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 mRNA of the rat hepatic S14 gene accumulates rapidly after administration of T3 and carbohydrate, making it an excellent model for studies of the effects of dietary and hormonal stimuli at the hepatocellular level. We undertook studies to assess circadian changes in responsivity of this sequence to intragastric sucrose administration combined with insulin injection, and evaluated the capacity of glucagon to reverse these effects. As in the case of T3, the response of mRNA-S14 to carbohydrate in the morning was brisk whereas there was no significant increment when the stimulus was applied in the evening. In confirmation of previous studies, glucagon markedly lowered levels of mRNA-S14 in the evening but exerted no effect in the morning. These results support the concept that the rate of hepatic production of mRNA-S14 in unmanipulated rats is maximal in the evening, thus allowing no further induction by carbohydrate or T3 but permitting reduction by glucagon. Conversely, the rate of production is minimal in the morning, permitting induction by carbohydrate or T3 but allowing no further reduction by glucagon. A major difference between the effects of carbohydrate and those of T3 was the observed failure of carbohydrate to reverse the effect of glucagon in the evening. The effect of glucagon was stimulated by (Bu)2cAMP, and this was reversed by T3. However, T3 did not modify the glucagon-induced increase in hepatic cAMP levels. We therefore conclude that the capacity of T3 to abolish the glucagon effect is mediated at a step distal to the generation of cAMP.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Interaction of dietary carbohydrate and glucagon in regulation of rat hepatic messenger ribonucleic acid S14 expression: role of circadian factors and 3',5'-cyclic adenosine monophosphate. 285 12

The rapid response of hepatic mRNA-S14 to T3 has made this sequence an important model for studying the mechanism of hormonal induction of gene expression. In previous studies we showed, in the intact rat, that glucagon administration during the peak of the mRNA S14 diurnal rhythm causes a monoexponential fall in the level of mRNA-S14, and that T3 reverses this effect. We have now defined more precisely the mechanism governing this interaction. Measurement of in vitro nuclear transcriptional rates shows that T3 can reverse the glucagon-induced reduction of mRNA-S14 transcription. Reversal can be demonstrated within 5 min after the iv injection of T3. Further, the reversal appears to be related to the occupation of specific nuclear receptors, as inferred from the calculated nuclear occupancy and the effects of various iodothyronine analogs of T3. These results suggest that the effects of T3 are mediated by varying rates of production of the nuclear precursor and not by its stabilization, as previously proposed. Ancillary evidence supporting this conclusion came from the demonstration that the apparent t1/2 of the 4.5-kilobase precursor was not prolonged by T3.
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PMID:Triiodothyronine rapidly reverses inhibition of S14 gene transcription by glucagon. 316 21

The mechanisms of the responses of an enzyme to different hormones and metabolites or several enzymes to a single hormone are surprisingly varied. There is neither an operon for lipogenic enzymes nor a common step at which hormones and metabolites coordinately regulate the expression of lipogenic genes. In bacteria, coordinated expression of several enzymes in a single metabolic pathway often is achieved by organizing the genes into operons. An operon is a group of genes linked together in a linear fashion and producing a polycistronic mRNA. Trans-acting factors regulate the transcription of these genes by interacting with promoter/regulatory sequences in the 5'-flanking region of the most 5'-ward of the genes. In vertebrate animals, however, coordinated control of gene transcription is not achieved by linking the individual genes, but by putting in the 5'-flanking regions of these genes a regulatory sequence that interacts with common trans-acting factors. Genes controlled by different hormones are expected to have regulatory elements for each hormone. The presence of glucocorticoid and cyclic AMP regulatory elements at the 5'-end of the PEPCK gene is consistent with this notion. Transcription is not the only step at which hormones and metabolites control the pathways for gene expression. The levels of the mRNAs for L-PK, ME, S11, and S14 are increased by T3 at post-transcriptional steps. Glucagon also regulates the accumulation of ME mRNA post-transcriptionally. Neither the mechanism nor the sequence organization of regulatory elements is known for post-transcriptional control of gene expression. In the case of PEPCK and HMG-CoA reductase, the next steps will be to determine more precisely the sequences in the 5'-region that mediate hormone sensitivity and feedback inhibition, respectively, and whether trans-acting factors are involved. For the other genes discussed, identification of the regulated step must precede identification of sequences that confer hormone or metabolite-sensitive regulation on a specific gene. In general, it is probable that the hybrid gene approach, so successful for PEPCK and HMG-CoA reductase, also will be effective in defining cis-acting hormone- or metabolite-regulatory elements in other genes. These techniques should be applicable to both transcriptional and post-transcriptional mechanisms. Our long-term objective is to understand the molecular basis of each event that intervenes between the binding of hormone or metabolite to its appropriate receptor and altered enzyme level.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Dietary regulation of gene expression: enzymes involved in carbohydrate and lipid metabolism. 330 Jul 31

