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)

Apolipoprotein B-100 (apo B) is the principal structural and functional protein of the pro-atherogenic lipoproteins, but its homeostasis in man has not been clearly established. The hepatic availability of cholesterol substrate may be a determining factor. We examined whether there was a direct correlation between plasma concentrations of mevalonic acid (MVA) and lathosterol (indices of in vivo cholesterol synthesis) and hepatic secretion of very-low-density lipoprotein (VLDL) apo B in 13 normolipidaemic, healthy male subjects. The secretion of VLDL apo B was measured using a primed constant intravenous infusion of 1-[13C]-leucine (1 mg/kg per h) over 8 h. Gas-chromatography mass spectrometry (GCMS) was used to derive isotopic enrichment of apo B and fractional turnover rate was calculated using a monoexponential function. There was a highly significant positive correlation between the absolute secretion rate (ASR) of VLDL apo B and the plasma concentrations of mevalonic acid (r = 0.72, P = 0.005) and lathosterol (r = 0.81, P = 0.001) and the lathosterol:cholesterol ratio (r = 0.79, P = 0.001). In multiple regression analysis, these correlations remained significant after adjusting for waist circumference, age, apolipoprotein E genotype and dietary fat intake. The data further support the notion that the availability of cholesterol substrate regulates the hepatic secretion rate of apo B.
Atherosclerosis 1997 Nov
PMID:Direct association between the hepatic secretion of very-low-density lipoprotein apolipoprotein B-100 and plasma mevalonic acid and lathosterol concentrations in man. 939 76

The accumulation of the oxidized apolipoprotein, apoB-100, containing lipoproteins in the arterial wall and the progression of coronary atherosclerotic lesions in rabbits with beta-VLDL and LDL hypercholesterolemia was compared. In New Zealand White (NZW) rabbits on a 0.125% cholesterol diet, LDL cholesterol levels increased from 14 +/- 1 mg/dL (mean +/- SEM; n = 9) to 170 +/- 34 mg/dL (n = 10, P = .0002). On 0.5% cholesterol, LDL cholesterol levels were similar, but beta-VLDL cholesterol levels increased from 60 +/- 4 mg/dL (n = 10) to 550 +/- 75 mg/dL (n = 8; P < .0001). In Watanabe heritable hyperlipidemic (WHHL) rabbits, LDL cholesterol levels were 2.3-fold higher (n = 13; P < .0001) than in NZW rabbits on 0.5% cholesterol, whereas their beta-VLDL cholesterol levels were 3.7-fold lower (P < .0001), resulting in similar total cholesterol levels. At 2 months, mean intimal areas of lesions in the coronary arteries of NZW rabbits on 0.125% cholesterol were 0.13 +/- 0.045 mm2 (n = 4; mean +/- SEM) and were 5.8-fold, (n = 4; P = .016) and 2.0-fold (n = 6; P = NS versus 0.125% cholesterol and P = .014 versus 0.5% cholesterol) higher in NZW rabbits on 0.5% cholesterol and in WHHL rabbits, respectively. At 5 months, mean intimal areas were 0.47 +/- 0.088 mm2 (n = 6) in NZW rabbits on 0.125% cholesterol and were 4.5-fold (n = 4; P = .0001) and 2.0-fold (n = 7; P = .012 and P = .0019) higher in rabbits on 0.5% cholesterol and in WHHL rabbits, respectively. Levels of oxidized apoB-100 containing lipoproteins (both beta-VLDL and LDL) in the lesions correlated with mean intimal area (r = .88; n = 31; P < .0001) of those lesions and with the plasma levels of total beta-VLDL/LDL (r = .72; P < .0001). Levels of oxidized apoB-100 containing lipoproteins in the arterial wall correlate with progression of hypercholesterolemia-induced coronary atherosclerotic lesions. Plasma levels of beta-VLDL relative to similar increases in LDL result in a more pronounced accumulation of oxidized apoB-100 containing lipoproteins in the arterial wall and in the plasma and a more rapid progression of coronary atherosclerosis.
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PMID:beta-VLDL hypercholesterolemia relative to LDL hypercholesterolemia is associated with higher levels of oxidized lipoproteins and a more rapid progression of coronary atherosclerosis in rabbits. 940 4

