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)

Fibroblasts from 12 normotriglyceridemic subjects and 30 hypertriglyceridemic patients and family members were used to investigate triglyceride synthesis and the influence of triiodothyronine on it. The monolayers were incubated for 72 hours with and without the thyroid hormone, followed by incorporation studies of radiolabeled acetic acid or palmitic acid into the cellular triglyceride fraction. Triiodothyronine had no influence on triglyceride synthesis of normal cell lines and of cells derived from patients with secondary hypertriglyceridemia, whereas fibroblasts from endogenous type IV patients showed higher rates of triglyceride synthesis under identical conditions. Values for type IV were in the range of 134% to 466% of the hormone-free control incubations. In cultures derived from patients with familial combined hyperlipidemia, no stimulation by triiodothyronine was observed: values were in the range of 64% to 144% of the hormone-free controls. Three out of four lines with type V gave "normal" values and are supposed to represent secondary hypertriglyceridemia, whereas one line may express endogenous type IV. The evidence obtained in vitro with cultured cells indicates different metabolic defects in endogenous type IV and familial combined hyperlipidemia; it also shows the biochemically heterogenous nature of the disease "hypertriglyceridemia."
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PMID:Effect of triiodothyronine on triglyceride synthesis in human fibroblasts in different types of hypertriglyceridemia. 229 72

To explore the possible association of hyperlipidemia with hyperammonemia and aspirin ingestion, the effects of NH4+, salicylate, and carnitine on the oxidation of [1-14C]palmitic acid to acid-soluble products (ASP) and to CO2 were investigated in rat liver slices. DL-carnitine (5 mM) increased total oxidation (ASP + CO2) more than oxidation to CO2. KCN (1.5 mM) inhibited more than 90% of the oxidation. NH4Cl inhibited the oxidation that reached a maximum at about 40 mM, but the inhibition of oxidation to CO2 (63%) was larger than that of total oxidation (30%). Carnitine did not influence NH4+ inhibition, which is consistent with the results reported for isolated mitochondria. Salicylate effects depended on salicylate concentration as well as on the presence of carnitine. In the absence of carnitine, inhibition of total oxidation reached 90% at 3 mM salicylate but that of oxidation to CO2 reached 50%. Velocity calculated at saturating palmitic acid concentration for total oxidation was slightly increased by 0.75 mM salicylate, but the increase for oxidation to CO2 was larger. At 3 mM salicylate, velocity at saturating palmitic acid concentration for the oxidation was decreased, but the decrease for oxidation to CO2 was smaller than for total oxidation. Carnitine partially relieved the inhibition of total oxidation and further increased the formation of CO2. The combination of 20 mM NH4Cl and 0.75 mM salicylate inhibited total oxidation, which was more than additive of the individual effects, and carnitine partially relieved the inhibition. It is concluded that NH4+ exerted a stronger inhibition of oxidation to CO2 than of oxidation to ASP, whereas salicylate strongly inhibited the oxidation to ASP but increased the oxidation to CO2 by uncoupling mitochondrial oxidative phosphorylation. Therefore, hyperammonemia and aspirin ingestion can inhibit fatty acid oxidation and mitochondrial metabolism that could lead to the pathophysiology seen in some childhood diseases such as Reye's syndrome. Carnitine therapy might offer some benefits.
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PMID:Effects of ammonium chloride, salicylate, and carnitine on palmitic acid oxidation in rat liver slices. 291 25

