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

• Published in: Molecular endocrinology (Baltimore, Md.) Vol. 19; no. 2; pp. 399 - 408
• Main Authors: Lee, Seunghee, Lee, Dong-Kee, Choi, Eunho, Lee, Jae W
• Format: Journal Article
• Language: English
• Published: United States Endocrine Society 01.02.2005; Oxford University Press
• Subjects: 3T3-L1 Cells; Adipocytes - cytology; Adipocytes - metabolism; Animals; Base Sequence; Bone Marrow Cells - cytology; Calcitriol - metabolism; Cell Differentiation; Dimerization; DNA Primers - chemistry; Dose-Response Relationship, Drug; Intracellular Signaling Peptides and Proteins - genetics; Ligands; Membrane Proteins - genetics; Mice; Models, Biological; Molecular Sequence Data; Plasmids - metabolism; PPAR gamma - metabolism; Promoter Regions, Genetic; Protein Binding; Receptors, Calcitriol - metabolism; Response Elements; Retinoid X Receptors - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Transcriptional Activation; Transfection; Vitamin D - metabolism
• ISSN: 0888-8809; 1944-9917
• DOI: 10.1210/me.2004-0324

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 1α,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 γ2 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.