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

Liver X receptors (LXRα and LXRβ) regulate glucose and lipid metabolism. Pancreatic β-cells and INS-1E insulinoma cells express only the LXRβ isoform. Activation of LXRβ with the synthetic agonist T0901317 increased glucose-induced insulin secretion and insulin content, whereas deletion of the recep...

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Bibliographic Details
Published in:Endocrinology (Philadelphia) 2006-08, Vol.147 (8), p.3898-3905
Main Authors: Zitzer, Heike, Wente, Wolf, Brenner, Martin B, Sewing, Sabine, Buschard, Karsten, Gromada, Jesper, Efanov, Alexander M
Format: Article
Language:English
Subjects:
Alternative Splicing
Animals
Biological and medical sciences
Cell Line, Tumor
DNA-Binding Proteins - agonists
DNA-Binding Proteins - metabolism
Fundamental and applied biological sciences. Psychology
Gene Expression Regulation - physiology
Glucose Intolerance - metabolism
Glucose Intolerance - physiopathology
Homeodomain Proteins - genetics
Homeodomain Proteins - metabolism
Hydrocarbons, Fluorinated
Insulin - genetics
Insulin - metabolism
Insulin Secretion
Insulinoma
Islets of Langerhans - cytology
Liver X Receptors
Male
Mice
Mice, Inbred C57BL
Mice, Knockout
Orphan Nuclear Receptors
Pancreatic Neoplasms
Receptors, Cytoplasmic and Nuclear - agonists
Receptors, Cytoplasmic and Nuclear - metabolism
RNA, Messenger - metabolism
RNA, Small Interfering
Sterol Regulatory Element Binding Protein 1 - genetics
Sterol Regulatory Element Binding Protein 1 - metabolism
Sulfonamides - pharmacology
Trans-Activators - genetics
Trans-Activators - metabolism
Vertebrates: endocrinology
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Summary:Liver X receptors (LXRα and LXRβ) regulate glucose and lipid metabolism. Pancreatic β-cells and INS-1E insulinoma cells express only the LXRβ isoform. Activation of LXRβ with the synthetic agonist T0901317 increased glucose-induced insulin secretion and insulin content, whereas deletion of the receptor in LXRβ knockout mice severely blunted insulin secretion. Analysis of gene expression in LXR agonist-treated INS-1E cells and islets from LXRβ-deficient mice revealed that LXRβ 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 LXRβ-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 LXRβ in pancreatic β-cells increases insulin secretion and insulin mRNA expression via SREBP-1-regulated pathway. These data support the role of LXRβ, SREBP-1, and cataplerosis/anaplerosis pathways in the control of insulin secretion in pancreatic β-cells.
ISSN:0013-7227
1945-7170
DOI:10.1210/en.2005-1483