ADD1/SREBP1 promotes adipocyte differentiation and gene expression linked to fatty acid metabolism.

Abstract

Adipocyte determination and differentiation-dependent factor 1 (ADD1) is a member of the basic helix-loop--helix leucine zipper (bHLH-LZ) family of transcription factors that binds to two distinct DNA sequences and has been associated with both adipocyte development and cholesterol homeostasis (where it has been termed SREBP1). To investigate the biological role of ADD1, we expressed wild-type and dominant negative forms of this protein with retroviral vectors in preadipocytes and nonadipogenic cells. A dominant-negative form of ADD1 with a point mutation in the DNA-binding domain sharply represses the differentiation of 3T3-L1 cells as observed morphologically or by the expression of adipocyte-specific mRNAs. When NIH-3T3 cells ectopically expressing ADD1 are cultured under hormonal conditions not favoring differentiation, they do not overtly differentiate but still activate expression of mRNAs for fatty acid synthase (FAS) and lipoprotein lipase (LPL), two key genes that regulate fatty acid metabolism. Under culture conditions permissive for differentiation including a PPAR activator, 15%-20% of the cells expressing ADD1 undergo adipogenesis while 2%-3% of cells containing a control vector differentiate. Simultaneous expression of ADD1 with PPAR-y increases the transcriptional activity of this adipogenic nuclear hormone receptor, suggesting involvement of ADD1 in this pathway. These data indicate that ADD1 plays an important role in fat cell gene expression and differentiation, and suggest that it may function by augmenting a step in PPAR3,-mediated transcription.

Obesity and polymorphisms in genes regulating human adipose tissue

“…27 The transcription factor Sterol regulatory element-binding protein (SREBP) 1c stimulates expression of genes, including Obesity genes in human adipose tissue I Dahlman and P Arner PPARG, promoting adipogenesis and TAG storage in experimental systems, making SREBP1c and interacting proteins SREBP cleavage-activation protein (SCAP), INSIG1 and INSIG2 candidates for obesity. 30,31 SREBP-1c is encoded by the same gene as SREBP-1a, which primarily regulates cholesterol metabolism. SREBP is synthesized as a precursor protein that is attached to the nuclear membrane and endoplasmic reticulum (ER).…”

Molecular analysis of lipid‐depleting factor in a colon‐26‐inoculated cancer cachexia model

“…Indeed, overexpression of SREBP-1 in cultured preadipocytes activated genes involved in fat cell differentiation and lipid accumulation. 41 The targets in the fatty acid and TG biosynthetic pathways include acetyl-CoA carboxylase, fatty acid synthase, stearoyl-CoA desaturase-1 and glycerol-3-phosphate acyltransferase. [37][38][39] Moreover, these SREBP-1 target genes control important steps in fatty acid metabolism, which may lead to the production of natural fatty acid-derived PPAR-␥ ligands and activators.…”

Isoform 1c of sterol regulatory element binding protein is less active than isoform 1a in livers of transgenic mice and in cultured cells.

“…Binding leads to transcriptional activation through interaction of the SREBPs with other transcription factors, including SP-1 (16,17) and NF-Y (18). The SREBPs also activate transcription of genes encoding HMG CoA reductase and several enzymes of fatty acid metabolism, including acetyl CoA carboxylase, fatty acid synthase, lipoprotein lipase, and stearoyl CoA desaturase-1 (2,3,5,19,20). These latter effects are mediated by interaction with sequences other than the classically defined sterol regulatory element (20,21).…”

“…Three sterol regulatory element binding proteins (SREBPs) 1 regulate the synthesis of cholesterol and fatty acids in animal cells (1)(2)(3)(4)(5). Two of these proteins, designated SREBP-1a and -1c, are derived from a single gene through the use of alternate transcription start sites that produce alternate forms of exon 1 (6)(7)(8).…”