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)

A sucrose-rich diet stimulates hepatic lipogenesis and induces net production of very low density lipoproteins in the liver. To study changes of hepatic apolipoprotein gene expression in response to such a diet, we measured the mRNA abundance of apolipoproteins A-I, C-III and A-IV in livers of rats fed a sucrose-rich diet or a control diet for 3 weeks. In livers of sucrose-fed rats, the abundance of cellular and nuclear apo A-IV mRNA increased to 185% +/- 21% and 142% +/- 22% of control values (P less than 0.01), respectively. In sucrose-fed rats, the transcriptional activity of the apo A-IV gene, measured in a cell-free transcription system using isolated liver nuclei, increased to 144% +/- 23% of control (P less than 0.05). In contrast, this diet neither affected the abundance of cellular and nuclear apo A-I and apo C-III mRNA nor the transcriptional activity of these genes in liver. These results are consistent with specialization of the regulatory elements of the genes coding for apolipoproteins A-I, C-III and A-IV. Alternatively, enhanced transcription of the apo A-IV gene may preclude increased synthesis of apo A-I and/or apo C-III mRNA due to the close linkage of the three genes in the rat genome.
Atherosclerosis 1992 Aug
PMID:Effect of sucrose diet on expression of apolipoprotein genes A-I, C-III and A-IV in rat liver. 141 89

The defect in a kindred with marked plasma high density lipoprotein (HDL) deficiency and premature atherosclerosis was examined. The homozygous proband died of coronary artery atherosclerosis at age 45 and had undetectable levels of plasma apolipoproteins A-I and C-III, proteins of HDL. In family studies 10 heterozygotes were identified whose mean apoA-I, apoC-III, apoA-IV, and HDL cholesterol levels were 67, 57, 65, and 62% of normal. These subjects were noted to have restriction fragment length polymorphisms following DNA digestion with a number of enzymes including BamHI, EcoRI, HindIII, XmnI, PstI, and PvuII, following hybridization with a probe spanning 1.1 kilobases approximately 2.5 kilobases 5' to the apoA-I gene. Cloning and sequence analysis of the abnormal allele indicated that the defect is due to the complete deletion of the apoA-I, -C-III, and -A-IV gene complex on chromosome 11, with both ends of the deletion being located in areas of highly repetitive DNA. The data support the concept of an independent role for HDL in the pathogenesis of atherosclerosis.
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PMID:Familial apolipoprotein A-I, C-III, and A-IV deficiency and premature atherosclerosis due to deletion of a gene complex on chromosome 11. 250 76

The effects of apolipoprotein (apo) A-IV and apoA-IV/phosphatidylcholine (PC) liposome on cholesterol efflux from the smooth muscle cells originating from the aorta of hypercholesterolemic rabbit model and control rabbits, and on the activation of lecithin cholesterol acyltransferase (LCAT) were studied respectively. Both apoA-IV/PC and apoA-I/PC liposomes have similar efficiency as the HDL's, i.e. a strong ability to clear intracellular cholesterol and the ability to activate LCAT. There were no differences noticed on the clearance ability between apoA-IV and apoA-I or between apoA-IV/PC and apoA-I/PC liposomes. These results suggest that apoA-IV may play an important role in the process of reverse cholesterol transport and apoA-IV/PC liposome may be effectively used instead of natural HDL to prevent the development of atherosclerosis.
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PMID:[Apolipoprotein A-IV and transportation of cholesterol from smooth muscle cells in experimental hyperlipidemia]. 778 Nov 20

The plasma low density lipoprotein (LDL) of an apolipoprotein (apo) E-deficient patient was reported to contain apoB-48 (D. Kurosaka et al., Atherosclerosis 1988;88:15), which is a structural protein of chylomicrons and is not present in the fasting plasma LDL of normal subjects. We separated the LDLs containing apoB-48 (apoB-48 LDL) and apoB-100 (apoB-100 LDL) from the plasma of this patient using heparin-sepharose column chromatography. The apoB-48 LDL contained apoA-I, apoA-IV, and apoCs besides apoB-48. There were no differences in size and lipid composition of the apoB-48 and the apoB-100 LDLs, both of which contained more triglyceride than LDL from normal subjects. After incubation with apoE, the apoB-48 LDL contained twice the amount of apoE than the apoB-100 LDL and showed a marked decrease in apoA-I and apoA-IV content. These results suggest that lipoproteins containing apoB-48 in normal subjects can be quickly taken up through an apoE-mediated receptor mechanism after receiving apoE in exchange for apoA-I and A-IV.
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PMID:Purification and characterization of low density lipoprotein containing apolipoprotein B-48 from the plasma of an apoE-deficient patient. 908 98

