Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P01275 (glucagon)
 26,492 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The studies described here suggest the potential physiological role of polypeptide and corticosteroid hormones in the regulation of cholesterol synthesis. Evidence was shown for substantial differences between various cell types in their responses to these agents and for certain degree of independence of the effects on biosynthesis of cholesterol from those on protein and DNA synthesis. Cholesterol synthesis and HMGCoA reductase are stimulated in a number of diploid cell lines following an incubation with insulin or with glucocorticoids for 4 hr or longer. Stimulation of sterol synthesis by insulin and by dexamethasone requires protein synthesis, but the two hormones do not compete for the same site. Addition of glucagon or of dibutyryl cyclic AMP, or elevation of intracellular cyclic AMP by PGE1 does not inhibit cholesterol synthesis in skin fibroblasts. A possibility of a relationship between the mechanisms of the hormonal effects and of feedback control of cholesterol synthesis is suggested.
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PMID:Studies on the effects of hormones on cholesterol synthesis in mammalian cells in culture. 19 5

Lipid metabolism was studied in experimental uremia. Uremic (U) rats were compared with sham-operated, pair-fed (PF) controls and with ad-lib-fed (AL) controls. In U animals, fasting glucose concentrations were normal, immunoreactive serum insulin (IRI) levels were decreased, and immunoreactive glucagon levels were increased. A significant increase in the serum concentration of all lipid classes was observed: triglycerides were elevated 10-fold above the values in PF and AL controls; phospholipids, twofold; total cholesterol, threefold; and free cholesterol, sixfold. Cholesterol concentration was increased in beta- and pre-beta-lipoproteins and even more so in alpha- and pre-alpha-lipoproteins. There was an increase in the ratio of free cholesterol/total cholesterol. The fatty acid composition of serum lipoproteins was unchanged. Concomitantly, in liver tissue, there was no change in lipid content (triglyceride, cholesterol) and fatty acid composition. These findings argue against glucose- or insulin-mediated changes in hepatic de novo fatty acid synthesis, chain elongation, or poly-desaturation. In U animals, the HMG-CoA-reductase activity of liver microsomes was slightly, but not significantly, reduced as was tritiated water incorporation into cholesterol in isolated perfused liver preparations. In adipose tissue, there was a decrease in triglyceride content. The results provide evidence against insulin-mediated hepatic overproduction as a major cause of hyperlipoproteinemia in this model of experimental renal insufficiency and point to peripheral under-utilization of lipoproteins.
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PMID:Hyperlipoproteinemia in experimental chronic renal insufficiency in the rat. 69 73

Cyclic AMP has been implicated to a greater or lesser extent in the regulation of four key enzymes which interact to regulate intracellular cholesterol metabolism; HMG CoA reductase; ACAT; cholesteryl ester hydrolase; and cholesterol 7 alpha hydroxylase. The relationship between these enzymes and the sites where current evidence suggests that cyclic AMP may be involved are summarized in Fig. 3. Cholesterol 7 alpha hydroxylase controls the catabolism of cholesterol to bile acids in the liver, and thus its removal from the body via the bile, but does not have a major role in cholesterol metabolism in extrahepatic tissues. It is clear that cyclic AMP is able to influence the activity of this enzyme in liver sub-cellular fractions and isolated hepatocytes in vitro, and studies in our laboratory have shown that changes in Ca2+ fluxes within the cell may be important in its mechanism of action. Whether or not the cyclic nucleotide has a role regulating cholesterol 7 alpha hydroxylase activity in vivo, however, is not known. HMG CoA reductase is inactivated by phosphorylation both in vitro and in vivo, but although cyclic AMP and glucagon have been shown to inhibit the enzyme, cyclic AMP-dependent protein kinase is not directly involved. The exact mechanism by which the cyclic nucleotide influences the system remains unclear, but it may be related to activation of microsomal phosphatases. The activity of ACAT has been shown to be modulated by phosphorylation in a number of tissues in vitro, but the involvement of cyclic AMP has not been unequivocally demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cyclic AMP and the regulation of cholesterol metabolism. 132 21

