UMLS:C0020473 - FACTA Search

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)

Systematic sequencing of the coding and exon flanking regions of the apolipoprotein (apo) A-I gene has identified a new polymorphic Msp I site (C C/T-GG). This polymorphism is situated between the transcriptional starting site and the signal peptide start coding site (intron 1), so may influence the efficiency of surrounding splicing, thereby interfering with the expression of the apo A-I gene product, or serve as a linkage marker with a hitherto unidentified mutation defect responsible for hyperlipidemia and/or premature coronary heart disease. However, there was no significant difference in the allele frequencies between control and coronary heart disease subjects in a Japanese population. The -78 G-->A promoter polymorphism of apo A-I, previously reported in Western populations, has also been analyzed. The results show that neither mutation is likely to be the etiology for predisposition to a change of high-density lipoprotein cholesterol and/or variation in lipid and lipoprotein levels, or for the occurrence of coronary heart disease in Japanese populations.
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PMID:Analysis of a new polymorphism in the human apolipoprotein A-I gene: association with serum lipoprotein levels and coronary heart disease. 893 36

The goal of the present study was to assess the influence of mealtime on postprandial lipemia. Thirteen healthy subject aged 19-32 y were given the same meal at night (0100) or during the day (1300) in random order: the meal contained 40% of estimated daily energy expenditure. Blood samples were drawn at baseline and hourly for 8 h after the meal. Serum total cholesterol, very-low-density-lipoprotein cholesterol (VLDL-C), low-density-lipoprotein cholesterol (LDL-C), high-density-lipoprotein cholesterol (HDL-C), triacylglycerols, VLDL-triacylglycerols, apolipoprotein (apo) A-I, and apo B were measured at each time point. In a subgroup of seven subjects a control fasting reference line was measured according to the same nocturnal and diurnal time schedule. The mean postprandial concentrations of triacylglycerol (P < 0.001), VLDL-triacylglycerol (P < 0.001), and VLDL-C (P < 0.001) were higher at night than during the day. In contrast, mean cholesterol (P < 0.01), LDL-C (P < 0.01), HDL-C (P < 0.001), apo A-I (P < 0.001), and apo B (P < 0.001) concentrations were lower after the night meal than after the day meal. The magnitude of the postprandial response was estimated by the area between the fasting and postprandial curves. The triacylglycerol and VLDL-triacylglycerol responses were not significantly different between night and day. The VLDL-C (P < 0.01) response was greater and LDL-C (P < 0.0001) and HDL-C (P < 0.01) responses were lower at night than during the day. These results indicate that circadian factors specifically affect serum cholesterol transport. Apo B (P < 0.01) and apo A-I (P < 0.01) responses followed LDL-C and HDL-C changes during the day but were dissociated from lipoprotein responses at night, suggesting that circadian apolipoprotein regulation is dissociated from that of serum lipids. The results of the present study indicate that postprandial lipid, lipoprotein, and apolipoprotein concentrations are affected by circadian factors.
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PMID:Circadian variation of postprandial lipemia. 909 75

