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Original Articles

Long-Chain Fatty Acids Inhibit Acetyl-CoA Carboxylase Gene Expression in the Pancreatic β-Cell Line INS-1

  1. Thierry Brun,
  2. Françhise Assimacopoulos-Jeannet,
  3. Barbara E Corkey and
  4. Marc Prentki
  1. Molecular Nutrition Unit, Department of Nutrition, University of Montreal Medical School Montreal, Quebec, Canada
  2. Département de Biochimie Médicale, Centre Médicale Universitaire, University of Geneva Geneva, Switzerland
  3. Division of Diabetes and Metabolism, Boston University Medical School Boston, Massachusetts
  1. Address correspondence and reprint requests to Dr. R.A. Rizza, Endocrine Research Unit, Mayo Clinic, 200 First St. S.W., Rochester, MN 55905.
Diabetes 1997 Mar; 46(3): 393-400. https://doi.org/10.2337/diab.46.3.393
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Abstract

The mechanism whereby long-term exposure of the β-cell to fatty acids alters the β-cell response to glucose is not known. We hypothesized that fatty acids may alter β-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 β-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); longchain ω3 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 β-cell insensitivity to glucose, i.e., by downregulating ACC with a resulting exaggerated fatty acid oxidation.

  • Received June 25, 1996.
  • Revision received October 31, 1996.
  • Accepted October 31, 1996.
  • Copyright © 1997 by the American Diabetes Association
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March 1997, 46(3)
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Long-Chain Fatty Acids Inhibit Acetyl-CoA Carboxylase Gene Expression in the Pancreatic β-Cell Line INS-1
Thierry Brun, Françhise Assimacopoulos-Jeannet, Barbara E Corkey, Marc Prentki
Diabetes Mar 1997, 46 (3) 393-400; DOI: 10.2337/diab.46.3.393

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Long-Chain Fatty Acids Inhibit Acetyl-CoA Carboxylase Gene Expression in the Pancreatic β-Cell Line INS-1
Thierry Brun, Françhise Assimacopoulos-Jeannet, Barbara E Corkey, Marc Prentki
Diabetes Mar 1997, 46 (3) 393-400; DOI: 10.2337/diab.46.3.393
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