Long-chain fatty acids inhibit acetyl-CoA carboxylase gene expression in the pancreatic beta-cell line INS-1.
The mechanism whereby long-term exposure of the beta-cell to fatty acids alters the beta-cell response to glucose is not known. We hypothesized that fatty acids may alter beta-cell function by changing the expression level of metabolic enzymes implicated in the regulation of insulin secretion, in particular acetyl-CoA carboxylase (ACC). This enzyme catalyzes the formation of malonyl-CoA, a key regulator of fatty acid oxidation. Using the beta-cell line INS-1 as a model, the results show that the polyunsaturated fatty acid linoleate (C18:2) inhibited both basal and glucose-stimulated ACC mRNA induction. The inhibition was detected by 4-6 h, and a maximal 60% effect occurred at 12 h after cell exposure to the fatty acid. Linoleate, as glucose, did not modify the half-life of the ACC transcript. Prolonged exposure of INS-1 cells to linoleate also inhibited ACC protein accumulation at low and high glucose. The saturated fatty acids myristate (C14:0), palmitate (C16:0), and stearate (C18:0) were also effective as well as the monounsaturated oleate (C18:1) and the short-chain fatty acids butyrate (C4:0) and caproate (C6:0); long-chain omega3 fatty acids were ineffective. The threshold concentration for long-chain fatty acids was 0.05 mmol/l, and maximal inhibition occurred at 0.3 mmol/l. 2-bromopalmitate, a nonmetabolizable analog, had no effect, suggesting that fatty acids must be metabolized to change ACC gene expression. Prolonged exposure of INS-1 cells to palmitate, oleate, and linoleate markedly altered the glucose-induced insulin response, resulting in high basal insulin release and a suppression of glucose-induced insulin secretion. This was associated with an exaggerated (twofold to threefold) rate of fatty acid oxidation at all tested glucose concentrations. The data provide a possible mechanism to at least partially explain how fatty acids cause beta-cell insensitivity to glucose, i.e., by downregulating ACC with a resulting exaggerated fatty acid oxidation.
Brun
T
T
Department of Nutrition, University of Montreal Medical School, Quebec, Canada.
Assimacopoulos-Jeannet
F
F
Corkey
B E
BE
Prentki
M
M
D000103:Acetyl-CoA Carboxylase / Q000096:biosynthesis*; D000818:Animals; D002087:Butyrates / Q000494:pharmacology; D020148:Butyric Acid; D002208:Caproates / Q000494:pharmacology; D002460:Cell Line; D005230:Fatty Acids, Nonesterified / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D005947:Glucose / Q000494:pharmacology; D007515:Islets of Langerhans / Q000201:enzymology*; D007700:Kinetics; D019787:Linoleic Acid; D008041:Linoleic Acids / Q000494:pharmacology; D019814:Myristic Acid; D009227:Myristic Acids / Q000494:pharmacology; D019308:Palmitic Acid / Q000494:pharmacology; D013229:Stearic Acids / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects*
D002087:Butyrates; D002208:Caproates; D005230:Fatty Acids, Nonesterified; D008041:Linoleic Acids; D009227:Myristic Acids; D013229:Stearic Acids; D019814:Myristic Acid; D020148:Butyric Acid; D019308:Palmitic Acid; C031183:stearic acid; D019787:Linoleic Acid; D000103:Acetyl-CoA Carboxylase; D005947:Glucose