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Query: UMLS:C0004153 (atherosclerosis)
 77,401 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

This review covers lipids, apolipoproteins, and receptors involved in the dyslipidemia of the nephrotic syndrome in humans and in rat or mouse models of the syndrome. It emphasizes research published during the last decade, though earlier work is cited. The focus is on the biosynthesis and catabolism of the plasma lipoprotein density classes and the role of receptors and enzymes in regulating lipoprotein metabolism in nephrosis. Although the factors responsible for the initiation of the hepatic and peripheral cellular responses to proteinuria and hypoalbuminemia remain elusive, recent work highlights the increased risk of atherosclerosis and the progression of renal disease associated with nephrotic dyslipidemia. Understanding of the role of the kidney in the catabolism of apolipoproteins entering the glomerular filtrate has been enhanced by the discovery of the receptor-mediated uptake of apolipoprotein A-I, the main apoprotein of HDL. The following aspects of lipid and lipoprotein metabolism in relation to nephrosis are discussed, with attention paid to differences between experimental nephrosis and the human nephrotic syndrome:(1) Albumin metabolism (2) Lipoprotein metabolism (3) Receptors (4) LCAT and CETP (5) Hepatic and Lipoprotein Lipase (6) Lipid metabolism (7) Lipiduria (8) Hypotheses and Questions (9) Summary.
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PMID:Lipoprotein metabolism in the nephrotic syndrome. 1213 20

Results from several atherosclerosis studies using morphometric procedures have proven controversial with regard to whether over-expression of human LCAT in transgenic (Tg) mice is atherogenic. The purpose of the present study was to determine the effect of 10-fold over-expression of human LCAT on aortic free and esterified cholesterol (EC) deposition as well as plasma lipoprotein cholesteryl ester (CE) fatty acid composition in mice fed an atherogenic diet containing cholic acid. C57Bl/6 (control) and human LCAT-Tg mice were fed chow or an atherogenic diet (15% of calories from palm oil, 1.0% cholesterol and 0.5% cholic acid) for 24 weeks before measurement of aortic cholesterol content. Compared with the chow diet, control and LCAT-Tg mice fed the atherogenic diet had a 2-fold increase in plasma total, free and EC, a 7-fold increase in plasma apoB lipoprotein cholesterol, and a 40-50-fold increase in hepatic cholesterol content. The aortic EC content was increased in control (0.7 vs. 1.2 mg/g protein) and LCAT-Tg (0.3 vs. 1.5 mg/g protein) mice fed the atherogenic diet compared with those consuming the chow diet; however, there was no difference in aortic free (14.4+/-6.8 vs. 18.5+/-7.7 mg/g protein) or esterified (1.2+/-1.0 vs. 1.5+/-1.2 mg/g protein) cholesterol content between atherogenic diet-fed control and LCAT-Tg mice, respectively. LCAT-Tg mice fed the atherogenic diet had a 2-fold increase in the ratio of saturated+monounsaturated to polyunsaturated CE species in plasma apoB lipoproteins compared with control mice (9.4+/-2.4 vs. 4.9+/-0.7). We conclude that over-expression of human LCAT in Tg mice fed an atherogenic diet containing cholic acid does not result in increased aortic cholesterol deposition compared with control mice, even though the CE fatty acid saturation index of plasma apoB lipoproteins was doubled.
Atherosclerosis 2002 Nov
PMID:Transgenic overexpression of human lecithin: cholesterol acyltransferase (LCAT) in mice does not increase aortic cholesterol deposition. 1220 74

Chlamydia pneumoniae is a well-known cause of respiratory infections, globally. Chronic C. pneumoniae infection has been associated with atherosclerosis. The aim of the present study was to investigate the effects of acute C. pneumoniae infection on serum lipid levels and some regulatory proteins/enzymes in NIH/S mice. Female mice (n=30) were intranasally infected with 5.3*10(5) inclusion forming units (IFU) of C. pneumoniae and control mice (n = 30) were inoculated with buffer. Six uninoculated mice at day 0 and then six mice from each group 3, 6, 9, 14 and 20 days post-inoculation were killed and serum samples were collected for analysis. Successful infection was confirmed by IgG response to C. pneumoniae and positive Chlamydia cultivation from the lungs. Serum triglycerides and total cholesterol, as well as the activities of hepatic lipase (HL), lecithin-cholesterol acyltransferase (LCAT) and phospholipid transfer protein (PLTP) and the concentration of lipopolysaccharide-binding protein (LBP) were analyzed. In C. pneumoniae infected mice, a minor change in triglyceride (corrected p-value 0.020) levels was observed 9 days post-infection (p.i.). LCAT activity declined remarkably, and the lowest activities were measured on day 9 p.i. (67% from the baseline value). HL and PLTP activities did not differ from those in the control group during the whole experimental period. There was a 2.5-fold increase in the serum LBP concentration owing to the C. pneumoniae infection 9 days p.i. The data indicate that acute C. pneumoniae infection, although clinically almost asymptomatic, causes small, transient changes in serum total lipids and some key proteins involved in lipoprotein metabolism in mice.
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PMID:Effect of acute Chlamydia pneumoniae infection on lipoprotein metabolism in NIH/S mice. 1246 3

