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)

We have studied hepatocytes cultured from Watanabe-heritable hyperlipidemic (WHHL) rabbits, animals that display striking elevation of plasma low density lipoprotein (LDL), spontaneous atherosclerosis, and an absence of LDL receptor activity in cultured fibroblasts. Degradation of LDL by WHHL hepatocytes differed from degradation by normal hepatocytes in several ways: 1) degradation by normal hepatocytes as a function of LDL concentration was curvilinear with a saturable component, while degradation by WHHL hepatocytes was a linear function of concentration; 2) degradation of 125I-labeled LDL by mutant cells was not decreased by excess unlabeled LDL, while degradation by normal cells was; 3) degradation of LDL by normal cells was inhibited by colchicine and chloroquine while degradation by the mutant cells was not; 4) both cell types catabolized LDL at nearly equal rates, but activity of 3-hydroxy-3-methylglutaryl-CoA reductase was suppressed only in the normal cells. These differences are analogous to those previously reported in describing the qualitatively different pathways for receptor-dependent and receptor-independent catabolism of lactosylated and native human LDL in rat hepatocytes. Thus, hepatocytes from WHHL rabbits lack LDL receptor activity. The peripheral and hepatic LDL receptors most likely are products of the same gene or depend for their activity on a single gene product.
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PMID:Low density lipoprotein receptor deficiency in cultured hepatocytes of the WHHL rabbit. Further evidence of two pathways for catabolism of exogenous proteins. 626 29

Human low-density lipoprotein (LDL) was glucosylated by incubation in vitro with glucose (20-80 mM) with or without addition of cyanoborohydride. The incorporation of covalently bound glucose was linear over time, and amino acid analysis showed the presence of glucosyllysine residues. The glucosylated LDL (glc LDL) moved more rapidly than normal LDL on agarose electrophoresis. The rate of degradation of 125I-labeled glucosylated LDL (glc LDL) by cultured human fibroblasts was reduced compared with that of native I-LDL, the difference increasing with extent of glucosylation. Effects were seen with blockage of as few as 6-15% of the LDL lysine residues; high-affinity degradation was completely lost when one-third of the lysine residues were blocked. Conjugation of LDL with glucose-6-phosphate also blocked high-affinity uptake and degradation. Whereas native LDL uptake inhibited the activity of beta-hydroxy-beta-methylglutaryl coenzyme A reductase and stimulated acyl coenzyme A:cholesterol acyltransferase activity, glc LDL had no effects on these enzymes. The fractional catabolic rate of glc LDL in guinea pigs was reduced. Degradation of glc LDL by mouse peritoneal macrophages was not significantly faster than that of native LDL. Finally, the presence of glc LDL in human plasma was demonstrated. Preliminary data show that 1.3% of lysine residues in normal LDL and 2-5.3% of lysines in diabetic LDL were glucosylated. Since, like other plasma proteins, LDL undergoes glucosylation in diabetes, its turnover and sites of catabolism may differ from normal and this may be relevant to the accelerated atherosclerosis of diabetes.
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PMID:Nonenzymatic glucosylation of low-density lipoprotein alters its biologic activity. 681 75

Regulation of the key enzyme of cholesterol synthesis, 3-hydroxy-3-methylglutaryl CoA reductase (EC: 1.1.1.34), by heterologous human lipoproteins and hormones was studied in a maintenance culture of rat hepatocytes. The liver cells were cultured under hormone and serum free conditions and maintained differentiated morphology and specific function. Under control conditions total HMG-CoA reductase increased by 50% after 24 h culture compared to 0 h values immediately after isolation. Thereafter a plateau of enzyme activity was reached lasting until 48 h, with a slight decline at 72 h. Concomitantly the "expressed" enzyme activity increased steadily, probably through dephosphorylation of latent reductase, the activation was largely complete at 48 h. During the steady state period of total reductase VLDL added to the medium at concentrations up to 50 microgram/ml protein had no effect o HMG-CoA reductase activity. In contrast, LDL suppressed the enzyme in a dose-dependent fashion to 40% of controls at 100 microgram/ml. On the other hand, HDL had the opposite effect with a significant induction up to 252% of controls at 50 microgram/ml. Insulin also caused a comparable dose-dependent stimulation of enzyme activity at 10(-8) and 10(-7)M, whereas glucagon inhibited reductase activity. Compared to the insulin action, triiodothyronine and triamcinolone prompted a minor, but still significant increase of reductase activity. Insulin and triamcinolone acted synergistically, but the combination of triamcinolone and tri-iodothyronine was only additive. All hormonal inductions of reductase could be blocked by cycloheximide. The present data establish that HMG-CoA reductase of maintenance cultured hepatocytes is subject to a complex regulation by heterologous lipoproteins as well as pancreatic, adrenal and thyroid hormones.
Atherosclerosis 1982 Jan
PMID:3-Hydroxy-3-methylglutaryl CoA reductase in cultured hepatocytes. Regulation by heterologous lipoproteins and hormones. 707 95