Palmitate, glucose, and glycerol oxidation to CO(2) have been investigated in the fasted state in ten normal subjects and nine patients (six hyperlipoproteinemias, one xanthomatosis, and two glycogenosis) after intravenous injection of [1-(14)C]palmitate, [1-(14)C]glucose, or [1-(14)C]glycerol in tracer amounts. The specific activities and concentrations of plasma palmitate, glycerol, or glucose and expired CO(2) were measured at various intervals after the injection for a period of 24 h. All the studies were analyzed in terms of a multicompartment model describing the structure for each of the subsystems, the transfer of carbon label between subsystems, and the oxidation to CO(2). A bicarbonate subsystem was also included in the model to account for its role in shaping the CO(2) curves. All the CO(2) activity following a palmitate injection could be accounted for by a direct oxidative pathway from plasm FFA with the addition of a 20-min delay compartment. The same also applied to glucose, except that the delay compartment had a mean time of about 150 min. Only about a third of the injected glycerol was directly oxidized to CO(2) from plasma; the delay time was about 4 min. Most of the remainder was converted to glucose. In normals about 45% of the FFA is oxidized to CO(2) directly. This constitutes about 30% of the total CO(2) output. In hyperlipemia the CO(2) output is nearly unchanged and the contribution from FFA is nearly the same. There is a considerable increase (factor of 2), however, in FFA mobilization, most of which is probably diverted to triglyceride synthesis. The glucose and glycerol subsystems are roughly the same in normals and hyperlipemics. About 50% of glucose is oxidized by the direct pathways which accounts for about 35% of the CO(2) output. Glycerol accounts for only 1.5% of the CO(2) produced. Major changes occurred in the glycerol and glucose subsystems in glycogenosis. The changes are consistent with the known deficiency in glucose-6-phosphatase in this disorder. There is a considerable reduction (factor of 2 or more) in the release of glucose to plasma (gluconeogenesis) and in the conversion of glycerol to glucose. Despite the integration of the kinetics of the glucose, glycerol, and FFA subsystems over a 24-h period, 36% of the CO(2) production was still unaccounted for in normals and 50% in hyperlipemics. Thus, some of the carbon must wind up in very slowly turning-over pools which supply CO(2) through subsystems not covered in these studies (triglycerides, glycogen, amino acids, etc.). All the modeling was carried out with the aid of the SAAM25 computer program.
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PMID:Interrelations in the oxidative metabolism of free fatty acids, glucose, and glycerol in normal and hyperlipemic patients. A compartmental model. 452 90

In rats, chronic ethanol feeding was found to enhance the postprandial hyperlipemia and to increase the incorporation of dietary palmitic acid-(3)H and intravenously injected L-lysine-(14)C into serum lipoproteins. The main increases of total amount, labeling, and specific activity of lipid and protein occurred in the d < 1.019 lipoprotein fraction. Fat absorption and the clearance of injected chylomicrons were not affected by ethanol feeding. Blocking of lipoprotein and chylomicron removal with Triton did not prevent the action of ethanol on serum lipids, indicating that the ethanol effect is not likely due to defective removal of lipids from the circulation. Ethanol enhanced the incorporation of chylomicron fatty acids into newly synthetized very low density lipoproteins, as shown by an increased reappearance of the fatty acid label into the lipids of this fraction after injection of palmitate-(14)C/glycerol-(3)H doubly labeled chylomicrons. These results indicate that alcoholic hyperlipemia is due, at least in part, to an increase in newly synthetized lipoproteins. The hyperlipemia produced by ethanol was accompanied by hepatic steatosis. The simultaneous production of fatty liver and hyperlipemia makes it unlikely that defective lipoprotein synthesis or secretion is a primary mechanism for the pathogenesis of the alcoholic fatty liver.
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PMID:Efcts of chronic ethanol feeding on serum lipoprotein metabolism in the rat. 544 77

The ultrastructural effects of a single brief intra-arterial infusion of palmitic, linoleic and acetoacetic acid on the arterial endothelium of the rat were investigated, and the following results obtained: (1) Palmitic acid, infused at a concentration of 4 mM/l, damaged the arterial lining by producing large cytoplasmic clefts and occasional blebbing and lysis of the endothelial cells. By contrast, linoleic acid, infused at the same concentration, had no damaging effects on arterial endothelium. (2) Acetoacetic acid damaged the arterial wall when infused at concentrations of 0.2 mM/l or higher by inducing extreme swelling and loss of cristae of the mitochondria in arterial endothelium and myocytes. The above results raise the possibility that (a) high saturated fatty acid diets may promote atherosclerosis not only by inducing hypercholesterolemia but also by injuring the arterial lining, and (b) diabetes may promote atherosclerosis not only by inducing hyperlipemia but also by damaging the arterial wall during periods of uncontrolled ketoacidosis.
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PMID:Arterial effects of palmitic, linoleic and acetoacetic acid. 722 70

