Short‐term hormonal control of hepatic carbohydrate and lipid catabolism

Hems, Douglas A.

doi:10.1016/0014-5793(77)80449-3

Cited by 59 publications

(24 citation statements)

References 58 publications

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“…The methodology developed for this study of glucagon action is equally applicable to the study of other hormones which acutely regulate hepatic fatty acid synthesis, i. e. insulin [45,46], a-agonists [40], vasopressin [47,48] and angiotensin I1 [49,50]. The mechanism of action of these other hormones is not well understood for any metabolic pathway and it is hoped that the regulation of acetyl-CoA carboxylase will prove to be a useful system with which to elucidate these mechanisms.…”

Section: Discussionmentioning

confidence: 99%

Glucagon inhibits fatty acid synthesis in isolated hepatocytes via phosphorylation of acetyl-CoA carboxylase by cyclic-AMP-dependent protein kinase

1984

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If isolated rat hepatocytes are preincubated for 90 min before addition of hormone, glucagon causes a significant (50 %) decrease in fatty acid synthesis without concomitant large decreases in the cellular content of the allosteric activator, citrate. We present evidence that this inhibition can be entirely accounted for by the phosphorylation of the rate-limiting enzyme, acetyl-CoA carboxylase, by cyclic-AMP-dependent protein kinase. In particular : (1) the effect is associated with a 50 % decrease in acetyl-CoA carboxylase activity (measured at physiological citrate concentration) which survives purification of the enzyme; (2) the effect is associated with a selective increase in the phosphorylation of a chymotryptic peptide (peptide 1) which is identical to the peptide containing the major site phosphorylated on purified acetyl-CoA carboxylase by cyclic-AMP-dependent protein kinase ; (3) the effects of glucagon on the kinetic parameters of the enzyme are very similar to the effect of phosphorylation of the purified enzyme, i.e. a decrease in V and an increase in K, for citrate; and (4) all of these effects occur at physiological concentrations of glucagon identical to those producing inhibition of fatty acid synthesis.The main function of fatty acid synthesis in mammals is the conversion of excess carbohydrate into fat, which provides a more concentrated store of energy for long-term utilization. During starvation, carbohydrate must be spared for more critical needs, such as the supply of glucose to the brain. It has been known for some years that glucagon, which is released on starvation, inhibits fatty acid synthesis in the liver [1,2] and that this correlates with a decreased activity of hepatic acetylCoA carboxylase [3,4]. However, the mechanism of this inhibition has not been clear. Acetyl-CoA carboxylase is subject to allosteric regulation, being completely dependent on the fatty acid precursor, citrate, for activity, and being potently inhibited by the end product, long-chain acyl-CoA [5]. Watkins et al. [6] reported that glucagon dramatically inhibited fatty acid synthesis in isolated chicken hepatocytes, and this correlated with a 90% decrease in cytosolic citrate levels. More recently, it has been proposed that phosphorylation of acetyl-CoA carboxylase is an important mechanism of regulation of fatty acid synthesis. This was first suggested by experiments with partially purified rat liver acetyl-CoA carboxylase [7] and our laboratories have now shown that the homogeneous rat mammary [8] and rat liver [9] enzymes can be phosphorylated and inactivated by cyclic-AMP-dependent protein kinase, both effects being reversed by addition of purified protein phosphatase. We have also characterized the protein phosphatases in rat liver which catalyze the dephosphorylation and reactivation [lo].Acetyl-CoA carboxylase becomes labelled when isolated rat [4] and chicken [Ill hepatocytes are incubated with [32P]phosphate. However, while glucagon clearly stimulates this phosphorylation in rat hepatocytes [4], i...

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Section: Discussionmentioning

confidence: 99%

Glucagon inhibits fatty acid synthesis in isolated hepatocytes via phosphorylation of acetyl-CoA carboxylase by cyclic-AMP-dependent protein kinase

1984

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“…The above hormones can exert catabolic effects on lipid metabolism [2] and on other processes in liver, so it is important to gain further insight into their mechanism of action and their effects on nucleotide levels in liver. As angiotensin II does not produce a stable activation of phosphorylase kinase in liver [ 1 l] it should follow that this hormone does not increase liver cyclic-AMP content.…”

Section: Introductionmentioning

confidence: 99%

Effect of hormones on content of purine nucleoside cyclic monophosphates in perfused rat liver

Hems

Davies²,

Siddle³

1978

FEBS Letters

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“…Several in vitro hepatocyte studies have shown that angiotensin II stimulates glycogen phosphorylase activity (4)(5)(6) and gluconeogenesis (7)(8)(9)(10). Recently, we have shown that RAS involvement in blood glucose regulation is of physiological significance, with angiotensin II producing a dose-dependent hyperglycemic response (1).…”

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confidence: 99%

The hyperglycemia induced by angiotensin II in rats is mediated by AT1 receptors

Machado

Marubayashi

Reis

et al. 1998

Braz J Med Biol Res

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We have shown that the renin-angiotensin system (RAS) is involved in glucose homeostasis during acute hemorrhage. Since almost all of the physiological actions described for angiotensin II were mediated by AT 1 receptors, the present experiments were designed to determine the participation of AT 1 receptors in the hyperglycemic action of angiotensin II in freely moving rats. The animals were divided into two experimental groups: 1) animals submitted to intravenous administration of angiotensin II (0.96 nmol/100 g body weight) which caused a rapid increase in plasma glucose reaching the highest values at 5 min after the injection (33% of the initial values, P<0.01), and 2) animals submitted to intravenous administration of DuP-753 (losartan), a nonpeptide antagonist of angiotensin II with AT 1 -receptor type specificity (1.63 µmol/100 g body weight as a bolus, iv, plus a 30-min infusion of 0.018 µmol 100 g body weight -1 min -1 before the injection of angiotensin II), which completely blocked the hyperglycemic response to angiotensin II (P<0.01). This inhibitory effect on glycemia was already demonstrable 5 min (8.9 ± 0.28 mM, angiotensin II, N = 9 vs 6.4 ± 0.22 mM, losartan plus angiotensin II, N = 11) after angiotensin II injection and persisted throughout the 30-min experiment. Controls were treated with the same volume of saline solution (0.15 M NaCl). These data demonstrate that the angiotensin II receptors involved in the direct and indirect hyperglycemic actions of angiotensin II are mainly of the AT 1 -type. Key wordsIn addition to affecting fluid volume, electrolytes and hemodynamic states, the renin-angiotensin system (RAS) is also involved in the regulation of metabolic and endocrine function, especially blood glucose homeostasis (1-3). Several in vitro hepatocyte studies have shown that angiotensin II stimulates glycogen phosphorylase activity (4-6) and gluconeogenesis (7-10). Recently, we have shown that RAS involvement in blood glucose regulation is of physiological significance, with angiotensin II producing a dose-dependent hyperglycemic response (1). In contrast, intravenous infusion of an angiotensin II peptide-analog antagonist, [1-sar,8-thr]-angiotensin II (sarthran), had an

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Short‐term hormonal control of hepatic carbohydrate and lipid catabolism

Cited by 59 publications

References 58 publications

Glucagon inhibits fatty acid synthesis in isolated hepatocytes via phosphorylation of acetyl-CoA carboxylase by cyclic-AMP-dependent protein kinase

Glucagon inhibits fatty acid synthesis in isolated hepatocytes via phosphorylation of acetyl-CoA carboxylase by cyclic-AMP-dependent protein kinase

Effect of hormones on content of purine nucleoside cyclic monophosphates in perfused rat liver

The hyperglycemia induced by angiotensin II in rats is mediated by AT1 receptors

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