ML-236B, a competitive inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase, was administered to 11 patients with primary hypercholesterolemia. After 4--8 weeks of drug treatment at doses of 50--150 mg/day, serum cholesterol levels were reduced by 11--37% (27% on average) in cases of heterozygous familial hypercholesterolemia and combined hyperlipidemia. A marked reduction in tuberous xanthomas was noticed in a homozygous case of familial hypercholesterolemia, but here the drug was less effective in reducing the serum cholesterol level and a higher dose was required for treatment. Softening of Achilles tendon xantomas was observed in a case of combined hyperlipidemia.
Atherosclerosis 1980 Mar
PMID:Therapeutic effects of ML-236B in primary hypercholesterolemia. 736 99

Oral administration of CS-500, a competitive inhibitor of 3-hydroxy-3-methylglutaryl CoA reductase, lowered the serum cholesterol level of both normal and WHHL-rabbits (the first example of heritable hyperlipidemic animals) at doses higher than 5 mg/kg/day. Phospholipids decreased concomitantly, whereas triglycerides did not in either normal or WHHL-rabbits.
Atherosclerosis
PMID:Hypolipidemic effects of CS-500 (ML-236B) in WHHL-rabbit, a heritable animal model for hyperlipidemia. 747 Feb 2

Familial hypercholesterolaemia (FH) is caused by mutations in the gene for the low density lipoprotein (LDL) receptor. It is generally believed that homozygous FH patients do not respond well to lipid-lowering drug therapy with inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase because they cannot respond to an increased demand for hepatic cholesterol by up-regulation of LDL-receptor activity. In this paper we show that serum cholesterol in a homozygous FH patient with a receptor-negative LDL-receptor phenotype was reduced by 30% after treatment with simvastatin alone and by a further 11% with simvastatin in combination with probucol and nicotinic acid. The patient was a true homozygote, with two identical alleles of the LDL receptor gene in which a previously undescribed point mutation in exon 11 introduces a premature termination codon at residue 540 in the protein; the mutant protein is predicted to be truncated in the domain with homology to the epidermal growth factor precursor. Cultured cells from the patient were unable to bind, internalise or degrade LDL by the receptor pathway and there was no immunodetectable LDL receptor protein in the cells. Thus the lipid lowering effect of simvastatin in this individual must involve mechanisms other than stimulation of LDL receptors.
Atherosclerosis 1993 Nov
PMID:Cholesterol-lowering drug therapy in a patient with receptor-negative homozygous familial hypercholesterolaemia. 829 93

In patients heterozygous for familial hypercholesterolemia, the low-density lipoprotein (LDL) cholesterol lowering effect of beta-hydroxy-beta-methylglutaryl coenzyme A reductase inhibitors may depend on the nature of the mutation in the LDL receptor gene. To test this hypothesis, we compared the response to simvastatin, 20 mg daily for 9 weeks, between heterozygous carriers of functionally different classes of mutations, i.e. mRNA negative or mRNA positive mutations. Out of 116 consecutive, unrelated patients with familial hypercholesterolemia, 27 patients were selected for molecular analyses: 14 patients with mRNA negative and 13 with mRNA positive mutations. Before simvastatin treatment, patients with mRNA negative mutations had higher levels of LDL cholesterol, lower levels of high-density lipoprotein (HDL) cholesterol and significantly more often tendon xanthomas, compared to patients with mRNA positive mutations. Simvastatin reduced the mean fasting LDL cholesterol levels to a similar percentage in the mRNA negative and mRNA positive patients (37, 36%, respectively, 95% CI of difference--8 to 5%, P = 0.2). This effect was similar to the 37% decrease observed in our total series of patients with familial hypercholesterolemia (n = 116). The increase in mean concentration of HDL cholesterol was greater in the mRNA negative group than in the mRNA positive group (16, 0%, respectively, 95%, CI of difference 8-25%, P = 0.002) independent of the response of total triglycerides to simvastatin. The percentage LDL cholesterol lowering response varied among multiple carriers of the same mutation, even in the case of mRNA negative mutations. We conclude that the percentage LDL lowering response to simvastatin treatment was similar in patients with mRNA negative and mRNA positive mutations. Moreover, variation of this response within multiple carriers of the same mutation suggests an influence of additional factors.
Atherosclerosis 1998 Feb
PMID:Similar response to simvastatin in patients heterozygous for familial hypercholesterolemia with mRNA negative and mRNA positive mutations. 954 95