The in vivo effects of pantethine were investigated on serum lipids and platelet lipid and platelet functions in 31 diabetic patients with hyperlipidemia. Pantethine decreased cholesterol from 236 +/- 62 mg/dl (M +/- SD) to 217 +/- 51 mg/dl (p less than 0.01) and increased high density lipoprotein cholesterol from 40 +/- 11mg/dl to 43 +/- 15 mg/dl. The diabetic platelets were larger when accompanied by higher microviscosity that healthy platelets. The characteristics of lipid composition in diabetic platelets were high levels of free cholesterol, phospholipid, triglyceride, cholesterol ester, palmitoleic acid, linoleic acid and palmitoleic acid/palmitic acid and low levels of the molar ratio of free cholesterol/phospholipids, phosphatidylethanolamine, oleic acid, arachidonic acid and oleic acid/stearic acid. Pantethine normalized these values of fatty acids to the control levels, and concomitantly reduced significantly the hyperaggregation of platelets induced by 10(6) M ADP and the hyper-ADP release reaction from platelets when exposed to 2 microgram of collagen, and made the volume smaller and the microviscosity lower after oral administration. From these data, it was concluded that pantethine normalized the abnormalities of serum lipids as well as platelet lipid compositions and subsequently reduced the hyper-aggregation and hyper-release reactions through the changes of volume and microviscosity of the platelets in diabetes mellitus with hyperlipidemia.
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PMID:Influence of pantethine on platelet volume, microviscosity, lipid composition and functions in diabetes mellitus with hyperlipidemia. 725 94

To clarify the relationship between lipid and glucose metabolism abnormalities in fructose-fed rats, we examined whether an improvement of insulin sensitivity by troglitazone (CS-045) or a decrease in plasma lipids by bezafibrate affects the relationship between serum levels of lipid and glucose. In addition, we also examined changes in liver glycogen metabolism and beta-oxidation in fructose-fed rats. Troglitazone ameliorated fasting hyperlipidemia, hyperglycemia, and hyperinsulinemia. In addition, it augmented glycogen synthase activity by 53%, and decreased the mitochondrial palmitic acid beta-oxidation rate and ketone body production rate by 27% and 55%, respectively. However, hyperglycemia and liver glycogen synthase activity were not improved by bezafibrate treatment despite a marked reduction of serum triglyceride (TG) levels resulting from a 1.76-fold increase in mitochondrial oxidation and a 2.04-fold increase in hepatic ketone body production. These results suggest that abnormalities in glucose and lipid metabolism in fructose-fed rats, which are ameliorated by troglitazone, may be closely linked to reduced glycogen synthase activity in the liver.
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PMID:Effect of troglitazone (CS-045) and bezafibrate on glucose tolerance, liver glycogen synthase activity, and beta-oxidation in fructose-fed rats. 878 34

To better understand the link between fatty acid signaling and the pleiotropic effects of fatty acids in the pancreatic beta-cell, we investigated whether fatty acids regulate immediate-early response genes (IEGs) coding for transcription factors implicated in cell proliferation, differentiation, and apoptosis. Palmitate and oleate, but not long-chain polyunsaturated fatty acids, caused a pronounced accumulation of c-fos and nur-77 mRNAs in beta-cells (INS cells) to an extent similar to that produced by the protein kinase C (PKC) activator phorbol myristate acetate (PMA). The effect was dose dependent and occurred at concentrations between 0.1 and 0.5 mmol/l in the presence of 0.5% albumin. The action of the fatty acid occurred at the transcriptional level, and the mRNA accumulation displayed a bell-shaped kinetics with a maximal effect at 1 h. 2-Bromopalmitate was ineffective, indicating that fatty acids must be metabolized to cause their effect. Neither fatty acid was able to induce c-fos and nur-77 in PKC-downregulated cells or cells incubated in the presence of the Ca2+ channel blocker nifedipine or the Ca2+ chelator EGTA, suggesting involvement of the PKC and Ca2+ signaling pathways. Palmitate and oleate also increased c-fos protein expression and DNA binding activity of the transcription factor AP-1. Oleate, but not palmitate, increased [3H]thymidine incorporation in INS cells. Finally, both palmitate and oleate caused c-fos and nur-77 mRNA accumulation in isolated rat islets. It is suggested that IEG induction by the most abundant circulating fatty acids plays a role in the adaptive process of the beta-cell to hyperlipidemia. These results have implications for our understanding of obesity-associated diabetes and the link between fatty acids and tumorigenesis.
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PMID:Palmitate and oleate induce the immediate-early response genes c-fos and nur-77 in the pancreatic beta-cell line INS-1. 1051 66

