This Article Full Text Full Text (PDF) All Versions of this Article: 147/8/3898    most recent Author Manuscript (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zitzer, H. Articles by Efanov, A. M. Search for Related Content PubMed PubMed Citation Articles by Zitzer, H. Articles by Efanov, A. M.

Sterol Regulatory Element-Binding Protein 1 Mediates Liver X Receptor-ß-Induced Increases in Insulin Secretion and Insulin Messenger Ribonucleic Acid Levels

Lilly Research Laboratories (H.Z., W.W., M.B.B., S.S., J.G., A.M.E.), D-22419 Hamburg, Germany; and Bartholin Instituttet (K.B.), Rigshospitalet, DK-2100 Copenhagen, Denmark

Address all correspondence and requests reprints to: Dr. Alexander M. Efanov, Lilly Research Laboratories, Essener Bogen 7, D-22419 Hamburg, Germany. E-mail: efanov_alexander{at}lilly.com.

Liver X receptors (LXR and LXRß) regulate glucose and lipid metabolism. Pancreatic ß-cells and INS-1E insulinoma cells express only the LXRß isoform. Activation of LXRß with the synthetic agonist T0901317 increased glucose-induced insulin secretion and insulin content, whereas deletion of the receptor in LXRß knockout mice severely blunted insulin secretion. Analysis of gene expression in LXR agonist-treated INS-1E cells and islets from LXRß-deficient mice revealed that LXRß positively regulated expression of ATP-binding cassette transporter A1 (ABCA1), sterol regulatory element-binding protein 1 (SREBP-1), insulin, PDX-1, glucokinase, and glucose transporter 2 (Glut2). Down-regulation of SREBP-1 expression with the specific small interfering RNA blocked basal and LXRß-induced expression of pancreatic duodenal homeobox 1 (PDX-1), insulin, and Glut2 genes. SREBP-1 small interfering RNA also prevented an increase in insulin secretion and insulin content induced by T0901317. Moreover, 5-(tetradecyloxy)-2-furoic acid, an inhibitor of the SREBP-1 target gene acetyl-coenzyme A carboxylase, blocked T0901317-induced stimulation of insulin secretion. In conclusion, activation of LXRß in pancreatic ß-cells increases insulin secretion and insulin mRNA expression via SREBP-1-regulated pathway. These data support the role of LXRß, SREBP-1, and cataplerosis/anaplerosis pathways in the control of insulin secretion in pancreatic ß-cells.

This article has been cited by other articles:

				F. Diraison, M. A. Ravier, S. K. Richards, R. M. Smith, H. Shimano, and G. A. Rutter SREBP1 is required for the induction by glucose of pancreatic {beta}-cell genes involved in glucose sensing J. Lipid Res., April 1, 2008; 49(4): 814 - 822. [Abstract] [Full Text] [PDF]

				S. S. Choe, A H. Choi, J.-W. Lee, K. H. Kim, J.-J. Chung, J. Park, K.-M. Lee, K.-G. Park, I.-K. Lee, and J. B. Kim Chronic Activation of Liver X Receptor Induces {beta}-Cell Apoptosis Through Hyperactivation of Lipogenesis: Liver X Receptor-Mediated Lipotoxicity in Pancreatic {beta}-Cells Diabetes, June 1, 2007; 56(6): 1534 - 1543. [Abstract] [Full Text] [PDF]

				J. Chen, P. B. Jeppesen, I. Nordentoft, and K. Hermansen Stevioside improves pancreatic beta-cell function during glucotoxicity via regulation of acetyl-CoA carboxylase Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1906 - E1916. [Abstract] [Full Text] [PDF]

				W. Wente, M. B. Brenner, H. Zitzer, J. Gromada, and A. M. Efanov Activation of Liver X Receptors and Retinoid X Receptors Induces Growth Arrest and Apoptosis in Insulin-Secreting Cells Endocrinology, April 1, 2007; 148(4): 1843 - 1849. [Abstract] [Full Text] [PDF]