Sterol 27-hydroxylase is important for the degradation of the steroid side chain in conversion of cholesterol into bile acids and has been ascribed a regulatory role in cholesterol homeostasis. Its deficiency causes the autosomal recessive disease cerebrotendinous xanthomatosis (CTX), characterized by progressive dementia, xanthomatosis, and accelerated atherosclerosis. Mice with a disrupted cyp27 (cyp27(-/-)) had normal plasma levels of cholesterol, retinol, tocopherol, and 1,25-dihydroxyvitamin D. Excretion of fecal bile acids was decreased (<20% of normal), and formation of bile acids from tritium-labeled 7alpha-hydroxycholesterol was less than 15% of normal. Compensatory up-regulation of hepatic cholesterol 7alpha-hydroxylase and hydroxymethylglutaryl-CoA reductase (9- and 2-3-fold increases in mRNA levels, respectively) was found. No CTX-related pathological abnormalities were observed. In CTX, there is an increased formation of 25-hydroxylated bile alcohols and cholestanol. In bile and feces of the cyp27(-/-) mice only traces of bile alcohols were found, and there was no cholestanol accumulation. It is evident that sterol 27-hydroxylase is more important for bile acid synthesis in mice than in humans. The results do not support the contention that 27-hydroxylated steroids are critical for maintenance of cholesterol homeostasis or levels of vitamin D metabolites in the circulation.
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PMID:Markedly reduced bile acid synthesis but maintained levels of cholesterol and vitamin D metabolites in mice with disrupted sterol 27-hydroxylase gene. 961 81

Pharmacological characterization of NTE-122 (trans-1,4-bis[[1-cyclohexyl-3-(4-dimethylamino phenyl)ureido]methyl]cyclohexane), a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, was performed with both in vitro and in vivo assay systems. NTE-122 inhibited microsomal ACAT activities of various tissues (liver of rabbit and rat, small intestine of rabbit and rat, and aorta of rabbit) and cultured cells (HepG2 and CaCo-2), with IC50 values from 1.2 to 9.6 nM. The inhibition mode of NTE-122 was competitive for HepG2 ACAT. NTE-122 had no effect on other lipid metabolizing enzymes, such as 3-hydroxy-3-methylglutaryl-CoA reductase, acyl-CoA synthetase, cholesterol esterase, lecithin:cholesterol acyltransferase, acyl-CoA:sn-glycerol-3-phosphate acyltransferase and cholesterol 7alpha-hydroxylase up to 10 microM. When NTE-122 was administered to the cholesterol diet-fed rats, serum and liver cholesterol levels were markedly reduced with an ED50 of 0.12 and 0.44 mg/kg/day, respectively. In the cholesterol diet-fed rabbits, NTE-122 significantly lowered plasma and liver cholesterol levels at more than 2 mg/kg/day. These results indicate that NTE-122 is a potent, selective and competitive inhibitor of ACAT, making it a worth while therapeutic agent for hypercholesterolemia and atherosclerosis.
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PMID:Cholesterol-lowering effects of NTE-122, a novel acyl-CoA:cholesterol acyltransferase (ACAT) inhibitor, on cholesterol diet-fed rats and rabbits. 986 70

The pathogenesis, clinical significance, and treatment options of the disturbances in lipid metabolism in children with persistent nephrotic syndrome are reviewed. The lipoprotein profile is characterized by elevations of total plasma cholesterol and often triglycerides, elevated very low-density lipoprotein and low-density lipoprotein cholesterol, whereas high-density lipoprotein-cholesterol levels are variable; plasma levels of the atherogenic and thrombogenic lipoprotein(a) are also elevated. The pathophysiology of nephrotic dyslipoproteinemia is multifactorial, including both an increased hepatic synthesis and a diminished plasma catabolism of lipoproteins. There is a rationale for treatment, since dyslipidemia may contribute to the development of atherosclerosis and the progression of chronic renal failure. However, the benefits of treatment with lipid-lowering drugs have not been proven. Short-term studies in adults with nephrotic syndrome have documented safety and efficacy of lipid-lowering drugs, including hydroxymethylglutaryl-CoA reductase inhibitors ("statins"), bile acid sequestrants, fibric acids, fish oil, and probucol. Statins are the most-effective mediation, resulting in a decrease of total cholesterol levels by about 30%-40%. Prospective controlled studies in children evaluating efficacy and safety of lipid-lowering drugs are needed.
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PMID:Should hyperlipidemia in children with the nephrotic syndrome be treated? 1010 Feb 96


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