We have studied the effect of glucagon on the expression of a triiodothyronine (T3) and carbohydrate-inducible mRNA sequence (mRNA-S14) in rat liver that undergoes a threefold diurnal variation (peak, 2200 h; nadir, 0800 h). Glucagon injection into euthyroid rats (25 micrograms/100 g body wt i.p., three doses at 15-min intervals) during the nocturnal plateau of mRNA-S14 caused a monoexponential disappearance of this sequence (t1/2, 90 min) accompanied by a 90% reduction in the transcriptional rate in a nuclear run-off assay, indicative of a near total reduction of synthesis. This effect was markedly attenuated in rats treated with T3 (200 micrograms/100 g body wt i.p.) 24 h before glucagon injection. When T3 was given 15 min after glucagon, the glucagon-initiated decline in mRNA-S14 was reversed within 90 min, suggesting a rapid interaction between the two hormones in the evening. Curiously, administration of T3 alone at this hour did not affect a significant increase in mRNA-S14. At 0800 h, however, T3 caused the expected brisk induction of this sequence, whereas glucagon was without effect. In essence, glucagon affected mRNA-S14 synthesis only in the evening, while T3 increased levels of this sequence above the baseline only in the morning. T3, however, reversed the effect of prior glucagon injection at night. The observed alterations in hormonal responsivity could underly the diurnal variation of mRNA-S14 expression. Moreover, the data suggest the hypothesis that T3 may act on S14 gene expression by antagonizing factors that inhibit its transcription.
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PMID:Opposing effects of glucagon and triiodothyronine on the hepatic levels of messenger ribonucleic acid S14 and the dependence of such effects on circadian factors. 376 Jan 85

We have investigated in normal subjects the possible role of plasma free fatty acids (FFA) and blood ketone bodies (KB) in the regulation of human somatostatin secretion. Heparin injected during the intravenous infusion of a fat emulsion raised FFA levels acutely from 0.4 +/- 0.1 to near 3 mmol/L. Plasma somatostatin-like immunoreactivity (SLI) rose from a mean (+/- SEM) basal value of 9.2 +/- 1.0 ng Eq S14/L to 20.0 +/- 6.0 ng Eq S14/L (P less than 0.05). Plasma immunoreactive insulin (IRI) level was unchanged and glucagon (IRG) concentration decreased from 156 +/- 20 to 107 +/- 2 ng/L (P less than 0.05). During this test, there was a rise not only in FFA but also in plasma triglycerides (TG) and in blood glycerol and KB levels. The infusion of a fat emulsion alone increased triglyceride and glycerol levels to a similar extent but induced also a mild rise of FFA (0.37 +/- 0.05 to 1.13 +/- 0.5 mmol/L, P less than 0.01), KB (78 +/- 12 to 360 +/- 45 mumol/L, P less than 0.01), and SLI (14.8 +/- 4.6 to 23.8 +/- 7.1 ng Eq S14/L, P less than 0.05). The induction by DL-Na-3-hydroxybutyrate infusion of a rise of KB was associated with a decrease of FFA (P less than 0.05) and SLI (P less than 0.05) without modification of IRI or IRG levels. Phentolamine infusion did not modify the SLI or glucagon response to acute elevations of FFA, whereas propranolol suppressed the increase of SLI without preventing the concomitant decrease of IRG.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of somatostatin secretion in man: study of the role of free fatty acids and ketone bodies. 614 47

The transcription of genes encoding proteins involved in the hepatic synthesis of lipids from glucose is strongly stimulated by carbohydrate feeding. It is now well established that in the liver, glucose is the main activator of the expression of this group of genes, with insulin having only a permissive role. While ADD1/SREBP-1 has been implicated in lipogenic gene expression through temporal association with food intake and ectopic gain-of-function experiments, no genetic evidence for a requirement for this factor in glucose-mediated gene expression has been established. We show here that the transcription of ADD1/SREBP-1c in primary cultures of hepatocytes is controlled positively by insulin and negatively by glucagon and cyclic AMP, establishing a link between this transcription factor and carbohydrate availability. Using adenovirus-mediated transfection of a powerful dominant negative form of ADD1/SREBP-1c in rat hepatocytes, we demonstrate that this factor is absolutely necessary for the stimulation by glucose of L-pyruvate kinase, fatty acid synthase, S14, and acetyl coenzyme A carboxylase gene expression. These results demonstrate that ADD1/SREBP-1c plays a crucial role in mediating the expression of lipogenic genes induced by glucose and insulin.
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PMID:ADD1/SREBP-1c is required in the activation of hepatic lipogenic gene expression by glucose. 1020 99