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)

HMG CoA reductase, which catalyzes the reaction, HMG CoA + 2 NADAPH2 leads to mevalonate + CoA-SH + 2 NADP, is considered to be the rate-limiting enzyme on cholesterol biosynthetic pathway. Since a degree in activity of this enzyme is almost proportional to the rate of cholesterol synthesis from acetate, elucidation of factors that regulate reductase activity would provide insight into the control mechanisms on the cholesterol biosynthesis. In the present study, attempts were made to establish standard assay conditions of HMG CoA reductase activiy, and to qualify the factors affecting the activity of the enzyme. The results obtained were as follows: (1) As standard assay conditions of HMG CoA reductase activity, 85, muM were chosen for substrate concentration, 25-80 mug for microsomal enzyme protein, and 20 min for incubation time in a final volume of 0.1 ml. (2) HMG CoA reductase activity of rat liver microsomes was exhibited diurnal variation. The level of reductase activity at night was 4 fold higher than that of at daytime. (3) Either ATP or insulin administration stimulated hepatic HMG CoA reductase activity. But, cyclic AMP had no effect on reductase activity. The stimulatory effect of ATP or insulin on reductase activity was inhibited by a preadministration of glucagon. These results suggested that an interplay of hormone might regulate reductase activity and consequently cholesterol biosynthesis. (4) HMG CoA reductase activity was increased by preincubation of microsomes with cytosol. Presence of ATP or Mg++ intensified this effect. When digested by trypsin or degenerated by heat treatment, cytosol lost the stimulating activity. These results suggested as existence of protein factors in cytosol, which might modulate the enzyme interconversion from inactive to active forms.
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PMID:[Studies on the regulatory factors of 3-hydroxy-3-methylglutaryl CoA reductase (HMG CoA reductase) activity]. 18 33

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

Incubation of rat hepatocytes for 3 hours in a sterol-free medium containing 1.5% albumin resulted in efflux of cellular sterol into the medium and an increased activity of 3-hydroxy-3-methylglutaryl CoA reductase. The secretion of cholesterol was inhibited when cells were incubated with glucagon, norepinephrine, or dibutyryl cyclic AMP. Glucagon and dibutyryl cyclic AMP also inhibited the induction of HMG-CoA reductase. Norepinephrine treatment resulted in a decrease in the synthesis and secretion of proteins but caused an increase in reductase activity. Insulin treatment had no effect either on reductase activity or on sterol efflux from rat hepatocytes.
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PMID:The effect of glucagon, norepinephrine, and dibutyryl cyclic AMP on cholesterol efflux and on the activity of 3-hydroxy-3-methylglutaryl CoA reductase in rat hepatocytes. 22 Mar 51

This paper reviews most of the clinical studies on the mode of action of halofenate, an established hypolipidemichypouricemic agent in man. In yeast cutlures and in isolated rat adipocytes, halofenate was found to inhibit the conversion of pyruvate to acetyl CoA. While pyruvate dehydrogenase was inhibited in vitro, halofenate also inhibited the activety of various other isolated enzymes. In rats maintained on halofenate in the diet (0.02-0.10%) for 2-14 days, there were 20-40% decreases in plasma cholesterol, trigly cerides, phospholipids, and free fatty acids. Inhibition of liver HMG-CoTA reductase does not appear to account for the hypocholesterolemic effect, and activation of mitochondrial alpha-glycerophosphate dehydrogenase does not explain the hypotriglyceridemic action. Kinetic measurements of the serum appearance and disappearance of triglycerides in drug-treated rats suggest that the hypotriglyceridemic activity is due to a net inhibition of hepatic triglyceride synthesis. Reduction of very low density lipoprotein (VLDL) and high density lipoprotein (HDL) levels in rats with sucrose-induced hyperlipidemia and normalization of the altered apolipoprotein profiles are in accord with the effects of halofenate on plasma triglyceride and cholesterol levels. The reduced insulin-to-glucagon ratio observed in Zucker obese hyperlipemic rats is also consistent with halofenat's hypotriglyceridemic activity. Preliminary experiments in rats on the mechanism of its hypoglycemic activity, observed in some diabetic hyperlipidemic patients, indicate that halofenate acts differently than conventional oral hypoglycemic agents. Some, but not all, of the effects of halofenate were observed with clofibrate at two to ten times higher levels.
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PMID:Studies on the mechanism of action of halofenate. 31 18

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

The mechanisms through which Ca2+ mobilization in rat hepatocytes results in the loss of total activity of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase [Zammit & Caldwell (1990) Biochem. J. 269, 373-379] were investigated. The loss of total activity was shown to be paralleled by an equal loss of immunoreactive HMG-CoA reductase protein after exposure of hepatocytes to optimal concentrations of vasopressin plus glucagon for 40 min. This loss of enzyme protein was due to an inhibition of enzyme synthesis; the rate of degradation was unaffected. Other Ca(2+)-mobilizing conditions (phenylephrine, glucagon, vasopressin added singly and A23187) also resulted in graded inhibition of synthesis of HMG-CoA reductase. These effects were accentuated by omission of Ca2+ from the cell incubation medium, suggesting that it is the depletion of an intracellular InsP3-sensitive pool of Ca2+ to which synthesis of HMG-CoA reductase is sensitive. In agreement with this we found that t-butylhydroxybenzoquinone, which inhibits the activity of the Ca(2+)-ATPase of the endoplasmic-reticular membrane, mimicked the action of Ca(2+)-mobilizing hormones. However, taurolithocholate, which transiently mobilizes Ca2+ from the same pool, was ineffective. All these effects on HMG-CoA reductase were accompanied by parallel inhibition of 35S incorporation from [35S]methionine into total protein, suggesting that inhibition of reductase synthesis formed part of a generalized response of the hepatocyte to Ca2+ mobilization. Inhibition of the rate of synthesis of HMG-CoA reductase was, however, more responsive to Ca2+ mobilization in the absence of added Ca2+ from the extracellular medium. The concentrations of vasopressin required to elicit the inhibition of synthesis of HMG-CoA reductase were of the same order as those that elicited activation of glycogen phosphorylase in hepatocytes.
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PMID:Rapid decrease in the expression of 3-hydroxy-3-methylglutaryl-CoA reductase protein owing to inhibition of its rate of synthesis after Ca2+ mobilization in rat hepatocytes. Inability of taurolithocholate to mimic the effect. 195 35

