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Submitted on November 25, 2003
Accepted on March 25, 2004
-Cell Lipotoxicity Model Overexpressing SREBP-1c
Department of Metabolic Diseases and Cardiovascular Medicine, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan; CREST of Japan Science and Technology Corporation, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan; Institute for Diabetes Care and Research, Asahi Life Foundation, 1-6-1 Marunouchi, Chiyoda-ku, Tokyo 100-0005, Japan
* To whom correspondence should be addressed. E-mail: kadowaki-3im{at}h.u-tokyo.ac.jp.
Triglyceride (TG) accumulation in pancreatic 
-cells is thought to be associated with impaired insulin secretory response to glucose (lipotoxicity). To better understand the mechanism of the impaired insulin-secretory response to glucose in -cell lipotoxicity, we overexpressed a constitutively active form of the sterol regulatory element binding protein (SREBP)-1c, a master transcriptional factor of lipogenesis, in INS-1 cells with an adenoviral vector. This treatment was associated with strong activation of transcription of the genes involved in fatty acid biosynthesis, increased cellular TG content, severely blunted glucose-stimulated insulin secretion, and enhanced expression of the uncoupling protein (UCP)-2, which supposedly dissipates the mitochondrial electrochemical potential. To decrease the up-regulated UCP-2 expression, small interfering RNA (siRNA) for UCP-2 was used. Introduction of the siRNA increased the [ATP]/[ADP] ratio and partially rescued the glucose-stimulated insulin secretion in the cells overexpressing SREBP-1c, but did not affect the cellular TG content. Next, the effect of the AMP-activated protein kinase (AMPK) agonist, 5-amino-4-imidazolecarboxamide riboside (AICAR), was examined in the lipotoxicity model. Exposure of the cells with lipotoxicity to AICAR increased FFA oxidation, partially reversed the TG accumulation, phosphorylated AMPK and acetyl-CoA carboxylase (ACC), and improved the impaired glucose-stimulated insulin secretion. These results suggest that UCP-2 downregulation and AMPK activation could be candidate targets for releasing -cells from lipotoxicity.
-cell •
Lipotoxicity •
SREBP-1c •
UCP-2 •
Triglyceride •
AICAR
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