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Journal ArticleDOI

Short-term control of hepatic lipogenesis by insulin

01 Nov 1980-Trends in Biochemical Sciences (Elsevier)-Vol. 5, Iss: 11, pp 288-290
TL;DR: Evidence that insulin acutely affects carbohydrate and lipid metabolism in isolated rat hepatocytes is presented and a coherent picture emerges of the concerted mechanism by which insulin sets the stage for lipogenesis in the hepatocyte.
About: This article is published in Trends in Biochemical Sciences.The article was published on 1980-11-01 and is currently open access. It has received 10 citations till now. The article focuses on the topics: Lipogenesis & Insulin.

Summary (2 min read)

Mitochondrial function

  • Insulin activates pyruvate kinase TM but slightly, and significantly, lowers pyruvate concentrations in hepatocyte suspensions (Table II ).
  • This would suggest that activation of pyruvate kinase is not the overall rate-limiting step of the pathway of fatty acid synthesis in the liver.
  • One could explain this fall in pyruvate concentration by the activation of pyruvate dehydrogenase in mitochondria which, as the authors have shown, is increased upon treatment of the intact hepatocytes with insulin 15.

Triacylglycerol synthesis

  • Since long-chain acyl-CoA esters are potent inhibitors of both pyruvate dehydrogenase and acetyl-CoA carboxylase, lipogenesis is dependent upon the liver's capacity to dispose of these CoA esters.
  • Insulin stimulates fatty acid esterification in short-term incubations of rat hepatocytes 14, thereby preventing feedback inhibition of lipogenesis by long-chain acyl-CoA.
  • The stimulation of fatty acid esterification by insulin may be due to a combination of an activation of glycerolphosphate acyltransferase, as demonstrated in the perfused liver TM, and an elev-ation of the intraceilular concentration of glycerol 3-phosphate", the precursor for the glycerol backbone of the glycerolipids.
  • The microsome-bound diacylglycerol acyltransferase, the only enzyme in the pathway exclusively concerned with triacylglycerol synthesis, was recently found to be inhibited by glucagon 2°.
  • Whether insulin activates this enzyme remains to be established.

Interconversion of regulatory enzymes between active and inactive forms by phosphorylation-dephosphorylation cycles

  • Studies with partially purified enzyme systems have demonstrated that the six regulatory enzymes involved in the conversion of glucose into triacylglycerols are subject to short-term regulation by covalent modulation (for review, see Ref. 21 ).
  • Immediate changes in enzyme activity in vitro can be evoked by phosphorylation and dephosphorylation by protein kinases and phosphoprotein phosphatases, respectively.
  • Glucagon causes phosphorylation of hepatic phosphofructokinase 22, pyruvate kinase 28 and acetyl-CoA carboxylase ~8' ~a, which is accompanied by inactivation of these enzymes.
  • It is attractive to speculate that insulin via one common mechanism triggers the dephosphorylation of all the regulatory enzymes of lipogenesis.
  • Unfortunately, experimental evidence for this hypothesis is largely lacking at present.

Interrelationship between short-term hormonal control of lipogenesis and of the other major metabolic processes in the liver

  • It is now recognized that glycogen metabolism, gluconeogenesis, glycolysis, fatty acid oxidation , fatty acid synthesis, fatty acid esterification and cholesterogenesis are all coordinately regulated in the liver by short-term regulatory mechanisms.
  • This seems necessary in view of the possible operation of futile cycles © Elsevier/North-Holland Biomedical Press 1980 between glucose and glycogen and between acetyl-CoA and fatty acyI-CoA.
  • In isolated hepatocytes, insulin stimulates glycolysis (Table II ), fatty acid synthesis 5'1°, glycogen synthesis (Table II ), fatty acid esterification" and cholesterol synthesis ~.
  • On the other hand, fatty acid oxidation" and gluconeogenesis (Table II ) are depressed by insulin.
  • All these metabolic pathways are affected by glucagon in a manner opposite to that of insulin (for review see Ref. 21 ) .