The roles of protein kinase C, Ca2+/calmodulin-dependent protein kinase and AMP-activated protein kinase in the phosphorylation of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase induced by Ca2(+)-mobilizing conditions in isolated hepatocytes were investigated. Only partial evidence for the involvement of AMP-activated kinase was found. Antagonism of calmodulin action prolonged the decrease in expressed/total activity ratio induced by vasopressin plus glucagon. Protease inhibitors active against Ca2(+)-dependent cytosolic proteases or lysosomal proteolysis did not attenuate the loss of total HMG-CoA reductase induced by glucagon plus vasopressin, but calmodulin antagonists largely prevented this effect.
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PMID:The roles of different protein kinases and of calmodulin in the effects of Ca2+ mobilization on 3-hydroxy-3-methylglutaryl-CoA reductase activity in isolated rat hepatocytes. 199 Oct 44

The development and hormonal regulation of thioredoxin and of the thioredoxin-reductase system were investigated during the perinatal period in rat liver. An immunological procedure was developed in order to quantify thioredoxin in fetal and neonatal hepatocytes. Both immunoreactive thioredoxin and thioredoxin-reductase activity appeared on day 16.5 of pregnancy. The level of immunoreactive thioredoxin increased during the late fetal period, and its level was the same 24 h after birth. Moreover, its development was not subjected to hormonal regulation by corticosteroids and glucagon. In contrast, thioredoxin-reductase activity increased 3 times during the late fetal period and presented a marked increase 24 h after birth. In the absence of glucocorticoids there was no increase in the level of thioredoxin reductase, while administration of hydrocortisone acetate and glucagon to fetuses prematurely evoked its activity. This study suggests that if thioredoxin acts physiologically, this activity is related to the state of reduction of the molecule rather than to the total concentration in the liver.
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PMID:Development and hormonal control of thioredoxin and the thioredoxin-reductase system in the rat liver during the perinatal period. 204 6

We investigated the effects of conditions that induce Ca2+ mobilization from intracellular stores and Ca2+ influx into hepatocytes on the expressed and total (fully dephosphorylated) activities of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase. Vasopressin and phenylephrine when added alone had small or negligible effects on the phosphorylation state of the enzyme, as judged from the expressed/total activity ratio. However, when added in combination with glucagon, they elicited appreciable increases in the phosphorylation of the enzyme. Glucagon on its own had no effect either on phosphorylation state or on total HMG-CoA reductase activity during 40 min of incubation. Under conditions of sustained Ca2+ influx (i.e. vasopressin or phenylephrine plus glucagon), there was a marked loss of total HMG-CoA reductase activity. This effect was more pronounced when vasopressin was used; 50% of the enzyme activity was lost within 40 min. The involvement of Ca2+ in these effects was verified directly by the use of ionophore A23187. Its addition to hepatocytes resulted both in a very pronounced increase in the phosphorylation state of the enzyme and in the loss of 50% of the total activity within 30 min. There was no correlation between the ability of any set of conditions to increase the phosphorylation of the enzyme and the subsequent loss of total HMG-CoA reductase activity. The latter parameter appeared to be directly related, however, to the maintenance of prolonged Ca2+ influx, as indicated by the continued activation of glycogen phosphorylase, measured in the same cells. The lack of a causal relationship between increased phosphorylation and loss of total activity was demonstrated directly by studies in which okadaic acid was used to induce phosphorylation of HMG-CoA reductase in hepatocytes by inhibition of phosphatase 1 and 2A activities. This was not accompanied by any loss of total enzyme activity. Neither did okadaic acid enhance the loss of reductase induced by A23187 when the two agents were added together. It is concluded that altered Ca2+ fluxes in hepatocytes in vivo, under conditions of acute or chronic stress (such as may be associated with trauma or diabetes respectively), may be involved in the regulation of the expression of HMG-CoA reductase activity through alteration of enzyme concentration in the liver.
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PMID:Conditions that result in the mobilization and influx of Ca2+ into rat hepatocytes induce the rapid loss of 3-hydroxy-3-methylglutaryl-CoA reductase activity that is not reversed by phosphatase treatment. 216 66

Plasma membranes were purified from deciduoma of pseudopregnant rats and rat liver. Preparations contained 80% plasma membrane-derived material as based on electron microscope morphometry and analysis of enzyme markers. Several plasma membrane enzymes were tested for direct response to hormones. NADH-ferricyanide reductase of plasma membranes from both tissues was stimulated by glucagon and inhibited by insulin but was unresponsive to steroids. For steroids, responsiveness was limited to a reduction in NaF-stimulated adenylate cyclase activity by the steroid R5020. Thus, interaction of steroid hormones with plasma membranes, unlike that of glucagon and insulin, is not reflected in an altered activity of plasma membrane-bound dehydrogenases but may be exerted directly on adenylate cyclase.
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PMID:Hormone regulated enzyme activities of plasma membrane of decidual endometrium of the rat. 220 37


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