The early colocalization of T cells and the potent immunostimulatory cytokine IFN-gamma to atherosclerotic lesions suggest that the immune system contributes to atherogenesis. Since mice with a targeted disruption of the apoE gene (apoE 0 mice) develop profound atherosclerosis, we examined the role of IFN-gamma in this process. First, the presence of CD4(+) and CD8(+) cells, which secrete lesional IFN-gamma, was documented in apoE 0 atheromata. Then, the apoE 0 mice were crossed with IFN-gamma receptor (IFNgammaR) 0 mice to generate apoE 0/IFNgammaR 0 mice. Compared to the apoE 0 mice, the compound knock-out mice exhibited a substantial reduction in atherosclerotic lesion size, a 60% reduction in lesion lipid accumulation, a decrease in lesion cellularity, but a marked increase in lesion collagen content. Evaluation of the plasma lipoproteins showed that the compound knockout mice had a marked increase in potentially atheroprotective phospholipid/apoA-IV rich particles as well. This correlated with an induction of hepatic apoA-IV transcripts. These observations suggest that IFN-gamma promotes and modifies atherosclerosis through both local effects in the arterial wall as well as a systemic effect on plasma lipoproteins. Therefore, therapeutic inhibition of IFN-gamma signaling may lead to the formation of more lipid-poor and stable atheromata.
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PMID:IFN-gamma potentiates atherosclerosis in ApoE knock-out mice. 916 6

The aims of the study were to investigate associations of the apolipoprotein (apo) A-IV polymorphisms Thr347Ser and Gln360His with anthropomorphic measurements and fasting and postprandial lipids in subjects participating in the European Atherosclerosis Research Study II (EARS II). The allelic frequencies of Ser347 and His360 were 0.185 and 0.067, respectively, in the sample as a whole. There were no significant differences in rare allele frequency between cases (offspring of fathers who suffered a myocardial infarction before the age of 55 years) and controls. Control subjects who were carriers of Ser347 had significantly higher body mass indices (BMIs), waist:hip ratios, total and low density lipoprotein cholesterol and triacylglycerol (TG) concentrations (all P < or = 0.02) than control subjects who were non-carriers, but these effects were not seen in the cases. Control subjects who were carriers of His360 had lower BMIs (P = 0.04), cholesterol and TG concentrations (both P < or = 0.07) compared to non-carriers, but these effects were not seen in the cases. After consumption of an oral fat load, carriers of His360 who were most obese (subjects in the third tertile of BMI) had significantly reduced postprandial lipemia (P < 0.03, as assessed by area under the curve).-Fisher, R. M., H. Burke, V. Nicaud, C. Ehnholm, and S. E. Humphries. Effect of variation in the apoA-IV gene on body mass index and fasting and postprandial lipids in the European Atherosclerosis Research Study II.
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PMID:Effect of variation in the apo A-IV gene on body mass index and fasting and postprandial lipids in the European Atherosclerosis Research Study II. EARS Group. 992 58

Lipoprotein lipase (LPL) is known to play a crucial role in lipoprotein metabolism by hydrolyzing triglycerides; however its role in atherogenesis has yet to be determined. We have previously shown that low density lipoprotein receptor knockout mice overexpressing LPL are resistant to diet-induced atherosclerosis due to the suppression of remnant lipoproteins. Plasma lipoproteins and atherosclerosis of apolipoprotein (apo) E knockout mice which overexpress the human LPL transgene (LPL/APOEKO) were compared with those of control apoE knockout mice (APOEKO). On a normal chow diet, LPL/APOEKO mice showed marked suppression of the plasma triglyceride levels compared with APOEKO mice (54 vs. 182 mg/dl), but no significant changes in plasma cholesterol and apoB levels. Non-high density lipoproteins (HDL) from LPL/APOEKO mice had lower triglyceride content, a smaller size, and a more positive charge compared with those from APOEKO mice. Cholesterol, apoA-I, and apoA-IV were increased in HDL. Although both groups developed hypercholesterolemia to a comparable degree in response to an atherogenic diet, the LPL/APOEKO mice developed 2-fold smaller fatty streak lesions in the aortic sinus compared to the APOEKO mice. In conclusion, overproduction of LPL is protective against atherosclerosis even in the absence of apoE.
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PMID:Overexpressed lipoprotein lipase protects against atherosclerosis in apolipoprotein E knockout mice. 1048 15

