Mouse steroid receptor coactivator-1 is not essential for peroxisome proliferator-activated receptor alpha-regulated gene expression.

Peroxisome proliferator-activated receptors (PPARs) are ligand-dependent transcription factors, and it is assumed that the biological effects of these receptors depend on interactions with recently identified coactivators, including steroid receptor coactivator-1 (SRC-1). We assessed the in vivo function of SRC-1 on the PPARalpha-regulated gene expression in liver by generating mice in which the SRC-1 gene was inactivated by gene targeting. The homozygous (SRC-1(-/-)) mice were viable and fertile and exhibited no detectable gross phenotypic defects. When challenged with a PPARalpha ligand, such as ciprofibrate or Wy-14,643, the SRC-1(-/-) mice displayed typical pleiotropic responses, including hepatomegaly, peroxisome proliferation in hepatocytes, and increased mRNA and protein levels of genes that are regulated by PPARalpha. These alterations were indistinguishable from those exhibited by SRC-1(+/+) wild-type mice fed either ciprofibrate- or Wy-14, 643-containing diets. These results indicate that SRC-1 is not essential for PPARalpha-mediated transcriptional activation in vivo and suggest redundancy in nuclear receptor coactivators.

Differential expression of the peroxisome proliferator-activated receptor gamma (PPARgamma) and its coactivators steroid receptor coactivator-1 and PPAR-binding protein PBP in the brown fat, urinary bladder, colon, and breast of the mouse.

Peroxisome proliferator-activated receptors (PPARs) regulate genes involved in lipid metabolism and adipocyte differentiation. Steroid receptor coactivator-1 (SRC-1) and PPAR-binding protein (PBP) interact with PPARgamma and act as coactivators to enhance ligand-dependent transcription. We report here that PPARgamma, SRC-1, and PBP are differentially expressed in the brown fat, transitional epithelium of the urinary bladder, colonic mucosa, and mammary epithelium of the adult mouse. PPARgamma and PBP are expressed in the transitional epithelium of urinary bladder and in brown adipose tissue, but not SRC-1. In the colonic mucosa, PPARgamma expression occurs throughout the villi, whereas the expression of both SRC-1 and PBP is confined mostly to the crypts. The expression of both SRC-1 and PBP is prominent in the breast epithelium of nonpregnant, pregnant, and lactating mice, whereas PPARgamma expression appeared prominent during lactation. During early embryonic development, PPARgamma, SRC-1, and PBP are differentially expressed, with only limited cell types displaying overlapping expression. PPARgamma and PBP expression overlapped in the brown fat and urogenital sinus at stage E15.5 of embryogenesis, whereas SRC-1 expression occurred mostly in neuroepithelium and cartilage between stages E9.5 and E13.5 of embryogenesis.