Some recent developments in lipoprotein metabolism, familial hyperlipidaemias and lipid lowering therapies with reference to coronary artery disease (CAD) are reviewed. LDL-cholesterol (LDL-C) level and particle subclass are important determinants of the extent of cholesterol delivery to the peripheral tissues and thereby of atherogenesis and CAD. LDL modifications (eg, oxidation, adduct formation, desialylation, glycation, etc) enhance the above process. HDL particles bring cholesterol from peripheral tissues to liver (reverse cholesterol transport, RCT). ApoA1, LCAT enzyme, ABCA1 and cholesterol ester transfer protein are involved in RCT. Paraoxonase of HDL prevents oxidation of other lipoproteins and probably hinders atherogenesis. Lp(a) particles are like LDL except the presence of apo(a) that inhibits fibrinolysis and are epidemiologicaly linked to the development of CAD. Indians have high Lp(a), in comparison to whites. Familial hyperlipidaemias are due to altered metabolism of lipoproteins affecting plasma lipid profile. Majority of such patients are prone to atherosclerosis and CAD. LDL-C is the primary target of lipid lowering therapy. Statins inhibit HMG-CoA reductase and are mainly used alone or with other drugs for lowering blood lipids. 'National Cholesterol Education Program' now recommends a stringent LDL-C control ( < 100 mg/dl) for CAD and CAD risk equivalents. Therapeutic lifestyle changes and drug therapy are the main modalities to reduce blood lipids, aiming at total reduction of short-and long-term coronary risk for all (primary prevention), and of coronary mortality and morbidity in patients with CAD (secondary prevention).
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PMID:Normal lipid metabolism, familial hyperlipidaemia, lipid intervention and their benefits. 1284 90

Low levels of high-density lipoprotein (HDL) cholesterol constitute a risk factor for coronary artery disease, and there is evidence that increasing HDL cholesterol levels reduces cardiovascular risk. The phenotype of low HDL cholesterol with or without elevated triglycerides is at least as common in patients hospitalized for cardiovascular disease as is hypercholesterolemia, and it is characteristic of diabetes and the metabolic syndrome, conditions associated with increased cardiovascular risk. Recent studies have elucidated mechanisms by which HDL acts to reduce cardiovascular risk, bolstering the rationale for targeting of HDL in lipid-modifying therapy. In particular, HDL (1) carries excess cholesterol from peripheral cells to the liver for removal in the process termed reverse cholesterol transport, (2) reduces oxidative modification of low-density lipoproteins (LDL), and (3) inhibits cytokine-induced expression of cellular adhesion molecules on endothelial cells. Studies of the newly described adenosine triphosphate-binding cassette protein A1 (ABCA1) transporter have established a crucial role for this transporter in modulating the levels of plasma HDL and intracellular cholesterol in the liver as well as in peripheral cells. Elevated levels of intracellular cholesterol stimulate the liver X receptor pathway, enhancing the expression of ABCA1, which increases intracellular trafficking of excess cholesterol to the cell surface for interaction with lipid-poor apolipoprotein A-I to form nascent HDL. Nascent HDL facilitates the removal of additional excess cellular cholesterol, which is esterified by lecithin-cholesterol acyltransferase with conversion of the nascent HDL to mature spherical HDL. Overexpression of ABCA1 in mice on a regular chow or Western diet results in a marked increase in plasma HDL, increased LDL, and increased transport of cholesterol to the liver. On a high cholesterol/cholate diet, transgenic mice overexpressing ABCA1 have increased HDL, reduced LDL, increased HDL-mediated cholesterol flux to the liver, and reduced atherosclerosis. Ongoing investigation of mechanisms by which HDL acts to reduce the risk of atherosclerosis will provide several new targets for the development of drugs to decrease the risk of atherosclerosis.
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PMID:Clinical significance of high-density lipoproteins and the development of atherosclerosis: focus on the role of the adenosine triphosphate-binding cassette protein A1 transporter. 1294 71

