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Chronic suppression of acetyl-CoA carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism.

Publication ,  Journal Article
Ronnebaum, SM; Joseph, JW; Ilkayeva, O; Burgess, SC; Lu, D; Becker, TC; Sherry, AD; Newgard, CB
Published in: J Biol Chem
May 23, 2008

Acetyl-CoA carboxylase 1 (ACC1) currently is being investigated as a target for treatment of obesity-associated dyslipidemia and insulin resistance. To investigate the effects of ACC1 inhibition on insulin secretion, three small interfering RNA (siRNA) duplexes targeting ACC1 (siACC1) were transfected into the INS-1-derived cell line, 832/13; the most efficacious duplex was also cloned into an adenovirus and used to transduce isolated rat islets. Delivery of the siACC1 duplexes decreased ACC1 mRNA by 60-80% in 832/13 cells and islets and enzyme activity by 46% compared with cells treated with a non-targeted siRNA. Delivery of siACC1 decreased glucose-stimulated insulin secretion (GSIS) by 70% in 832/13 cells and by 33% in islets. Surprisingly, siACC1 treatment decreased glucose oxidation by 49%, and the ATP:ADP ratio by 52%, accompanied by clear decreases in pyruvate cycling activity and tricarboxylic acid cycle intermediates. Exposure of siACC1-treated cells to the pyruvate cycling substrate dimethylmalate restored GSIS to normal without recovery of the depressed ATP:ADP ratio. In siACC1-treated cells, glucokinase protein levels were decreased by 25%, which correlated with a 36% decrease in glycogen synthesis and a 33% decrease in glycolytic flux. Furthermore, acute addition of the ACC1 inhibitor 5-(tetradecyloxy)-2-furoic acid (TOFA) to beta-cells suppressed [(14)C]glucose incorporation into lipids but had no effect on GSIS, whereas chronic TOFA administration suppressed GSIS and glucose metabolism. In sum, chronic, but not acute, suppression of ACC1 activity impairs GSIS via inhibition of glucose rather than lipid metabolism. These findings raise concerns about the use of ACC inhibitors for diabetes therapy.

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Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

May 23, 2008

Volume

283

Issue

21

Start / End Page

14248 / 14256

Location

United States

Related Subject Headings

  • Time Factors
  • Rats
  • RNA, Small Interfering
  • Pyruvic Acid
  • Oxidation-Reduction
  • Lipid Metabolism
  • Isoenzymes
  • Insulin-Secreting Cells
  • Insulin Secretion
  • Insulin
 

Citation

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Ronnebaum, S. M., Joseph, J. W., Ilkayeva, O., Burgess, S. C., Lu, D., Becker, T. C., … Newgard, C. B. (2008). Chronic suppression of acetyl-CoA carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism. J Biol Chem, 283(21), 14248–14256. https://doi.org/10.1074/jbc.M800119200
Ronnebaum, Sarah M., Jamie W. Joseph, Olga Ilkayeva, Shawn C. Burgess, Danhong Lu, Thomas C. Becker, A Dean Sherry, and Christopher B. Newgard. “Chronic suppression of acetyl-CoA carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism.J Biol Chem 283, no. 21 (May 23, 2008): 14248–56. https://doi.org/10.1074/jbc.M800119200.
Ronnebaum SM, Joseph JW, Ilkayeva O, Burgess SC, Lu D, Becker TC, et al. Chronic suppression of acetyl-CoA carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism. J Biol Chem. 2008 May 23;283(21):14248–56.
Ronnebaum, Sarah M., et al. “Chronic suppression of acetyl-CoA carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism.J Biol Chem, vol. 283, no. 21, May 2008, pp. 14248–56. Pubmed, doi:10.1074/jbc.M800119200.
Ronnebaum SM, Joseph JW, Ilkayeva O, Burgess SC, Lu D, Becker TC, Sherry AD, Newgard CB. Chronic suppression of acetyl-CoA carboxylase 1 in beta-cells impairs insulin secretion via inhibition of glucose rather than lipid metabolism. J Biol Chem. 2008 May 23;283(21):14248–14256.

Published In

J Biol Chem

DOI

ISSN

0021-9258

Publication Date

May 23, 2008

Volume

283

Issue

21

Start / End Page

14248 / 14256

Location

United States

Related Subject Headings

  • Time Factors
  • Rats
  • RNA, Small Interfering
  • Pyruvic Acid
  • Oxidation-Reduction
  • Lipid Metabolism
  • Isoenzymes
  • Insulin-Secreting Cells
  • Insulin Secretion
  • Insulin