Identification of a functional vitamin D response element in the murine Insig-2 promoter and its potential role in the differentiation of 3T3-L1 preadipocytes.
Insulin-induced gene-1 (Insig-1) and its homolog Insig-2 encode closely related proteins of the endoplasmic reticulum that block proteolytic activation of sterol regulatory element binding proteins, membrane-bound transcription factors that activate synthesis of cholesterol and fatty acids in animal cells. These proteins also restrict lipogenesis in mature adipocytes and block differentiation of preadipocytes. Herein, we identified a novel 1alpha,25-dihydroxyvitamin D3 [1,25-(OH)2D3] response element in the promoter region of Insig-2 gene, which specifically binds to the heterodimer of retinoid X receptor and vitamin D receptor (VDR) and directs VDR-mediated transcriptional activation in a 1,25-(OH)2D3-dependent manner. Interestingly, 1,25-(OH)2D3 is known to directly suppress the expression of peroxisome proliferator-activated receptor gamma2 protein and inhibits adipocyte differentiation of 3T3-L1 preadipocytes and murine bone marrow stromal cells. Consistent with an idea that the antiadipogenic action of 1,25-(OH)2D3 may also involve up-regulation of Insig-2, we found that 1,25-(OH)2D3 transiently but strongly induces Insig-2 expression in 3T3-L1 cells. This novel regulatory circuit may also play important roles in other lipogenic cell types that express VDR, and collectively our results suggest an intriguing, new linkage between 1,25-(OH)2D3 and lipogenesis.
Lee
Seunghee
S
Department of Medicine, Division of Diabetes, Endocrinology & Metabolism, Baylor College of Medicine, Houston, Texas 77030, USA.
Lee
Dong-Kee
DK
Choi
Eunho
E
Lee
Jae W
JW
D041721:3T3-L1 Cells; D017667:Adipocytes / Q000166:cytology* / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001854:Bone Marrow Cells / Q000166:cytology; D002117:Calcitriol / Q000378:metabolism; D002454:Cell Differentiation; D017931:DNA Primers / Q000737:chemistry; D019281:Dimerization; D004305:Dose-Response Relationship, Drug; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D008024:Ligands; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008954:Models, Biological; D008969:Molecular Sequence Data; D047495:PPAR gamma / Q000378:metabolism; D010957:Plasmids / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D018167:Receptors, Calcitriol / Q000378:metabolism; D020218:Response Elements; D047488:Retinoid X Receptors / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015533:Transcriptional Activation; D014162:Transfection; D014807:Vitamin D / Q000378:metabolism*
D017931:DNA Primers; C467727:INSIG2 protein, human; D047908:Intracellular Signaling Peptides and Proteins; D008024:Ligands; D008565:Membrane Proteins; D047495:PPAR gamma; D018167:Receptors, Calcitriol; D047488:Retinoid X Receptors; D014807:Vitamin D; D002117:Calcitriol