Hepatic carbon flux after re-feeding. Hyperthyroidism blocks glycogen synthesis and the suppression of glucose output observed in response to carbohydrate re-feeding

Abstract

1. The work investigated hepatic glycogen synthesis and glucose output after the intragastric administration of glucose or glycerol or the provision of chow ad libitum to 48 h-starved euthyroid or hyperthyroid rats. 2. After glucose administration, glycogen synthesis via the indirect pathway [Newgard, Hirsch, Foster & McGarry (1983) J. Biol. Chem. 258, 8046-8052] occurred concomitantly with reversal of glucose flux across the liver and re-activation of pyruvate kinase in the euthyroid controls. Glycogen synthesis was decreased and net glucose output continued in the hyperthyroid rats, but normal re-activation of pyruvate kinase was observed. 3. Use of 3-mercaptopicolinate indicated that the glucose released from liver of hyperthyroid rats was synthesized from substrates metabolized via the gluconeogenic pathway. 4. Hepatic glycogen synthesis was also impaired in hyperthyroid rats after administration of glycerol or chow. Measurement of portal-minus-hepatovenous concentration differences and arterial glucose concentrations after the administration of glycerol in combination with 3-mercaptopicolinate indicated that flux from triose phosphate to glucose 6-phosphate was not decreased. 5. Inhibited glycogen synthesis after chow re-feeding was associated with accelerated re-activation of hepatic pyruvate dehydrogenase complex in the hyperthyroid rats. 6. The results indicate three distinct and independent actions of hyperthyroidism after re-feeding: (i) it inhibits the reversal of glucose flux across the liver normally observed in response to carbohydrate; (ii) it affects glycogen deposition at a site distal to glucose 6-phosphate; (iii) it allows more rapid re-activation of liver pyruvate dehydrogenase complex in response to a mixed diet.

The disposition of carbohydrate between glycogenesis, lipogenesis and oxidation in liver during the starved-to-fed transition

“…0.06 munit/ml at 2 h, a value which is subsequently maintained [21]. In view of the striking resemblance between the time courses of PDH reactivation in vitro [9] and in vivo in response to chow refeeding (the present study, and [4]), it is suggested that reactivation of hepatic PDH in vivo is mediated primarily via increased plasma insulin.…”

“…In vivo, in an investigation of the effects of experimental hyperthyroidism on the hepatic response to re-feeding, we observed re-activation of PDH in the euthyroid controls by 4 h after chow administration [4]. It might be expected that re-activation of hepatic PDH after re-feeding would be coupled to increased glycolysis, and would result in increased lipogenesis.…”

“…PDH complex (active form, PDHa) and citrate synthase activities were measured in freezeclamped liver extracts (see [14]). PDHa activities are expressed relative to citrate synthase, to correct for possible differences in mitochondrial extraction [4,8,14]. A unit of enzyme activity converts 1 ,umol of substrate into product/min at 30 'C.…”

“…2 and 3), and, although an increased L-pyruvate kinase activity [4,20,25] may permit significant flux from triose phosphate to pyruvate (particularly after 4 h, when phosphoenolpyruvate carboxykinase activity is decreased [26]), glycolysis from glucose 6-phosphate and flux through PDH may nevertheless be uncoupled. Consequently lactate and pyruvate derived from glycolysis in extrahepatic tissues rather than in the liver (but see [20]) may be used as oxidative substrate.…”

“…Consequently the predominant direction of carbon flux is towards gluconeogenesis rather than glycolysis, and to fat oxidation rather than synthesis. This pattern continues to be observed immediately after re-feeding, except that the gluconeogenic product (glucose 6-phosphate) is directed towards glycogen synthesis, not glucose output [1][2][3][4][5]. The maintenance of the metabolic profile is facilitated by a failure to restore fructose 2,6-bisphosphate (Fru-2,6-P2) and malonyl-CoA concentrations [6,7], continued inactivation of hepatic pyruvate dehydrogenase (PDH) [8], increased CPT 1 activity [3] and decreased sensitivity of CPT 1 to inhibition by malonyl-CoA [3].…”