Hypercholesterolemia and mesangial cell proliferation have been proposed to play a role in the progression of glomerulosclerosis in diabetic nephropathy and other renal diseases. Although LDL is mitogenic for and cytotoxic to mesangial cells, the effect of HDL on these cells is unknown. HDL stimulates fibroblast mitogenesis and is the principal cholesterol-bearing lipoprotein in the rat, the experimental model for studying the effect of hyperlipidemia on renal disease. Insulin is mitogenic in several cell systems, and its levels are increased in serum in non-insulin-dependent diabetes mellitus. This study investigates whether HDL acts as a growth factor in mesangial cells and whether it functions in parallel with insulin. It was found that HDL at protein concentrations between 10 and 500 microg/ml, both alone and in the presence of 100 nM insulin, increased DNA synthesis in mesangial cells (129 to 165% of control for HDL alone; 140 to 235% for HDL plus insulin), whereas HDL at 1000 microg/ml and greater inhibited mesangial cell proliferation. Insulin alone at 100 nM stimulated [3H]thymidine incorporation in the same cell system (145% of control); the mitogenic effect of insulin was additive to that of HDL. Purified apo A-I had a similar effect, but at significantly lower concentrations. Specific binding of HDL to mesangial cells was demonstrated (B(max) [binding constant] of 5.19 +/- 0.70 x 10(-7) micromol of HDL bound/mg cell protein and K(b) of 2.83 +/- 0.22 nM). Tetranitromethane alters apo A-I, preventing binding to its cognate receptor. Tetranitromethane-modified HDL did not bind to mesangial cells and had no effect on [3H]thymidine incorporation. Addition of HDL to mesangial cells caused an immediate transient increase in free intracellular calcium in several representative mesangial cells, similar to the response seen with platelet-derived growth factor. The mitogenic effect of HDL was not altered after attenuation of cellular protein kinase C activity, but the stimulatory effect of HDL alone and in combination with insulin on DNA synthesis was completely eliminated after inhibition of cellular tyrosine kinases by 24-h pretreatment with 0.25 microM herbimycin A. Thus, HDL binds to a specific apo A-I-dependent receptor, promotes DNA synthesis, and initiates second-messenger events by a tyrosine kinase-dependent and protein kinase C-independent mechanism.
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PMID:HDL causes mesangial cell mitogenesis through a tyrosine kinase-dependent receptor mechanism. 925 51

No monotherapy is able to tackle effectively all atherogenic features of familial combined hyperlipidemia: high low-density lipoprotein (LDL) cholesterol, triglycerides (TG), and plasma fibrinogen, as well as low high-density lipoprotein (HDL) cholesterol. The present study investigated the safety and efficacy of combined pravastotin or simvastatin with gemfibrozil or ciprofibrate treatment on total cholesterol, LDL, TG, plasma fibrinogen, and apoproteins B and A-I in patients with refractory familial combined hyperlipidemia, with or without coronary artery disease. From the initial 420 patients included in the study, 389 (294 men and 95 women, mean age 51 years [range 30 to 65]) completed the study. These patients were followed for a mean period of 29 months (1 year [n = 107], 2 years [n = 102], 3 years [n = 95], and 4 years [n = 85]). Patients given a hypolipidemic diet were randomly assigned to pravastatin + gemfibrozil (n = 135, 20 and 1,200 mg/day, respectively), simvastatin + gemfibrozil (n = 130, 20 and 1,200 mg), or simvastotin + ciprofibrate (n = 124, 20 and 100 mg). Lipid parameters, apoproteins B and A-I, and plasma fibrinogen were assessed every 3 months. Physical and laboratory investigations for adverse effects were performed every month for the first 3 months and every 3 months thereafter. No patient exhibited myopathy or rhabdomyolysis. Five patients (1.3%) were withdrawn from the study because of high transaminases (more than threefold the upper normal limit). Five nonfatal coronary artery disease events were recorded. All 3 combination treatments were more effective in normalizing lipid profile than any monotherapy in the past. Simvastatin + ciprofibrate was more effective than pravastatin + gemfibrozil in reducing LDL, TG, and plasma fibrinogen levels. Simvastatin + gemfibrozil increased HDL levels more than the other 2. The apoprotein B decrease was analogous to the LDL reduction by all combinations, whereas apoprotein A-I was increased more with simvastatin + gemfibrozil. The data suggest that the statin-fibrate combinations used in the study are safe and have a favorable effect on all major coronary artery disease risk factors in patients with refractory familial combined hyperlipidemia with or without coronary artery disease. Early detection of the rare drug-induced reversible hepatotoxicity calls for close monitoring of patients.
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PMID:Safety and efficacy of long-term statin-fibrate combinations in patients with refractory familial combined hyperlipidemia. 929 90

