Regulation of PAI‐1 gene expression during adipogenesis

AbstractObesity 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 desensitis