Regulation of PAI‐1 gene expression during adipogenesis

Abstract

Obesity is characterized by elevated levels of circulating plasminogen activator inhibitor-1 (PAI-1), which contribute towards the development of secondary disorders such as type 2 diabetes mellitus and cardiovascular complications. This increase in plasma PAI-1 levels is attributed to an increase in PAI-1 derived from adipose tissue. This study shows that adipose tissue evolved into a major PAI-1 producing organ by gaining capacity during adipocyte differentiation to respond to inducers of PAI-1 transcription. This is mediated by a decrease in E2F1 protein levels, an increase in pRB levels and a decrease in pRB phosphorylation, all leading to a decrease in levels of free E2F, a known transcriptional repressor of PAI-1. Depletion of E2F1-3 was sufficient for inducers such as insulin to potently induce PAI-1 gene expression in pre-adipocytes. Conversely, forced release of pRB-bound endogenous E2F using cell-penetrating peptides can suppress PAI-1 gene expression in adipocytes. This study describes the novel paradigm of cellular differentiation-associated increase in PAI-1 gene expression which is mediated by a decrease in repressor activity, and describes a way of desensitising terminally differentiated cells to PAI-1 inducing agents by restoring endogenous repressor activity.

Plasminogen Activator Inhibitor-1 Is a Transcriptional Target of the Canonical Pathway of Wnt/β-Catenin Signaling

“…3). This is consistent with earlier reports showing that PI3K inhibits PAI-1 gene expression in vascular endothelial cells and adipocytes (46,47). Therefore, it appears clear that some branches of the TGF-␤1 downstream signals, such as Smad and PI3K, actually inhibit PAI-1 induction in tubular epithelial cells.…”

Transcriptional activation of pref-1 by E2F1 in 3T3 L1 cells

“…Consistent with our results, the phosphorylation of Rb during clonal expansion causes the release of Rb-associated E2F1, which forms the E2F1/DP complex and stimulates the transcriptional activity of PPARγ (10,13). In addition, E2F1 inhibits the expression of the PAI-1 gene, a member of the serine proteinase inhibitor family, resulting in the induction of PPARγ, C/EBPα and AP2 (14). During differentiation, the progressively reduced levels of pRb cause a concomitant increase in both free E2F1 and its transcriptional capacity (15).…”

Quantitative Comparison of Adipocytokine Gene Expression during Adipocyte Maturation in Non-obese and Obese Rats

“…The concentrations of these agents, especially dexamethasone and insulin, have been shown to influence adipocytokine expression. 22,23) These data suggest that differential induction conditions may have affected the expression of PAI-1, HB-EGF and visfatin. The expression of some adipocytokines can vary depending on the cell type and the concentration of differentiationinducing agents, but the expression patterns of adiponectin, resistin, and leptin were consistent during adipocyte maturation in this study.…”