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This version published online on April 27, 2006
Endocrinology, doi:10.1210/en.2005-1483
A more recent version of this article appeared on August 1, 2006
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Submitted on November 22, 2005
Accepted on April 14, 2006

SREBP-1 mediates liver X receptor {beta} - induced increases in insulin secretion and insulin mRNA levels

Heike Zitzer, Wolf Wente, Martin B. Brenner, Sabine Sewing, Karsten Buschard, Jesper Gromada, and Alexander M. Efanov*

Lilly Research Laboratories, Essener Bogen 7, D-22419 Hamburg, Germany; Bartholin Instituttet, Rigshospitalet, DK-2100 Copenhagen, Denmark; Present address: Novartis Institute for Biomedical Research, Cambridge, USA

* To whom correspondence should be addressed. E-mail: efanov alexander{at}lilly.com.

Liver X receptors (LXR{alpha} and LXR{beta}) regulate glucose and lipid metabolism. Pancreatic {beta}-cells and INS-1E insulinoma cells express only the LXR{beta} isoform. Activation of LXR{beta} with the synthetic agonist T0901317 increased glucose-induced insulin secretion and insulin content, whereas deletion of the receptor in LXR{beta} knockout mice severely blunted insulin secretion. Analysis of gene expression in LXR agonist-treated INS-1E cells and islets from LXR{beta} deficient mice revealed that LXR{beta} positively regulated expression of ABCA1, SREBP-1, insulin, PDX-1, glucokinase and glucose transporter 2 (Glut2). Downregulation of SREBP-1 expression with the specific siRNA blocked basal and LXR{beta}-induced expression of PDX-1, insulin and Glut2 genes. SREBP-1 siRNA also prevented an increase in insulin secretion and insulin content induced by T0901317. Moreover, TOFA, an inhibitor of the SREBP-1 target gene - acetyl-CoA carboxylase, blocked T0901317-induced stimulation of insulin secretion. In conclusion, activation of LXR{beta} in pancreatic {beta}-cells increases insulin secretion and insulin mRNA expression via SREBP-1 regulated pathway. These data support the role of LXR{beta}, SREBP-1 and cataplerosis/anaplerosis pathways in the control of insulin secretion in pancreatic {beta}-cells.
Key words: islets • insulin • liver X receptors • SREBP-1 • PDX-1




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