Apolipoprotein (apo) E is a predominant protein in developing mammalian brain and in damaged peripheral nerve. Of particular interest is the observation that astrocytes in the central nervous system cease to produce apoE after nerve damage, whereas an increase in apoE production results after peripheral nerve injury. Differences in the response to injury with regard to the production of apoE may be related to dissimilarities in the abilities of the central and peripheral nervous systems to regenerate. As there are few data concerning the regulation of apoE gene expression in extrahepatic tissues, we employed a human astrocytoma cell line (CCF-STTG1) as a model to study apoE production in astrocytes. CCF-STTG1 cells secreted apoE constitutively in serum-free media. Cholesterol added to the media as cholesterol:phospholipid liposomes (2-100 micrograms/ml) or as human plasma LDL increased the amount of apoE secreted into the media, but had little or no effect on the relative abundance of apoE mRNA. By contrast, the commercially available triglyceride-phospholipid emulsion Intralipid added at dilutions of 1:50 to 1:500 caused a total inhibition of apoE secretion by the cells, but again, little change was noted in the relative abundance of apoE mRNA. Insulin (5 micrograms/ml) caused a 45-55% reduction in the amount of apoE secreted by the astrocytoma cells. Glucagon (5 micrograms/ml), on the other hand, did not increase apoE secretion, and apoE mRNA concentrations were not affected by either hormone treatment. ApoE was secreted from the astrocytoma cells associated with particles of plasma VLDL to IDL and HDL size. After feeding the cells with 20 micrograms/ml cholesterol as cholesterol:phospholipid liposomes, an increased proportion of apoE was secreted associated with the larger VLDL to IDL size particles, with a concomitant decrease in the proportion associated with the smaller HDL-size particles. When cells were incubated with 5 micrograms/ml insulin, most of the apoE was associated with the HDL-size particles. When cholesterol:phospholipid liposomes were added in the presence of insulin virtually all of the secreted apoE was found associated with the VLDL to IDL size particles. In summary, the regulation of apoE production in CCF-STTG1 cells in many respects resembles that of other cells, including hepatocytes. However, it is clear that there remain to be identified cell specific factors which regulate apoE production in astrocytes. The CCF-STTG1 cell line promises to provide a suitable model to investigate these questions.
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PMID:Secretion of apolipoprotein E by an astrocytoma cell line. 140 94

In primary cultures of adult rat hepatocytes the level of cholesterol 7 alpha-hydroxylase steady-state mRNA markedly decreased by 72 h. However, the addition of L-thyroxine (T4) and dexamethasone synergistically returned cholesterol 7 alpha-hydroxylase steady-state mRNA levels near to that of cholestyramine-fed animals. The maximal responses to T4 and dexamethasone in serum-free medium were at 1.0 and 0.1 microM, respectively. The addition of T4 in combination with dexamethasone resulted in an 11-fold increase in transcriptional activity of the cholesterol 7 alpha-hydroxylase gene as compared to no addition controls. The specific activities of cholesterol 7 alpha-hydroxylase in microsomes prepared from cultures treated with dexamethasone and T4 were 1.56 +/- 1.17 nmol/h/mg protein which is similar to that of intact liver (1.70 +/- 0.062 nmol/h/mg protein), but lower than cholestyramine-fed animals. Cholesterol 7 alpha-hydroxylase activity was not detectable (less than 0.020 nmol/h/mg protein) at 72 h in cultures without the addition of both dexamethasone and T4. In the presence of optimal concentrations of dexamethasone and T4, glucagon (0.2 microM), or dibutyryl cAMP (50 microM) decreased (90%) cholesterol 7 alpha-hydroxylase mRNA within 6 h. Transcriptional activity decreased (62%) in 6 h following the addition of glucagon (0.2 microM) to the culture medium. The results reported in this paper suggest an important role for multiple hormones in the regulation of cholesterol 7 alpha-hydroxylase in the liver.
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PMID:Hormonal regulation of cholesterol 7 alpha-hydroxylase mRNA levels and transcriptional activity in primary rat hepatocyte cultures. 151 29

Twenty Type 2 diabetic patients, recently converted to insulin because of inadequate control on oral hypoglycaemic agents, were studied. Endogenous insulin reserve was measured by glucagon stimulation, and insulin-mediated peripheral glucose disposal by a hyperglycaemic (11 mmol l-1) clamp, measurements being repeated after 8 weeks of glipizide or placebo therapy in addition to the patients' usual insulin. The study was randomized and double blind. Fasting and stimulated C-peptide levels did not change on glipizide or placebo. Insulin-mediated glucose disposal rose from 2.5 (1.5-8.0) (median (range] to 4.2 (2.3-8.4) mg kg-1 min-1 in the glipizide group (n = 9, p less than 0.01), but did not change in the placebo group. Glycosylated haemoglobin did not change in either group, but median fasting plasma glucose fell from 10.6 (6.1-15.1) to 9.0 (6.4-11.2) mmol l-1 in the glipizide group (p less than 0.02). Fasting insulin rose on glipizide from 10.1 (4.0-23.2) to 13.0 (6.4-33.8) mU l-1 (p less than 0.02). Insulin dosage fell in the glipizide group from 36 to 26 U day-1, as 4 patients experienced hypoglycaemic symptoms. HDL-Cholesterol fell in all patients on glipizide, from 0.94 (0.79-2.13) to 0.79 (0.62-1.95) mmol l-1 (p less than 0.01). Combination of insulin with the sulphonylurea glipizide in secondary failure Type 2 diabetic patients leads to increased insulin-mediated peripheral glucose disposal. Glipizide may have an adverse effect on HDL-cholesterol, which is unrelated to change in diabetic control.
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PMID:Combination of insulin with glipizide increases peripheral glucose disposal in secondary failure type 2 diabetic patients. 213 55

