Glucose regulation of acetyl-CoA carboxylase in hepatoma and islet cells.
The regulation of acetyl-CoA carboxylase (ACC) by glucose and other fuel molecules has been examined in Fao Reuber hepatoma cells and Syrian hamster insulin tumor (HIT) cells in order to determine whether lipogenic substrates acutely alter ACC activity and to examine the mechanism of such regulation. In Fao cells, preincubated in simple medium without substrates, glucose addition results in a rapid activation of ACC. This effect, mimicked by other fuels such as lactate, is characterized by an increase in enzyme Vmax and a decrease in the activation constant for citrate. Several lines of evidence indicate that this activation of ACC is due to enzyme dephosphorylation, including the kinetic changes observed, the persistence of enzyme activation through ACC isolation, the necessity of inclusion of sodium fluoride/EDTA in the cell lysis buffer for preservation of the glucose-induced change, and the direct demonstration of diminished 32P-labeling of ACC after glucose exposure. Identical effects of glucose are also observed in HIT cells, although the ACC activation is smaller in magnitude and less sensitive than that observed in Fao cells. Other insulin secretagogues such as glutamine, lactate, and isobutylmethylxanthine are also found to activate HIT ACC. Others have suggested that glucose-induced changes in malonyl-CoA in beta-cells may be linked to glucose-induced insulin secretion. However, studies conducted in late passage HIT cells, which fail to secrete insulin in response to glucose stimulation, reveal the same glucose-induced activation seen in early passages, secretion-competent HIT cells, suggesting that glucose-induced ACC activation is not by itself sufficient to provoke insulin secretion. Taken together, these findings indicate that glucose and other fuel molecules can play a major role in the rapid regulation of the fatty acid synthesis pathway. The activation of fatty acid synthesis by substrate-induced ACC dephosphorylation insures ultimate fuel storage of glucose-derived carbon as fatty acid, while substrate-induced increases in the ACC product, malonyl CoA, would serve to simultaneously limit the rate of fatty acid oxidation through its allosteric regulation of carnitine palmitoyltransferase I.
Department of Medicine, Dartmouth Medical School, Hanover, New Hampshire 03756.
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Louis
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LA
Witters
D019325:3-O-Methylglucose; D000103:Acetyl-CoA Carboxylase / Q000378:metabolism*; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D001426:Bacterial Proteins / Q000378:metabolism; D015153:Blotting, Western; D002951:Citrates / Q000378:metabolism; D019343:Citric Acid; D006224:Cricetinae; D004591:Electrophoresis, Polyacrylamide Gel; D005947:Glucose / Q000378:metabolism*; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000201:enzymology*; D007700:Kinetics; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D008114:Liver Neoplasms, Experimental / Q000201:enzymology*; D008647:Mesocricetus; D008757:Methylglucosides / Q000378:metabolism; D010766:Phosphorylation; D051381:Rats; D019809:Streptavidin
D001426:Bacterial Proteins; D002951:Citrates; D007328:Insulin; D007773:Lactates; D008757:Methylglucosides; D019325:3-O-Methylglucose; D019343:Citric Acid; D019344:Lactic Acid; D019809:Streptavidin; D000469:Alkaline Phosphatase; D000103:Acetyl-CoA Carboxylase; D005947:Glucose