The effects of positional distribution of triacylglycerol (TAG) fatty acids to TAG structures in chylomicrons and VLDL, and to postprandial lipemia, were studied in 10 healthy premenopausal women using a 6-h oral fat load test and a randomized, double-blind cross-over design. Molecular level information of TAG regioisomerism was obtained with a tandem mass spectrometric method. The positional distribution of fatty acids in chylomicron TAGs was similar to the respective dietary fat; 79% of the analyzed regioisomers in palm oil and 84% of the analyzed regioisomers in transesterified oil were found in chylomicron TAGs 3 h after the oral fat loads. VLDL TAGs were equal after the two fat loads in all but one regioisomer. Similarities in the fatty acid compositions of chylomicron TAGs suggest that palmitic acid was absorbed equally from both test fats. The proportion of palmitoleic acid in the chylomicrons was increased. Fat with palmitic acid predominantly in the sn-1 and sn-3 positions caused a larger incremental area of total TAGs in plasma and reduced plasma insulin values at the beginning of the postprandial response (0-90 min) compared with fat with palmitic acid randomly distributed. The relationship between TAG molecular structures in dietary fats and in lipoproteins provides new means for understanding the effects of fatty acid positional distribution on human lipid metabolism.
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PMID:Effects of palm oil and transesterified palm oil on chylomicron and VLDL triacylglycerol structures and postprandial lipid response. 1159 Feb 18

Neutral endopeptidase (NEP), a membrane-bound metallopeptidase enzyme that degrades neuropeptides, bradykinin, atrial natriuretic factor, enkephalins, and endothelin may regulate response to injury. We have previously demonstrated increased NEP localization and enzyme activity in diabetic wounds and skin compared with normal controls. We hypothesized that hyperlipidemia and hyperglycemia associated with type 2 diabetes mellitus may induce excessive NEP activity and thereby diminish normal response to injury. Human microvascular endothelial cells were treated with five different fatty acids (40 microM) with varying degrees of saturation, including oleic acid, linoleic acid, palmitic acid, stearic acid, and linolenic acid and/or glucose (40 mM) for 48 h. The effect of the antioxidative agents vitamin E and C on NEP enzyme activation was determined by treating the cultured cells with alpha-tocopherol succinate and/or L-ascorbic acid. Cell membrane preparations were assayed for NEP activity by incubation with glutaryl-Ala-Ala-Phe-4-methoxy-beta naphthylamide to generate a fluorescent degradation product methoxy 2 naphthylamine. High glucose or fatty acid concentration upregulated NEP activity. The highest NEP activity was observed with combined elevated glucose, linoleic acid, and oleic acid (P < 0.05). Antioxidant vitamin E and C treatment significantly reduced NEP enzyme activity after fatty acid exposure (P < 0.05). Thus, hyperglycemia and hyperlipidemia associated with type 2 diabetes mellitus may increase endothelial cell NEP activity and thereby decrease early pro-inflammatory responses. The modulator effect of vitamin E and C on NEP membrane enzyme activity after exposure to fatty acid stimulation suggests that lipid oxidation may activate NEP.
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PMID:Fatty acids and glucose increase neutral endopeptidase activity in human microvascular endothelial cells. 1278 4


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