Fatty acid and amino acid modulation of glucose cycling in isolated rat hepatocytes

Biochem J. 2001 Sep 15;358(Pt 3):665-71. doi: 10.1042/0264-6021:3580665.


We studied the influence of glucose/glucose 6-phosphate cycling on glycogen deposition from glucose in fasted-rat hepatocytes using S4048 and CP320626, specific inhibitors of glucose-6-phosphate translocase and glycogen phosphorylase respectively. The effect of amino acids and oleate was also examined. The following observations were made: (1) with glucose alone, net glycogen production was low. Inhibition of glucose-6-phosphate translocase increased intracellular glucose 6-phosphate (3-fold), glycogen accumulation (5-fold) without change in active (dephosphorylated) glycogen synthase (GSa) activity, and lactate production (4-fold). With both glucose 6-phosphate translocase and glycogen phosphorylase inhibited, glycogen deposition increased 8-fold and approached reported in vivo rates of glycogen deposition during the fasted-->fed transition. Addition of a physiological mixture of amino acids in the presence of glucose increased glycogen accumulation (4-fold) through activation of GS and inhibition of glucose-6-phosphatase flux. Addition of oleate with glucose present decreased glycolytic flux and increased the flux through glucose 6-phosphatase with no change in glycogen deposition. With glucose 6-phosphate translocase inhibited by S4048, oleate increased intracellular glucose 6-phosphate (3-fold) and net glycogen production (1.5-fold), without a major change in GSa activity. It is concluded that glucose cycling in hepatocytes prevents the net accumulation of glycogen from glucose. Amino acids activate GS and inhibit flux through glucose-6-phosphatase, while oleate inhibits glycolysis and stimulates glucose-6-phosphatase flux. Variation in glucose 6-phosphate does not always result in activity changes of GSa. Activation of glucose 6-phosphatase flux by fatty acids may contribute to the increased hepatic glucose production as seen in Type 2 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Amides / pharmacology*
  • Amino Acids / pharmacology*
  • Animals
  • Antiporters
  • Cells, Cultured
  • Enzyme Inhibitors / pharmacology*
  • Fasting
  • Glucokinase / metabolism
  • Gluconeogenesis / drug effects
  • Gluconeogenesis / physiology*
  • Glucose / metabolism*
  • Glucose-6-Phosphate / metabolism
  • Hepatocytes / drug effects
  • Hepatocytes / metabolism*
  • Imidazoles / pharmacology*
  • Indoles / pharmacology*
  • Kinetics
  • Liver / cytology
  • Liver Glycogen / biosynthesis*
  • Male
  • Monosaccharide Transport Proteins
  • Oleic Acid / pharmacology*
  • Phosphorylase b / antagonists & inhibitors
  • Phosphotransferases / antagonists & inhibitors
  • Pyridines / pharmacology*
  • Rats
  • Rats, Wistar


  • Amides
  • Amino Acids
  • Antiporters
  • Enzyme Inhibitors
  • Imidazoles
  • Indoles
  • Liver Glycogen
  • Monosaccharide Transport Proteins
  • Pyridines
  • S 4048
  • Slc37a4 protein, rat
  • glucose 6-phosphate(transporter)
  • Oleic Acid
  • Glucose-6-Phosphate
  • Adenosine Triphosphate
  • Phosphorylase b
  • Phosphotransferases
  • Glucokinase
  • CP 320626
  • Glucose