The apolipoprotein (apo)A-I/C-III/A-IV gene cluster is involved in lipid metabolism and atherosclerosis. Overexpression of apoC-III in mice causes hypertriglyceridemia and induces atherogenesis, whereas overexpression of apoA-I or apoA-IV increases cholesterol in plasma high density lipoprotein (HDL) and protects against atherosclerosis. Each gene has been studied alone in transgenic mice but not in combination as the entire cluster. To determine which phenotype is produced by the expression of the entire gene cluster, transgenic mice were generated with a 33-kb human DNA fragment. The results showed that the transgene contained the necessary elements to direct hepatic and intestinal expression of the 3 genes. In the pooled data, plasma concentrations were 257+/-9, 7.1+/-0.5, and 1.0+/-0.2 mg/dL for human apoA-I, apoC-III, and apoA-IV, respectively (mean+/-SEM). Concentrations of these apolipoproteins were higher in males than in females. Human apoA-I and apoC-III concentrations were positively correlated, suggesting that they are coregulated. Transgenic mice exhibited gross hypertriglyceridemia and accumulation of apoB(48)-containing triglyceride-rich lipoproteins. Plasma triglyceride and cholesterol concentrations were correlated positively with human apoC-III concentration, and HDL cholesterol was correlated with apoA-I concentration. In an apoE-deficient background, despite being markedly hypertriglyceridemic, cluster transgenic animals compared with nontransgenic animals showed a 61% reduction in atherosclerosis. This suggests that apoA-I and/or apoA-IV can protect against atherosclerosis even in the presence of severe hyperlipidemia. These mice provide a new model for studies of the regulation of the 3 human genes in combination.
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PMID:Expression of human apolipoprotein A-I/C-III/A-IV gene cluster in mice induces hyperlipidemia but reduces atherogenesis. 1103 Dec 14

New therapeutic approaches to the prevention and treatment of atherosclerotic cardiovascular disease (ASCVD) are needed. Plasma levels of high-density lipoprotein (HDL) cholesterol are inversely associated with risk of ASCVD. Genes involved in the metabolism of HDL represent potential targets for the development of such therapies. Because HDL metabolism is a dynamic process, the effect of a specific HDL-oriented intervention on atherosclerosis cannot necessarily be predicted by its effect on the plasma HDL cholesterol level. Based on available data in animal models, some gene products are candidates for pharmacologic upregulation, infusion, or overexpression, including apolipoprotein (apo)A-I, apoE, apoA-IV, lipoprotein lipase (LPL), ATP-binding cassette protein 1 (ABC1), lecithin cholesterol acyltransferase (LCAT), and scavenger receptor B-I (SR-BI). In contrast, some gene products are potential candidates for inhibition, including apoA-II, cholesteryl ester transfer protein (CETP), and hepatic lipase. The next decade will witness the transition from preclinical studies to clinical trials of a variety of new therapies targeted toward HDL metabolism and atherosclerosis.
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PMID:High-density lipoprotein metabolism: molecular targets for new therapies for atherosclerosis. 1112 67

Tangier disease (TD) is characterized by severe high-density lipoproteins (HDL) deficiency, hypercatabolism of HDL constituents, impaired cellular cholesterol efflux, and mutations in the gene of ATP-binding cassette 1 (ABC-1). In the present study, we determined plasma lipid and apolipoprotein levels, and HDL subpopulations, in 110 subjects from a large TD kindred in which the proband was homozygous for an A-->C missense mutation at nucleotide 5338 of the ABC-1 transcript. In the proband HDL-C, apoA-I, and apoA-II concentrations were 2, 1, and 2 mg/dl, respectively, apoA-I was present only in prebeta(1), while apoA-II was found free of apoA-I in two distinct alpha mobility subpopulations with different sizes. The smaller size particles contained only apoA-II while the larger one contained apoA-II and apo(a). Relative to unaffected male relatives (n=30), male heterozygotes (n=21) had significant reductions (P<0.001) in plasma HDL-C (-45%), apoA-I (-34%), apoA-II (-59%), apoA-IV (-40%), Lp(a) (-62%), and apoB (-55%) concentrations, and a significant increase (P<0.05, +33%) in plasma apoC-III levels. Female heterozygotes (n=11) similarly had significant reductions (P<0.001) in the concentrations of plasma HDL-C (-42%), apoA-I (-27%), apoA-II (-52%), Lp(a) (-27%), and (P<0.01) apoA-IV (-28%), apoB (-13%), and a significant increase (P<0.05) in plasma apoE levels (+29%) as compared to unaffected female relatives (n=41). Large size HDL subpopulations, especially the two LpA-I particles: alpha(1) and prealpha(1) were dramatically reduced in both male and female heterozygotes relative to their unaffected family members. Since apoA-II decreased more than apoA-I in both male and female heterozygotes, the ratios of apoA-I/apoA-II were significantly (P<0.01) increased. The prevalence of CHD was 60% higher in the 32 heterozygotes than in the 71 unaffected relatives even though the latter group was on average 7 years older. We conclude that TD homozygotes have only prebeta(1) apoA-I-containing HDL subpopulations, while heterozygotes have HDL that is selectively depleted in the large alpha(1), prealpha(1), and alpha(2), prealpha(2) subpopulations, resulting in HDL particles that are small in size, poor in cholesterol, but relatively enriched in apoA-I compared to those of their unaffected relatives. These abnormalities appear to result in a higher risk of CHD in heterozygotes than in unaffected controls.
Atherosclerosis 2001 May
PMID:Subpopulations of high density lipoproteins in homozygous and heterozygous Tangier disease. 1136 17


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