Oxidized LDL is implicated in the pathogenesis of atherosclerosis. A widely studied model for oxidation of the lipid in LDL involves Cu2+. Recent studies suggest that Cu2+ may be reduced to Cu1+ by alpha-tocopherol to initiate LDL lipid peroxidation. LDL demonstrates binding sites for Cu2-, but the nature of these binding sites, as well their role in promoting Cu2+ reduction and lipid peroxidation, has not been established. In the current studies, we used diethylpyrocarbonate (DEPC) to modify the histidine residues of apolipoprotein B100, the major protein in LDL. First, we demonstrated that histidine residues were preferentially modified by DEPC under our experimental conditions. Then we monitored the kinetics of Cu(2+)-promoted oxidation of LDL and DEPC-modified LDL. In both cases, the progress curve of lipid peroxidation exhibited a lag phase and a propagation phase. However, when LDL was modified with DEPC, the length of the lag phase was prolonged whereas the rate of lipid peroxidation during the propagation phase was lower. Studies with LDL oxidized by 2,2'-azobis (2-amidinopropane) hydrochloride and phosphatidylcholine liposomes oxidized with hydroxyl radical established that DEPC was not acting simply as a nonspecific inhibitor of lipid peroxidation. DEPC treatment of LDL almost completely inhibited its ability to bind Cu2+. These observations suggest that peroxidation of the lipids in LDL can proceed with normal kinetics only when Cu2+ binds preferentially to sites on apolipoprotein B100 that contain histidine residues. We also compared the kinetics of Cu2+ reduction in the absence and presence of DEPC. There was no effect of DEPC modification on either the rate or extent of Cu2+ reduction by LDL. Therefore LDL is likely to contain a second class of binding sites for Cu2+ that does not involve histidine residues. Thus, LDL appears to contain at least two classes of Cu(2+)-binding sites: histidine containing sites, which are responsible in part for promoting lipid peroxidation during the propagation phase, and sites at which Cu2+ is reduced without binding to histidine.
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PMID:Copper ions promote peroxidation of low density lipoprotein lipid by binding to histidine residues of apolipoprotein B100, but they are reduced at other sites on LDL. 940 31

The atherogenicity of intestinally derived postprandial lipoproteins has been confirmed in a number of recent studies. We have shown abnormalities in postprandial lipoprotein metabolism in diabetic patients, a group with an increased susceptibility to atherosclerosis. This study examined the relationship between dietary cholesterol and the postprandial, intestinally derived, apolipoprotein B48 and apolipoprotein B100 from the liver. We compared 10 non-insulin-dependent (Type 2, NIDDM) diabetic patients and 10 age-matched non-diabetic control subjects. Fasting blood was taken and subjects were fed a cholesterol-free, high fat meal. Blood samples were repeated at 2 h, 4 h, 6 h, and 8 h postprandial. The following week fasting blood was collected and subjects were given the same meal with 1 g of added cholesterol. Blood was collected at the same time points. Chylomicrons and very low density lipoprotein were isolated by sequential ultracentrifugation and their lipoprotein composition determined. Apolipoproteins B48 and B100 were separated by gradient gel electrophoresis and quantified by densitometric scanning using a low density lipoprotein apolipoprotein B100 standard. Post prandial chylomicron cholesterol and triglyceride increased after the high cholesterol meal in both groups (p < 0.001). The postprandial chylomicron apolipoprotein B48 response of both diabetic and control subjects to the cholesterol meal was less than to the cholesterol-free meal (p < 0.001). Fasting very low density lipoprotein apolipoprotein B48 was higher in diabetic patients compared to control subjects and their postprandial increase following the cholesterol-free meal was significantly greater (p < 0.001). There was a 10-fold increase in the incremental postprandial VLDL apolipoprotein B48 area under the curve after the cholesterol-rich meal in the diabetic patients compared to a 3-fold increase in control subjects. The postprandial very low density lipoprotein apolipoprotein B100 was similar in the two groups with both meals. The study demonstrates a very significant increase in the amount of intestinally derived small apolipoprotein B48-associated particles in the very low density lipoprotein fraction following a cholesterol-rich meal in diabetic patients. Synthesis rather than clearance may be the major cause of the increase in these atherogenic postprandial particles.
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PMID:The role of dietary cholesterol in the regulation of postprandial apolipoprotein B48 levels in diabetes. 945 33

