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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.

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