Hepatic Accumulation of Metabolites After Fructose Loading

Abstract

Abstract. The changes in the metabolite content in freeze‐clamped livers of fed rats occurring on perfusion with 10 mM D‐fructose have been examined under aerobic and anaerobic conditions. During aerobic perfusion the main effects of fructose were an accumulation of fructose 1‐phosphate, as already known, up to 8.7 μmol/g of liver within 10 min, a loss of total adenine nucleotides (up to 35 % after 40 min) with a decrease in the ATP content to 23 % within 10 min, a seven‐fold rise in the concentration of IMP to 1.1 μmol/g and an eight‐fold rise of a‐glycerophosphate to 1.1 μmol/g. There was a transient decrease in Pi from 4.2 to 1.7 μmol/g. Within 40 min the Pi content recovered to the normal value. The content of lactate increased to 4.3 μmol/g at 80 min; pyruvate also increased and the [lactate]/[pyruvate] ratio remained within physiological limits. The concentration of free fructose within the liver remained much below that in the perfusion medium, indicating that the rate of penetration of fructose into the tissue was lower than the rate of utilisation. The fission of fructose 1‐phosphate by liver aldolase is inhibited by several phosphorylated intermediates, especially by IMP. This inhibition is competive with a Ki of 0.1 mM. The maximal rates of the enzyme synthesising and splitting fructose 1‐phosphate are about equal. The accumulation of fructose 1‐phosphate on fructose loading is due to the inhibition of the fission of fructose 1‐phosphate by the IMP arising from the degradation of the adenine nucleotides. When the conditions were anaerobic fructose was readily converted to lactate and the fructose 1‐phosphate content of the liver after 40 min rose to 5.5 μmol/g. The total adenine nucleotide content decreased to 1.74 μmol/g. The contents of a‐glycerophosphate and lactate were 4.3 μmol/g and 5.6 μmol/g respectively, the [lactate]/[pyruvate] increased to 53.

Dietary fructose in nonalcoholic fatty liver disease

“…Fructokinase action is 10 times faster than glucokinase and hexokinase, and fructose accumulates in the liver as fructose‐1‐phosphate 26. Perfusion studies of liver tissue show that this step is rapid enough to precipitate a depletion of adenosine triphosphate (ATP) content to 23%, although ATP recovers to normal within 40 minutes 27. Fructose‐1‐phosphate is converted into triose phosphates, which become substrates for gluconeogenesis or the downstream steps of glycolysis and DNL.…”