Familial defective apolipoprotein B100 (FDB) is caused by a mutation of apo-B100 (R3500Q) that disrupts the receptor binding of low density lipoproteins (LDL), which leads to hypercholesterolemia and premature atherosclerosis. In this study, mutant forms of human apo-B were expressed in transgenic mice, and the resulting human recombinant LDL were purified and tested for their receptor-binding activity. Site-directed mutagenesis and other evidence indicated that Site B (amino acids 3,359-3,369) binds to the LDL receptor and that arginine-3,500 is not directly involved in receptor binding. The carboxyl-terminal 20% of apo-B100 is necessary for the R3500Q mutation to disrupt receptor binding, since removal of the carboxyl terminus in FDB LDL results in normal receptor-binding activity. Similarly, removal of the carboxyl terminus of apo-B100 on receptor-inactive VLDL dramatically increases apo-B-mediated receptor-binding activity. We propose that the carboxyl terminus normally functions to inhibit the interaction of apo-B100 VLDL with the LDL receptor, but after the conversion of triglyceride-rich VLDL to smaller cholesterol-rich LDL, arginine-3,500 interacts with the carboxyl terminus, permitting normal interaction between LDL and its receptor. Moreover, the loss of arginine at this site destabilizes this interaction, resulting in receptor-binding defective LDL.
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PMID:Identification of the low density lipoprotein receptor-binding site in apolipoprotein B100 and the modulation of its binding activity by the carboxyl terminus in familial defective apo-B100. 948 79

We have generated mice with markedly elevated plasma levels of human low density lipoprotein (LDL) and reduced plasma levels of high density lipoprotein. These mice have no functional LDL receptors [LDLR-/-] and express a human apolipoprotein B-100 (apoB) transgene [Tg(apoB+/+)] with or without an apo(a) transgene [Tg(apoa+/-)]. Twenty animals (10 males and 10 females) of each of the following four genotypes were maintained on a chow diet: (i) LDLR-/-, (ii) LDLR-/-;Tg(apoa+/-), (iii) LDLR-/-;Tg(apoB+/+), and (iv)LDLR-/-;Tg(apoB+/+);Tg(apo+/-). The mice were killed at 6 mo, and the percent area of the aortic intimal surface that stained positive for neutral lipid was quantified. Mean percent areas of lipid staining were not significantly different between the LDLR-/- and LDLR-/-;Tg(apoa+/-) mice (1.0 +/- 0.2% vs. 1.4 +/- 0.3%). However, the LDLR-/-;Tg(apoB+/+) mice had approximately 15-fold greater mean lesion area than the LDLR-/- mice. No significant difference was found in percent lesion area in the LDLR-/-;Tg(apoB+/+) mice whether or not they expressed apo(a) [18.5 +/- 2.5%, without lipoprotein(a), Lp(a), vs. 16.0 +/- 1.7%, with Lp(a)]. Histochemical analyses of the sections from the proximal aorta of LDLR-/-;Tg(apoB+/+) mice revealed large, complex, lipid-laden atherosclerotic lesions that stained intensely with human apoB-100 antibodies. In mice expressing Lp(a), large amounts of apo(a) protein colocalized with apoB-100 in the lesions. We conclude that LDLR-/-; Tg(apoB+/+) mice exhibit accelerated atherosclerosis on a chow diet and thus provide an excellent animal model in which to study atherosclerosis. We found no evidence that apo(a) increased atherosclerosis in this animal model.
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PMID:Low density lipoprotein receptor-negative mice expressing human apolipoprotein B-100 develop complex atherosclerotic lesions on a chow diet: no accentuation by apolipoprotein(a). 953 74

