Essential role of acetyl-CoA carboxylase in the glucose-induced insulin secretion in a pancreatic beta-cell line.
The current model of the nutrient sensing mechanism in pancreatic beta-cells implies that malonyl-CoA plays a key role. According to this hypothesis, glucose activation of acetyl-CoA carboxylase triggers a rapid production of malonyl-CoA which inhibits carnitine palmitoyltransferase 1 and the importation of fatty acyl-CoA into the mitochondria for oxidation. The increase in cytosolic long chain fatty acyl-CoA leads to the exocytosis of insulin by a mechanism which has not yet been clearly defined. To obtain direct evidence that ACC plays a central role in this process, we generated stable transfectants of an insulin secreting cell line (INS-1) that express ACC specific antisense mRNA. The amounts of ACC mRNA and the protein level were specifically decreased in these stable clones compared to those of the control cells. The glucose activation of ACC in these cells was also significantly diminished. Both acute and long-term induction of insulin secretion by glucose were decreased. This decrease was inversely correlated to the levels of ACC activity in clones. In these clones, the insulin secretion induced by other nutrients, amino acids and ketocaproate, is also impaired, while the KCl-induced insulin secretion remains unchanged. Decreased ACC expression was accompanied by impaired malonyl-CoA production and elevated fatty acid oxidation. The expressions of the pancreatic specific glucokinase, glucose transporter 2 or beta-actin in these cells, as well as glucose utilisation were not affected, suggesting that the effect of the expression of the ACC mRNA specific gene on insulin secretion is specifically related to the decrease in the amount of ACC gene products. These results provide direct evidence of a causal relationship between ACC and insulin secretion.
Zhang
S
S
Department of Biochemistry, Purdue University, West Lafayette, IN 47907, USA.
Kim
K H
KH
D000103:Acetyl-CoA Carboxylase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002460:Cell Line; D005227:Fatty Acids / Q000378:metabolism; D015870:Gene Expression; D005947:Glucose / Q000502:physiology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000378:metabolism*; D008316:Malonyl Coenzyme A / Q000378:metabolism; D010084:Oxidation-Reduction; D016372:RNA, Antisense; D012333:RNA, Messenger; D051381:Rats
D005227:Fatty Acids; D007328:Insulin; D016372:RNA, Antisense; D012333:RNA, Messenger; D008316:Malonyl Coenzyme A; D000103:Acetyl-CoA Carboxylase; D005947:Glucose