The effect of lovastatin, an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase activity, on the kinetics of de novo cholesterol synthesis and apolipoprotein (apo) B in very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) was investigated in five male patients with combined hyperlipidemia. Subjects were counseled to follow a Step 2 diet and were treated with lovastatin and placebo in randomly assigned order for 6-week periods. At the end of each experimental period, subjects were given deuterium oxide orally and de novo cholesterol synthesis was assessed from deuterium incorporation into cholesterol and expressed as fractional synthesis rate (C-FSR) and production rate (C-PR). Simultaneously, the kinetics of VLDL, IDL, and LDL apo B-100 were studied in the fed state using a primed-constant infusion of deuterated leucine to measure fractional catabolic rates (FCR) and production rates (PR). Drug treatment resulted in significant decreases in total cholesterol (-29%), VLDL cholesterol (-40%), LDL cholesterol (-27%), and apo B (-16%) levels and increases in HDL cholesterol (+13%) and apolipoprotein (apo) A-I (+11%) levels. Associated with these plasma lipoprotein responses was a significant reduction in both de novo C-FSR (-40%; P = .04) and C-PR (-42%; P = .03). Treatment with lovastain in these patients had no significant effect on the FCR of apoB-100 in VLDL, IDL, or LDL, but resulted in a significant decrease in the PR of apoB-100 in IDL and LDL. Comparing the kinetic data of these patients with those of 10 normolipidemic control subjects indicates that lovastatin treatment normalized apoB-100 IDL and LDL PR. The results of these studies suggest that the declines in plasma lipid levels observed after treatment of combined hyperlipidemic patients with lovastatin are attributable to reductions in the C-FSR and C-PR of de novo cholesterol synthesis and the PR of apoB-100 containing lipoproteins. The decline in de novo cholesterol synthesis, rather than an increase in direct uptake of VLDL and IDL, may have contributed to the decline in the PR observed.
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PMID:Lovastatin decreases de novo cholesterol synthesis and LDL Apo B-100 production rates in combined-hyperlipidemic males. 935 53

Two substrains of the fawn-hooded (FH) rat have been developed, one of which develops progressive hypertension and proteinuria, the FHH, and one which shows little increase in blood pressure and no renal damage, the FHL. Other hypertensive rodent models show primary metabolic disturbances before the development of renal damage, notably hypertriglyceridemia, which may also contribute to progression of renal disease. In this study we evaluated whether hyperlipidemia is a primary disturbance in FHH, or only occurs secondary to proteinuria. Lipid levels were determined before and after development of proteinuria, and compared to those found in age-matched FHL. We also determined whether reducing proteinuria with lisinopril would normalize lipid levels in aging FHH. At 4 weeks of age, proteinuria was very low (2-3 mg/day) in both FHH and FHL. While proteinuria increased steadily in aging FHH, reaching 350 +/- 62 mg/day at 40 weeks, much less increase was observed in FHL over the same period (32 +/- 5 mg/day at 40 weeks). Blood pressure was markedly higher in adult FHH than in FHL (158 +/- 2 vs. 129 +/- 2 mm Hg, p < 0.01). In 4-week-old FHL and FHH, plasma cholesterol levels were similar. Subsequently, cholesterol increased in FHH, reaching 3.4 +/- 0.9 mmol/l at 40 weeks, whereas cholesterol was barely affected by aging in FHL (2.1 +/- 0.2 mmol/l at 40 weeks). At 4 weeks, triglyceride levels were lowest in FHH. Subsequently, triglycerides increased in FHH, reaching 3.5 +/- 1.5 mmol/l at 40 weeks, as compared to 1.3 +/- 0.2 mmol/l in FHL. Besides a transient increase in triglyerides in lisinopril-treated FHH at 11 weeks, increments in blood pressure, proteinuria, cholesterol, triglycerides and apolipoproteins A-I, B and E aging FHH were effectively prevented by lisinopril. These data strongly suggest that there is no primary difference in lipid metabolism between FHH and FHL and that changes in plasma lipids in FHH as compared to FHL are all secondary to proteinuria.
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PMID:Hyperlipidemia is secondary to proteinuria and is completely normalized by angiotensin-converting enzyme inhibition in hypertensive fawn-hooded rats. 937 31