Familial hypobetalipoproteinemia is an autosomal co-dominant disorder, which in a minority of cases is due to a truncation producing mutation in the apoB gene. We have identified an apoB mutation in a 40-year old hypobetalipoproteinemic man with Type II diabetes mellitus. Immunoblotting of plasma revealed a major band for apoB-100 and a minor band with estimated size between apoB-52 and apoB-55. The proband's 75-year old father with Type II diabetes and a non-diabetic daughter also possessed the truncated protein. Direct sequencing of the amplified fragment of genomic DNA revealed a C-->T transition at nt 7692 in exon 26 of the apoB gene. This substitution yielded a premature stop codon at residue 2495 and abolished a BsaI restriction endonuclease site. The identical mutation has been described previously; however, the genotypes and ancestors of the kindred were different, suggesting that the mutation may have occurred independently. The majority of apoB-55 was eluted as particles smaller than LDL-sized apoB-100, and floated mostly between the LDL and HDL density range. It is worth noting that despite the presence of Type II diabetes, both the proband and his father have very low plasma lipid levels and neither have any clinically manifest macrovascular complications.
Atherosclerosis 1998 Feb
PMID:Diabetes mellitus in a new kindred with familial hypobetalipoproteinemia and an apolipoprotein B truncation (apoB-55). 954

The present study was conducted to determine whether alimentary lipemia alters platelet activity in vivo. Normolipidemic volunteers were given a fatty meal and platelet function was assessed before, and 3 and 6 h after the meal. Platelet aggregability and secretion was determined using whole blood flow cytometry (expression of platelet P-selectin and fibrinogen binding), filtragometry ex vivo (reflecting platelet aggregability in vivo) and by measurements of platelet specific products in plasma (beta-thromboglobulin and platelet factor 4). Plasma triglycerides increased from 0.8 (0.6:1.1; median, 25th and 75th percentiles) to 1.7 (1.0:2.3) mmol/l at 3 h and returned to baseline after 6 h (P < 0.001, one-way ANOVA). Apo B-100 and apo B-48 were both markedly increased 3 h postprandially in the Sf 60-400 fraction (large VLDLs, P < 0.001 for both), whereas the Sf 20-60 (small VLDLs) and Sf 12-20 fractions (IDL) did not change. The platelet function assessments revealed that the percentage of platelets expressing P-selectin increased by 40% (5%; 64%) after 3 h and by 51% (- 7%; 85%) 6 h postprandially in unstimulated samples (P < 0.05 for both). In samples stimulated by ADP in vitro P-selectin expression increased by 45% (6%; 58%) after 3 h and by 30% (12%; 58%) (P<0.01 for both) after 6 h at 0.1 microM. Platelet P-selectin expression was less influenced at higher ADP concentrations. The plasma levels of beta-thromboglobulin (approximately 20 ng/ml) and platelet factor 4 (approximately 0.3 ng/ml) were not affected by the fat load. Flow cytometric analyses of fibrinogen binding and filtragometry measurements also failed to reveal any postprandial alterations. The present finding of enhanced platelet P-selectin expression suggests that platelets are mildly sensitized postprandially. Whether this is of importance for thrombus formation and atherosclerosis needs to be studied further.
Atherosclerosis 1998 Mar
PMID:Alimentary lipemia enhances the membrane expression of platelet P-selectin without affecting other markers of platelet activation. 956 42

