoE(-/-) mice have less atherosclerosis than C57BL apoE(-/-) mice despite having a more atherogenic serum lipid profile. 1092 15

We describe the characterization of a novel mutation in the low density lipoprotein receptor (LDL-R) gene in a patient with true homozygous familial hypercholesterolemia (FH). The combined use of denaturing gradient gel electrophoresis (DGGE) and sequencing of genomic DNA revealed a guanine to adenine base substitution at nucleotide position 1013 of the LDL-R cDNA. This point mutation results in a change from cysteine to tyrosine at amino acid residue 317 of repeat A of the epidermal growth factor (EGF) precursor homology domain. Binding, uptake and degradation of iodinated LDL in skin fibroblasts from the homozygous patient were less than 10% of normal. In contrast, binding, uptake and degradation of iodinated VLDL was reduced by only 60, 30, and 38%, respectively. Incubation of the patient's fibroblasts in the presence of cholesterol diminished the residual binding of VLDL by 50%, suggesting that the loss of the highly conserved cysteine at position 317 results in a LDL-R that fails to bind LDL, but retains some ability to bind VLDL by interacting with the apolipoprotein E. Both parents were heterozygous for the C317Y mutation. Interestingly, however, the father presented with markedly elevated levels of triglycerides and VLDL cholesterol, whereas his LDL cholesterol was unexpectedly low. The mother of the index patient had only slightly elevated LDL cholesterol. These observations testify to the biological complexity of genotype-environment interactions in individuals carrying mutations at the LDL-R locus and indicate that genetic analysis importantly complements the clinical and biochemical diagnosis of patients with hyperlipidemia.
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PMID:FH-Freiburg: a novel missense mutation (C317Y) in growth factor repeat A of the low density lipoprotein receptor gene in a German patient with homozygous familial hypercholesterolemia. 1092 30

Diabetic nephropathy is associated with an altered lipid profile characterized by elevated triglyceride rich lipoproteins, present even in the earlier stages of the renal disease. Although many experimental studies have demonstrated a significant deleterious role for hyperlipidemia in both the initiation and progression of renal injury, data remain more conflicting in humans. A few prospective studies, mostly in type 2 diabetes, have suggested an independent role for serum cholesterol level in the subsequent development of incipient or overt diabetic nephropathy. Furthermore, studies have reported in both types of diabetes an independent deleterious influence of serum total cholesterol on the decline in renal function and/or progression of albuminuria. However, the majority of these studies were post hoc analyses of previously controlled therapeutic trials with several observational studies not confirming these findings. It remains controversial whether apolipoprotein E gene polymorphism is an important factor in the development of diabetic nephropathy. Most of the interventional studies with lipid-lowering therapy in diabetic nephropathy have used HMG CoA reductase inhibitors and have been inconclusive. This may be due to a too short follow-up or insufficient number of patients. Further larger prospective studies are therefore required to better ascertain the role of lipids in the progression of diabetic nephropathy.
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PMID:Potential influence of lipids in diabetic nephropathy: insights from experimental data and clinical studies. 1101 Dec 17

Neointimal hyperplasia is a critical component of restenosis, a major complication of angioplasty and related therapeutic procedures. We studied the effects of hyperlipidemia and the nonsteroidal anti-inflammatory drugs, aspirin (acetyl-salicylic acid; ASA), and sulindac, on neointimal formation in a mouse femoral arterial injury model. At 2 months of age, normolipidemic, wild-type (WT), and hyperlipidemic, apolipoprotein E-deficient (apoE-/-) mice were divided into three treatment groups: Western-type diet (WD), WD + ASA (200 mg/kg food), and WD + sulindac (300 mg/kg food). After 1 week, mice underwent arterial injury and treatments were maintained for 4 weeks. Histomorphometry of the injured arteries showed striking effects of plasma cholesterol levels and drug treatment on neointimal hyperplasia. In the WD or WD + ASA groups, apoE-/- mice had twice the neointimal area than WT mice ( approximately 30,000 vs. 13,000 microm(2) per section; P < 0.0001). Compared with ASA or WD alone, sulindac treatment resulted in approximately 70% (P = 0.0001) and 50% (P = 0.01) reductions in the neointimal area in apoE-/- and WT mice, respectively. ASA, at a dose sufficient to inhibit platelet aggregation, did not affect neointimal formation in mice of either genotype. Evidence of macrophages was noted in the lesions of apoE-/- mice in the WD and WD + ASA groups, but remarkably, none was detectable with sulindac treatment, despite hyperlipidemia, suggesting early steps in the response to injury were abrogated. These results demonstrate sulindac reduces neointimal formation in both normolipidemic and hyperlipidemic settings and raise the possibility that similar benefits may be obtained in patients undergoing angioplasty and related procedures.
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PMID:Sulindac inhibits neointimal formation after arterial injury in wild-type and apolipoprotein E-deficient mice. 1105 72

To develop an adequate animal model for atherosclerosis in large vessels of patients with diabetes, i.e. diabetic macroangiopathy, we induced diabetes in APA hamsters with a single injection of streptozotocin (SZ) and examined the aorta histopathologically and immunohistochemically. As a result, hyperglycemia and hyperlipidemia were continuously observed for 26 weeks after the SZ injection (WAI) in APA hamsters. Fatty streaks characterized by a subendothelial accumulation of many foam cells were observed, limited to the aortic arches as early as 6 WAI. In addition to larger fatty streaks developing with the duration of diabetes, fibrous plaques and plaques containing calcium deposits or cholesterol clefts developed at 26 WAI. These lesions are generally similar to the atheromatous lesions developed in humans. Moreover, depositions of apolipoprotein E and advanced glycation end-products immunohistochemically detected in the lesions were very similar to those found in humans. The diabetic APA hamster is therefore considered to be a useful model for studying the formation of atheromatous lesions in diabetic patients.
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PMID:Aortic atheromatous lesions developed in APA hamsters with streptozotocin induced diabetes: a new animal model for diabetic atherosclerosis. 1. Histopathological studies. 1110 51

Lipatrophic diabetes, also referred to as familial partial lipodystrophy, is a rare disease that is metabolically characterized by hypertriglyceridemia and insulin resistance. Affected patients typically present with regional loss of body fat and muscular hypertrophic appearance. Variable symptoms may comprise pancreatitis and/or eruptive xanthomas due to severe hypertriglyceridemia, acanthosis nigricans, polycystic ovaria, and carpal tunnel syndrome. Mutations within the LMNA gene on chromosome 1q21.2 were recently reported to result in the phenotype of familial partial lipodystrophy. The genetic trait is autosomal dominant. We identified a family with partial lipodystrophy carrying the R482W (Arg(482)Trp) missense mutation within LMNA. Here we present the lipoprotein characteristics in this family in detail. Clinically, the loss of sc fat and muscular hypertrophy especially of the lower extremities started as early as in childhood. Acanthosis and severe hypertriglyceridemia developed later in life, followed by diabetes. The characterization of the lipoprotein subfractions revealed that affected children present with hyperlipidemia. The presence and severity of hyperlipidemia seem to be influenced by age, apolipoprotein E genotype, and the coexistence of diabetes mellitus. In conclusion, dyslipemia is an early and prominent feature in the presented lipodystrophic family carrying the R482W mutation within LMNA.
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PMID:Dyslipemia in familial partial lipodystrophy caused by an R482W mutation in the LMNA gene. 1134 41

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


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