Familial combined hyperlipidemia (FCHL) is a heterogeneous genetic disorder characterized by multiple lipoprotein phenotypes. The genetic defect is unknown, although linkage to the region of the apolipoprotein (apo) A-I-apoC-III-apo A-IV gene cluster on chromosome 11 has been suggested. The metabolic abnormality in many affected individuals is overproduction of apoB-containing lipoproteins causing elevated levels of plasma cholesterol, triglycerides, or both. Low levels of high-density lipoprotein (HDL) cholesterol and an abundance of dense low-density lipoprotein (LDL) particles are other features contributing to the high association of this disorder with premature coronary artery disease. Many affected individuals need drug therapy to lower their lipid levels. The hepatic 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, or "statins," offer a potent therapeutic option in patients with FCHL. These drugs significantly decrease levels of total cholesterol, LDL cholesterol, and apoB, although their effects on HDL cholesterol and triglycerides are limited. The mechanisms by which statins exert their beneficial effects in patients with FCHL remain controversial. We studied 7 patients with FCHL and 5 genetically uncharacterized patients with mixed lipemia during treatment with pravastatin 20 mg/day. Metabolic parameters of very-low-density lipoprotein (VLDL)-apoB and LDL-apoB were studied using endogenous labeling with stable isotopes. In all patients pravastatin caused an increase in fractional catabolic rates of LDL-apoB without a significant effect on the production rates of apoB-containing lipoproteins. We cannot exclude the possibility that higher doses of statins may decrease VLDL and LDL production.
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PMID:Role of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors ("statins") in familial combined hyperlipidemia. 952 13

Elevated concentrations of plasma cholesterol and triglycerides are characteristic of familial combined hyperlipidemia (FCHL) which may also present with reduced high density lipoprotein (HDL) cholesterol concentrations. Lecithin:cholesterol acyltransferase (LCAT) plays a key role in reverse cholesterol transport by converting unesterified cholesterol to cholesterol ester in the process of maturation of HDL in the presence of its activator, apolipoprotein (apo) A-I. We hypothesised that alterations in LCAT activity or plasma concentrations or gene sequence of apo A-I could influence HDL metabolism in these patients. We studied cholesterol concentrations of high density lipoprotein subfractions and LCAT activity in 25 FCHL subjects and 48 controls. Total HDL (p=0.018) and HDL2 (p=0.008) were significantly decreased in the FCHL group compared with controls. After analyses with adjusted data only HDL2 remained significantly decreased in the FCHL group (p=0.050). The LDLc/HDLc and A-I/HDLc ratios were significantly elevated in the FCHL group (p <0.0001), the latter suggesting the existence of compositional differences in the HDL particles of the FCHL individuals. LCAT activity assessed in the FCHL (19.94+/-3.95 nmol/ml per h) and control (20.13+/-6.86 nmol/ml per h) groups showed no statistically significant differences. A significant positive correlation of LCAT activity with total HDL (r=0.42), HDL3 cholesterol (r=0.46) and apolipoprotein A-I (r=0.47) was observed in affected subjects but not in controls. An association between a Ga(-75)-A variation in the promoter region of the apo A-I gene and elevated concentrations of apo A-I (p=0.009) and apo C-III (p=0.041) was observed. This association was strongly influenced by the status of the subject providing further evidence for a regulatory role of this genetic region in the expression of FCHL. Our data suggests that LCAT activity is normal in FCHL and, therefore, does not account for the abnormalities observed in these patients essentially with regard to the HDL2 subfraction.
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PMID:Evidence against alterations in Lecithin:cholesterol acyltransferase (LCAT) activity in familial combined hyperlipidemia. 969 Sep 23