Hepatic expression of apolipoprotein (apo) B mRNA-editing enzyme catalytic polypeptide 1 (APOBEC-1) has been proposed as a gene therapy approach for lowering plasma low density lipoprotein (LDL) levels. However, high-level expression of APOBEC-1 in transgenic mouse and rabbit livers causes liver dysplasia and hepatocellular carcinoma. To determine the physiological and pathological effects of low-level hepatic expression of APOBEC-1, we used a 52-kb rat APOBEC-1 genomic clone (RE4) to generate transgenic mice expressing low levels of APOBEC-1 (2 to 5 times those in nontransgenic mice). Liver function, liver histology, editing of apoB mRNA at the normal editing site (C6666), and abnormal editing at multiple sites (hyperediting) in these mice were compared with those in transgenic mice expressing intermediate (I-20) or high (I-28) levels of APOBEC-1 in the liver. Hyperediting of mRNA coding for the novel APOBEC-1 target 1 (NAT1) was also examined. In the high-expressing I-28 line, 50% of the mice had palpable tumors at 15 weeks of age, whereas in the intermediate-expressing I-20 line, 50% of the mice had evidence of liver tumors after 1 year. In contrast, low-expressing RE4 mice had normal liver function and histology and did not develop liver tumors when examined at 3 to 17 months of age. Moreover, hyperediting of apoB and NAT1 mRNA in the liver was robust in the I-20 mice but barely detectable in the RE4 mice. The low-level expression resulted in sufficient APOBEC-1 to edit essentially all apoB mRNA at the normal editing site, virtually eliminating apoB-100 and LDL in the plasma of RE4 mice. When RE4 mice were crossed with human apoB transgenic mice, which possess high plasma LDL concentrations, plasma LDL levels in the offspring were reduced to very low levels. These results indicates that long-term hepatic expression of APOBEC-1 at low levels sufficient to eliminate LDL does not cause apparent liver damage or liver tumors in transgenic mice. RE4 APOBEC-1 transgenic mice should prove valuable for studying the roles of apoB-containing lipoproteins in lipid metabolism and atherosclerosis.
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PMID:Low expression of the apolipoprotein B mRNA-editing transgene in mice reduces LDL levels but does not cause liver dysplasia or tumors. 963 45

Triglyceride-rich lipoproteins (TRLs) that are modified during alimentary lipemia and their remnants are indicated to play an important role in the development of atherosclerosis. Although recent studies in transgenic and gene knock-out animal models have shed new light on the function of different apolipoproteins (apos) in the metabolism of TRLs and on their respective role in atherogenesis in these models, little is known about the compositional properties of human chylomicron remnants and very low density lipoprotein (VLDL). To address this issue, apos E, C-I, C-II, and C-III and lipids (triglycerides, phospholipids and cholesterol) were measured in Svedberg flotation rate (Sf) 60-400 and Sf 20-60 subfractions of VLDL and chylomicron remnants isolated from fasting and postprandial plasma samples in ten normotriglyceridemic men. VLDL was separated from chylomicron remnants by immunoaffinity chromatography using monoclonal antibodies (4G3 and 5E11) recognizing apoB-100 but not apoB-48 epitopes. The triglyceride, cholesterol and apoC-II contents of large (Sf 60-400) chylomicron remnants were significantly higher compared with large VLDL particles, while the small (Sf 20-60) chylomicron remnants contained significantly more apoC-II molecules but fewer apoC-I molecules than small VLDL. Whereas the apoC-III contents of large chylomicrons decreased, the apoC-III contents of large VLDL increased postprandially. The cholesterol to triglyceride ratio of large VLDL particles increased transiently by 50% in response to the oral fat load, whereas the cholesterol to triglyceride ratio of large chylomicron remnant particles and small TRL remnants increased 50-100% throughout the entire postprandial period. The specific alterations of the apolipoprotein and lipid composition of chylomicron remnants and VLDL particles observed during alimentary lipemia are likely to target these lipoprotein species differently to metabolic routes and to confer both endogenous and exogenous remnant lipoprotein roles in atherogenesis.
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PMID:Differences in apolipoprotein and lipid composition between human chylomicron remnants and very low density lipoproteins isolated from fasting and postprandial plasma. 968 44


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