Sterol regulatory element-binding protein 1 mediates liver X receptor-beta-induced increases in insulin secretion and insulin messenger ribonucleic acid levels.
Liver X receptors (LXRalpha and LXRbeta) regulate glucose and lipid metabolism. Pancreatic beta-cells and INS-1E insulinoma cells express only the LXRbeta isoform. Activation of LXRbeta with the synthetic agonist T0901317 increased glucose-induced insulin secretion and insulin content, whereas deletion of the receptor in LXRbeta knockout mice severely blunted insulin secretion. Analysis of gene expression in LXR agonist-treated INS-1E cells and islets from LXRbeta-deficient mice revealed that LXRbeta 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 LXRbeta-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 LXRbeta in pancreatic beta-cells increases insulin secretion and insulin mRNA expression via SREBP-1-regulated pathway. These data support the role of LXRbeta, SREBP-1, and cataplerosis/anaplerosis pathways in the control of insulin secretion in pancreatic beta-cells.
Zitzer
Heike
H
Lilly Research Laboratories, Essener Bogen 7, D-22419 Hamburg, Germany.
Wente
Wolf
W
Brenner
Martin B
MB
Sewing
Sabine
S
Buschard
Karsten
K
Gromada
Jesper
J
Efanov
Alexander M
AM
D017398:Alternative Splicing; D000818:Animals; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000819:agonists / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology; D018149:Glucose Intolerance / Q000378:metabolism / Q000503:physiopathology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006845:Hydrocarbons, Fluorinated; D007328:Insulin / Q000235:genetics* / Q000378:metabolism*; D000078790:Insulin Secretion; D007340:Insulinoma; D007515:Islets of Langerhans / Q000166:cytology; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057093:Orphan Nuclear Receptors; D010190:Pancreatic Neoplasms; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists / Q000378:metabolism*; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism*; D013449:Sulfonamides / Q000494:pharmacology; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D005466:Fluorocarbons; D000096926:Benzenesulfonamides
D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D006845:Hydrocarbons, Fluorinated; D007328:Insulin; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018160:Receptors, Cytoplasmic and Nuclear; D051780:Sterol Regulatory Element Binding Protein 1; D013449:Sulfonamides; D015534:Trans-Activators; C000605214:Nr1h3 protein, mouse; C497388:Srebf1 protein, mouse; C423915:T0901317; D005466:Fluorocarbons; D000096926:Benzenesulfonamides; C084010:pancreatic and duodenal homeobox 1 protein