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Citations
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Journal ArticleDOI
TL;DR: The fasted-to-fed transition of hepatic carbohydrate and lipid metabolism can be accomplished in vitro over a time frame similar to that operative in vivo, and the requirement for insulin in the reversal of the fasting state of liver metabolism in vivo can best be explained by its ability to offset the catabolic actions of glucagon.
Abstract: Studies were conducted to determine whether the direction of hepatic carbohydrate and lipid metabolism in the rat could be switched simultaneously from a "fasted" to a "fed" profile in vitro. When incubated for 2 h under appropriate conditions hepatocytes from fasted animals could be induced to synthesize glycogen at in vivo rates. There was concomitant marked elevation of the tissue malonyl-coenzyme A level, acceleration of fatty acid synthesis, and suppression of fatty acid oxidation and ketogenesis. In agreement with reports from some laboratories, but contrary to popular belief, glucose was not taken up efficiently by the cells and was thus a poor substrate for eigher glycogen synthesis or lipogenesis. The best precursor for glycogen formation was fructose, whereas lactate (pyruvate) was most efficient in lipogenesis. In both case the addition of glucose to the gluconeogenic substrates was stimulatory, the highest rates being obtained with the further inclusion of glutamine. Insulin was neither necessary for, nor did it stimulate, glycogen deposition or fatty acid synthesis under favorable substrate conditions. Glucagon at physiological concentrations inhibited both glycogen formation and fatty acid synthesis. Insulin readily reversed the effects of glucagon in the submaximal range of its concentration curve. The following conclusions were drawn. First, the fasted-to-fed transition of hepatic carbohydrate and lipid metabolism can be accomplished in vitro over a time frame similar to that operative in vivo. Second, reversal appears to be a substrate-driven phenomenon, in that insulin is not required. Third, unless an unidentified factor (present in protal blood during feeding) facilitates the uptake of glucose by liver it seems unlikely that glucose is the immediate precursor for liver glycogen or fat synthesis in vivo. A likely candidate for the primary substrate in both processes is lactate, which is rapidly formed from glucose by the small intestine and peripheral tissues. Fructose and amino acids may also contribute. Fourth, the requirement for insulin in the reversal of the fasting state of liver metabolism in vivo can best be explained by its ability to offset the catabolic actions of glucagon.

123 citations


Cites background from "Short-term control of hepatic lipog..."

  • ...sis in rat hepatocytes have also been reported (4, 32-34), but again were not of great magnitude....

    [...]

Journal ArticleDOI
TL;DR: It is concluded that the effects of insulin and glucagon on the overall process of triacylglycerol secretion are reflections of the hormone-determined rate of Triacyl Glycerol synthesis.

54 citations

Journal ArticleDOI
TL;DR: Findings suggest that insulin-induced increases in DAG may lead to increases in protein kinase C activity, and may explain some of the insulin-like effects of phorbol esters and vasopressin on hepatocyte metabolism.

50 citations

Journal ArticleDOI
TL;DR: The stimulation of glycolysis by insulin was investigated in monolayer cultures of adult rat hepatocytes and dexamethasone acted both as a long-term and short-term modulator, and the stimulatory effects of insulin may in part be attributed to the activated pyruvate kinase.
Abstract: Evidence for a direct metabolic effect of insulin in isolated liver preparations is scarce. The stimulation of glycolysis by insulin previously demonstrated in monolayer cultures of adult rat hepatocytes [(1982) Eur. J. Biochem. 126, 271-278] was further investigated. The degree of stimulation varied with the age of the culture and amounted to 250%, 200%, 500% and 200% of the control value using cells at the culture age of 2 h, 24 h, 48 h, and 72 h, respectively. Half-maximal dose of insulin was 0.1 nM. Maximal stimulation was reached within 5 min and lasted for at least 4 h. Dexamethasone acted both as a long-term and short-term modulator. Long-term pretreatment of the cells with dexamethasone proved necessary to permit insulin action. In addition to this permissive action, pretreatment with dexamethasone reduced the insulin-independent basal glycolytic rate. In short-term experiments dexamethasone decreased the basal glycolytic flux, however, it did not affect the absolute increase in glycolysis brought about by insulin. The half-maximal dose of dexamethasone was 10 nM. The stimulatory effects of insulin may in part be attributed to the activation of pyruvate kinase. Insulin produced a left-shift of the substrate saturation curve, decreasing the K0.5 value for phosphoenolpyruvate.