Male adult Wistar rats received daily, at 9 a.m. and 5 p.m., 10 micrograms of Zn-protamine glucagon for 21 days by subcutaneous injections. The blood glucose level was not significantly modified. Cholesterol and triacylglycerol levels were decreased by 40 and 70% in plasma but not in the liver. The rates of cholesterol turnover processes were determined in vivo with an isotope balance method. Internal secretion of cholesterol (13.8 +/- 0.5 mg/day per rat in control rats and 22.4 +/- 0.9 mg/day per rat in glucagon-treated rats) and cholesterol transformation into bile acids were strikingly increased by chronic administration of glucagon. Biliary secretion rates of bile acids measured by a wash-out method were increased by 139%, while the intestinal bile acid pool was not changed. The enterohepatic cycle number was increased from five per day in control rats to nine per day in glucagon-treated rats. An increased turnover rate of the exchangeable cholesterol would explain the hypocholesterolemic effect of glucagon.
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PMID:Effects of chronic glucagon administration on cholesterol and bile acid metabolism. 305 12

Portacaval anastomosis (PCA) lowered by 50% the cholesterol concentration in the plasma of rats. The free and esterified cholesterol contents in the lipoproteins were decreased with the very low density lipoproteins most affected (-85%). Cholesterol concentration as total content in the liver was reduced. The major change in the cholesterol metabolism, as studied with an isotopic equilibrium method, was the decrease in the intestinal absorption coefficient of dietary cholesterol (56.0 +/- 2.7% instead of 73.3 +/- 1.9% in controls). The rate of cholesterol transformation into bile acids was decreased (10.5 +/- 0.3 vs 14.5 +/- 0.5 mg/day/rat in controls). The rate of internal secretion of cholesterol was slightly reduced while the rate of fecal external secretion was increased, suggesting that the synthesis of cholesterol by extra-digestive tissues (including liver) was reduced after PCA. The effects of PCA on cholesterol metabolism were similar to those described for glucagon administration. Since this shunt results in hyperglucagonemia, it is suggested that this hormonal perturbation was the main factor involved in the modifications of cholesterol metabolism after PCA. Moreover, mesentericocaval anastomosis, which shunts only the intestinal blood and allows the pancreatic hormones a normal transport through the liver, did not significantly modify cholesterol metabolism. Only cholesterolemia (-28%) and the absorption coefficient of dietary cholesterol (66.0 +/- 2.3%) were slightly reduced.
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PMID:Effect of portacaval or mesentericocaval anastomosis on cholesterol metabolism in rats. 683 96

Cholesterol has a large effect on the binding of glucagon to dimyristoylphosphatidylcholine (DMPC) and to dipalmitoylphosphatidylcholine (DPPC). At cholesterol concentrations of 20 mol% or greater there is virtually no interaction of glucagon with phospholipid. Glucagon can, however, solubilize DMPC or DPPC with 10% cholesterol. In the case of DPPC the solubilized lipid is depleted of cholesterol relative to the starting material. These results suggest that glucagon excludes cholesterol from its surroundings. It is shown from solubility, light scattering, and glucagon fluorescence measurements that the glucagon-DMPC complex containing 10% cholesterol is stable only in the region of the phase transition temperature. Scatchard analysis of lipid binding to glucagon indicates a decrease in the amount of bound lipid below 22 degrees C or above 24 degrees C. The effect of the phase transition on the interaction of glucagon with lipids is compared with that found for other membrane proteins. Several aspects of the effect of cholesterol on glucagon-lipid interactions are analogous to effects which have been observed with serum apolipoproteins.
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PMID:The effect of cholesterol on the interaction of glucagon with the gel state of dimyristoylphosphatidylcholine. 689 48

The effects of dietary manipulations on plasma lipid concentrations were studied over a 3 month period in 8 stable uremic patients on dialysis. Each of the 4 diets was of 3 weeks' duration, and consisted of the following periods: Control (regular diet), high carbohydrate (60% of total calories ingested), control, and a low carbohydrate diet (20% of total calories ingested). The patients' weight remained stable throughout the study. A 33% reduction in plasma triglyceride concentration was observed during the low carbohydrate period (P less than 0.05, paired analysis), and a 33% increase above control values was observed during the high carbohydrate period (P less than 0.05, paired analysis). Cholesterol concentrations did not vary and remained within normal limits throughout the study. There was no significant correlation observed between either insulin or glucagon levels and variations in triglyceride concentration. Reduction in the proportion of carbohydrate in the diet of dialysis patients, may be an effective long-term therapeutic approach to their hypertriglyceridemia.
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PMID:Dialysis hyperlipemia: response to dietary manipulations. 699 Nov 84


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