A cohort of 13 female and 14 male heterozygotes for ATP binding cassette A1 (ABCA1) gene defects was directly compared with 13 and 14 unaffected female and male family members of almost exact same age. The activities of three proteins that play key roles in HDL metabolism were measured in addition to extensive lipid and (apo) lipoprotein subfraction analysis. Compared to controls, LCAT activity was reduced by 15% in affected subjects (P < 0.001) while PLTP activity was unaffected. Interestingly, CETP activity was elevated by 50% in the heterozygote siblings of one kindred but was unaffected in heterozygotes of the three other families. With respect to lipids, the heterozygotes had normal total cholesterol (TC), and LDL-cholesterol concentrations but presented with a trend towards increased triglyceride levels (13%; P = 0.08). HDL metabolism, by contrast, was severely affected as illustrated by 40% reductions in HDL-cholesterol (P < 0.001) with concomitant reductions in apoAI (25%; P < 0.001) levels and in lipoprotein subfraction LpAI (28%; P < 0.001), LpAI:AII (24%; P=0.014), and LpCIII:nonB (34%; P < 0.001) concentrations. We furthermore observed reduced average HDL particle size (5%; P = 0.004; 16% in female and 3.6% in male) and reduced plasma apoCIII concentration (15%; P = 0.006) while apoAII, apoAIV, apoE and apoB levels were unchanged. In conclusion, heterozygosity for ABCA1 defects was associated with reduced LCAT activity in absence of effects on PLTP activity. Of special interest was our finding that the effects of compromised ABCA1 function on HDL were more pronounced in women than in men.
Atherosclerosis 2003 Dec
PMID:Heterozygosity for ABCA1 gene mutations: effects on enzymes, apolipoproteins and lipoprotein particle size. 1464 2

Familial HDL deficiency (FHD) is a rare autosomal dominant lipoprotein disorder. We describe a novel genetic variant of the apolipoprotein A-I (apoA-I) gene resulting in FHD. The proband is a 51-year-old woman who was hospitalized due to severe heart failure. Her plasma HDL-cholesterol (C) and apoA-I concentrations were 0.08mmol/l and 1mg/dl, respectively. She exhibited corneal opacities and planar xanthomas on eyelids and elbows. Coronary angiography demonstrated extensive obstructions in two major vessels. Genomic DNA sequencing of the patient's apoA-I gene revealed a homozygosity for a GC deletion between 5 GC repeats in exon 4, creating a frameshift and a stop codon at residue 178. We designated this mutation as apoA-I Shinbashi. The proband's father, son, and daughter were found to be heterozygous for this mutation and their HDL-C and apoA-I levels were about half of normal levels, demonstrating a gene dosage effect. The father underwent coronary bypass surgery at age of 70 years. Lecithin-cholesterol acyltransferase (LCAT) activity was decreased by 63% in the homozygote and 31% in heterozygotes, respectively. This new case of apoA-I deficiency, apoA-I Shinbashi, is the first case involving a single gene defect of the apoA-I gene to develop all the characteristics for apoA-I deficiency, including premature coronary heart disease.
Atherosclerosis 2004 Jan
PMID:A novel two nucleotide deletion in the apolipoprotein A-I gene, apoA-I Shinbashi, associated with high density lipoprotein deficiency, corneal opacities, planar xanthomas, and premature coronary artery disease. 1470 55