32 citations

Journal ArticleDOI
TL;DR: It is proposed that all of the drugs exert an inhibitory action at the level of acetyl-CoA carboxylase, the enzyme generally considered to catalyse the rate-limiting step in hepatic fatty acid synthesis.

15 citations

References
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Journal ArticleDOI
01 Sep 1979-Diabetes
TL;DR: Conditions for the isolation of rat hepatocytes that are responsive to insulin with regard to fatty acid synthesis were explored and the activity of acetyl-CoA carboxylase correlates with the rate of fatty acids synthesis, which in turn correlates withThe cellular level of malonyl-Coa.
Abstract: Conditions for the isolation of rat hepatocytes that are responsive to insulin with regard to fatty acid synthesis were explored. Cells prepared according to the procedure of Ingebretsen and Wagle require the presence of fetal calf serum for insulin expression. Cells isolated by the Seglen method are the preparation of choice, since they respond to insulin in a simple, well-defined medium and, moreover, show much higher basal rates of fatty acid synthesis. In the latter cells isolated from fed male rats, the rate of fatty acid synthesis, as determined by tritium incorporation from [3H]H2O at 37 degrees C, is enhanced within 30 min after addition of insulin to the incubation medium; with glucagon, it is depressed. In the presence of insulin, the cellular content of malonyl coenzyme A is noticeably increased, whereas the concentrations of pyruvate, lactate, and citrate are not markedly affected. Glucagon, on the other hand, decreases the concentrations of all four intermediates. The activity of acetyl-CoA carboxylase is stimulated and depressed after addition of insulin and glucagon, respectively. In all conditions tested, the activity of acetyl-CoA carboxylase correlates with the rate of fatty acid synthesis, which in turn correlates with the cellular level of malonyl-CoA.

118 citations

Journal ArticleDOI
TL;DR: The large size of the precursor of asparagine-linked oligosaccharides may be essential if certain proteins are to achieve the correct tertiary structure.

113 citations

Journal ArticleDOI
TL;DR: Phosphofructokinase appears to be phosphorylated in vivo by a cyclic AMP-dependent protein kinase, which renders the enzyme significantly more sensitive to ATP inhibition and exhibits considerably lower activity than the unphosphorylated enzyme.

112 citations

Journal ArticleDOI
TL;DR: The potency of the stimulatory effects of vasopressin and angiotensin on hepatic gluconeogenesis suggests they are operative in vivo and Ca2+ plays a role in the stimulation by these hormones.
Abstract: 1. In hepatocytes from starved rats, vasopressin, angiotensin (angiotensin II) and oxytocin stimulated gluconeogenesis from lactate by 25--50%; minimal effective concentrations were about 0.02pM, 1 nM and 0.2 nM respectively. 2. Vasopressin and angiotensin also stimulated gluconeogenesis from alanine, pyruvate, serine and glycerol. EGTA decreased gluconeogenesis from these substrates. 3. Hormonal stimulation of gluconeogenesis from lactate was abolished in the absence of extracellular Ca2+. 4. Insulin did not prevent stimulation of gluconeogenesis by vasopressin or angiotensin. 5. The potency of the stimulatory effects of vasopressin and angiotensin on hepatic gluconeogenesis suggests they are operative in vivo. Also, the data suggest that Ca2+ plays a role in the stimulation by these hormones.

111 citations

Journal ArticleDOI
TL;DR: Rat hepatic pyruvate kinase (type L) has been purified to homogeneity by a simple, rapid procedure involving DEAE-cellulose chromatography and elution from a blue Sepharose column and the hypothesis that glucagon regulates pyruVate Kinase activity, at least in part, by a phosphorylation mechanism is supported.

107 citations