This study compared the efficacy and safety of a once-a-night, time-release niacin formulation, Niaspan (Kos Pharmaceuticals, Miami Lakes, FL), with plain niacin and placebo for the treatment of primary hypercholesterolemia. The study was conducted in nine academic lipid research clinics in a randomized, double-blind design. Niaspan 1.5 g at bedtime was compared with plain niacin 1.5 g/d after 8 weeks and 3.0 g/d after 16 weeks in divided doses and with placebo. A total of 223 hypercholesterolemic adult men and women participated. Compared with placebo at 8 weeks, Niaspan versus plain niacin at 1.5 g/d showed comparable efficacy, comparably lowering total cholesterol (C) (8%/8%), triglycerides (16%/18%), low-density lipoprotein (LDL)-C (12%/12%), apolipoprotein (apo B) (12%/12%), apo E (9%/7%), and lipoprotein(a) [Lp(a)] (15%/11%), and raising high-density lipoprotein (HDL)-C (20%/17%), HDL2-C (37%/33%), HDL3-C (17%/16%), and apo A-I (8%/6%) (P < or = .05 in all instances). After 16 weeks, the Niaspan effect on LDL-C and triglyceride was unchanged while the plain niacin effect approximately doubled. At equal doses of 1.5 g/d of Niapan versus plain niacin, respectively, AST increased 5.0% versus 4.8% (difference not significant [NS]), fasting plasma glucose increased 4.8% versus 4.5% (NS), and uric acid concentrations increased less, 6% versus 16% (P=.0001). Flushing events were more frequent with plain niacin versus Niaspan (1,905 v 576, P < .001). Flushing severity was slightly greater with Niaspan, but still well tolerated. In conclusion, Niaspan 1.5 g hour of sleep (hs) has comparable efficacy, a lower incidence of flushing, a lesser uric acid rise, and an equivalent hepatic enzyme effect than 500 mg thrice-daily plain niacin in hyperlipidemic subjects. Niaspan may be an equivalent or better alternative to plain niacin at moderate doses in the management of hyperlipidemia.
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PMID:Equivalent efficacy of a time-release form of niacin (Niaspan) given once-a-night versus plain niacin in the management of hyperlipidemia. 975 Dec 39

Chromium (Cr), an essential element, mainly affects saccharide (potentiated insulin action via interaction with insulin receptor on the cell surface) and lipid metabolism (inhibition of hydroxymethylglutaryl-CoA reductase with a hypolipidemic effect). The aim of the study was to describe Cr serum levels in different diseases (malignant, metabolic, renal) using an advanced analytical technique with correlation to other biochemical parameters. The concentration was measured using atomic absorption spectrometry with electrothermal atomization. The Cr levels were increased in hemodialysis patients-HD (3.67 +/- 0.35 micrograms/L) compared to controls-C (0.40 +/- 0.12 microgram/L), in significantly changed in diabetic patients-DM (0.29 +/- 0.08 microgram/L) and patients with lymphoproliferative disease-LP (0.24 +/- 0.07 microgram/L), and decreased in hyperlipidemic patients-HL (0.15 +/- 0.03 microgram/L). There were no differences in Cr concentration between DM treated by diet or peroral antidiabetic drugs; likewise hypolipidemic drugs in HL did not change the Cr concentration. The biochemical parameters-total protein, transferrin in LP group, glucose in DM group, total cholesterol, triacylglycerols, LDL-cholesterol, apolipoprotein B and A-I did not correlate with serum Cr concentration. However, the HDL-cholesterol concentration marginally significantly (p < 0.07) correlated with it. The role of Cr in humans has not yet been fully characterized. To prevent some complications in patients, it may be important to monitor the Cr levels. Chromium supplementation may be indicated in some diseases with no controversy concerning the importance of decreased serum and/or tissue levels and documented positive effects of Cr supplementation on the quality of life (e.g. hyperlipidemia).
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PMID:Chromium levels in patients with internal diseases. 980 4

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