Evidence suggests that ACAT2 is a proatherogenic enzyme that contributes cholesteryl esters (CEs) to apoB-containing lipoproteins, whereas LCAT is an antiatherogenic enzyme that facilitates reverse cholesterol transport by esterifying free cholesterol on HDL particles. We hypothesized that deletion of LCAT and ACAT2 would lead to absence of plasma CEs and reduced atherosclerosis. To test this hypothesis, ACAT2-/- LCAT-/- LDLr-/-, ACAT2-/- LDLr-/-, and LCAT-/- LDLr-/- mice were fed a 0.15% cholesterol diet for 20 weeks. In comparison to LDLr-/- mice, the total plasma cholesterol (TPC) of ACAT2-/- LCAT-/- LDLr-/- mice was 67% lower because of the complete absence of plasma CEs, leading to 94% less CE accumulation in the aorta. In the LCAT-/- LDLr-/- mice, TPC and atherosclerosis were significantly higher because of increased accumulations of ACAT2-derived CE. In ACAT2-/- LDLr-/- mice, again compared with LDLr-/- mice, TPC was 19% lower, whereas atherosclerosis was 88% lower. Therefore, the absence of ACAT2 led to a significant reduction in TPC although benefits in reduction of atherosclerosis were much more pronounced. Overall, the data suggest that ACAT2-derived CE is the predominant atherogenic lipid in blood, and that an important goal for prevention of atherosclerosis is to limit ACAT2-derived CE accumulation in lipoproteins.
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PMID:Plasma cholesteryl esters provided by lecithin:cholesterol acyltransferase and acyl-coenzyme a:cholesterol acyltransferase 2 have opposite atherosclerotic potential. 1548 18

Dietary fatty acids alter HDL cholesterol concentrations, presumably through mechanisms related to reverse cholesterol transport. The effect of dietary fats (coconut oil, butter, traditional stick margarine, soybean oil, canola oil) differing in fatty acid profile on this antiatherogenic process was assessed with respect to plasma lipids; exogenous and endogenous lecithin-cholesterol acyltransferase (LCAT), cholesterol ester transfer protein (CETP), phospholipid transfer protein (PLTP) activities; and LCAT, apolipoprotein (apo) A-I and scavenger receptor B class-1 (SR-B1) mRNA abundance. Golden-Syrian hamsters were fed a nonpurified (6.25 g/100 g fat) diet containing an additional 10 g/100 g experimental fat and 0.1 g/100 g cholesterol for 6 wk. Canola and soybean oils significantly lowered serum HDL cholesterol concentrations relative to butter. Canola oil, relative to butter, resulted in higher exogenous LCAT activity, and both soybean and canola oils significantly increased hepatic apo A-I and SR-B1 mRNA abundance. Butter, relative to margarine, coconut and soybean oils, significantly increased serum non-HDL cholesterol concentrations. Endogenous and exogenous LCAT, CETP, and PLTP activities did not differ in hamsters fed margarine or saturated fat diets, despite lower hepatic LCAT, apo A-I, and SR-B1 mRNA abundance, suggesting that changes in available substrate and/or modification to the LCAT protein may have been involved in lipoprotein changes. These results suggest that lower HDL cholesterol concentrations, as a result of canola and soybean oil feeding, may not be detrimental due to increases in components involved in the reverse cholesterol transport process in these hamsters and may retard the progression of atherosclerosis.
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PMID:Dietary fatty acids and cholesterol differentially modulate HDL cholesterol metabolism in Golden-Syrian hamsters. 1573 83

Apolipoprotein A-I (apoA-I), the major protein in high density lipoprotein (HDL) regulates cholesterol homeostasis and is protective against atherosclerosis. An examination of the amino acid sequence of apoA-I among 21 species shows a high conservation of positively and negatively charged residues within helix 6, a domain responsible for regulating the rate of cholesterol esterification in plasma. These observations prompted an investigation to determine if charged residues in helix 6 maintain a structural conformation for protein-protein interaction with lecithin-cholesterol acyltransferase (LCAT) the enzyme for which apoA-I acts as a cofactor. Three apoA-I mutants were engineered; the first, (3)/(4) no negative apoA-I, eliminated 3 of the 4 negatively charged residues in helix 6, no negative apoA-I (NN apoA-I) eliminated all four negative charges, while all negative (AN apoA-I) doubled the negative charge. Reconstituted phospholipid-containing HDL (rHDL) of two discrete sizes and compositions were prepared and tested. Results showed that LCAT activation was largely influenced by both rHDL particle size and the net negative charge on helix 6. The 80 A diameter rHDL showed a 12-fold lower LCAT catalytic efficiency when compared to 96 A diameter rHDL, apparently resulting from an increased protein-protein interaction, at the expense of lipid-protein association on the 80 A rHDL. When mutant apoproteins were compared bound to the two different sized rHDL, a strong inverse correlation (r = 0.85) was found between LCAT catalytic efficiency and apoA-I helix 6 net negative charge. These results support the concept that highly conserved negatively charged residues in apoA-I helix 6 interact directly and attenuate LCAT activation, independent of the overall particle charge.
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PMID:Apolipoprotein A-I helix 6 negatively charged residues attenuate lecithin-cholesterol acyltransferase (LCAT) reactivity. 1580 34


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