Regulation by insulin and free fatty acids of pyruvate dehydrogenase activity in perfused rat liver [proceedings

Abstract

An inverse logarithmic relationship has been observed in the perfused liver between the synthesis of long-chain fatty acids (lipogenesis) and serum free (non-esterified) fatty acid concentration (Mayes & Topping, 1974; Topping & Mayes, 1976). This diminution in lipogenesis with increasing concentrations of free fatty acid is similar to the diminution that is observed in active liver pyruvate dehydrogenase (Wieland et al., 1972) in the presence of free fatty acids, and it was proposed that changes in activity of this enzyme might be a regulatory point in the supply of acetyl-CoA for hepatic lipogenesis (Mayes T Jaworek et al., 1974). Perfusate free fatty acids and ketone bodies were assayed as described previously (Topping & Mayes, 1972). In both control and insulin-infused livers there was a significant (P<O.OI) inverse logarithmic relationship between perfusate free fatty acid concentrations and pyruvate dehydrogenase a activity. In control livers at low (0.2pmol of free fatty acid/ml of serum) concentrations, enzyme activity was maximal, at approx. 0.4unit/g of liver. With increasing concentrations of free fatty acid, pyruvate dehydrogenase a activity fell until, at 0.9pmol of free fatty acid/ml of serum, enzyme activity was only 0.1 unit/g of liver. Infusion of insulin increased pyruvate dehydrogenase a activity, and it was shown by the matched-pairs ‘t’ test that for any given concentration of free fatty acid, enzyme activity was significantly raised by insulin (P<O.l). This increase averaged 66 % over the whole range of fatty acid concentrations used. Pyruvate dehydrogenase a activity, as a fraction of total enzyme activity, was also significantly (Pi0.05) raised by insulin. In the absence of infused oleate, total liver adenine nucleotides were approx. 4.7pmol/g of liver and the ratio [ATP]/[AMP] was 6.5. With increasing free fatty acid concentrations, total adenine nucleotides decreased significantly (P<O.O5) and [ATP]/[AMP] rose (P<O.OOl). Pyruvate dehydrogenase a activity correlated negatively with the latter ratio (P<O.OOl) and with the ratio [ATP]/[ADP] (PiO.01). Production of ketone bodies was significantly (P <0.05) raised by oleate infusion, but decreased by insulin (P <0.05).