Molecular Physiology of Steroid Hormones Glucocorticoids and Angiopoietin-like Proteins

Glucocorticoids are steroid hormones that convey their signals thorough an intracellular glucocorticoid receptor (GR), which is a transcriptional regulator, to modulate various aspects of mammalian physiology. Because of their potent anti-inflammatory activity, glucocorticoids are also frequently used to treat various inflammatory diseases. However, excess and/or chronic glucocorticoid exposure causes metabolic syndrome including insulin resistance, dyslipidemia, and hyperglycemia. The goal of our research is to elucidate the mechanisms underlying the effects of glucocorticoids on metabolic homeostasis and the inflammatory response. Currently, there are three major research topics in the laboratory. First, we have identified a list of GR primary target genes and are currently analyzing their roles in metabolic functions of glucocorticoids. Second, recent studies have shown that certain transcriptional coregulators are selectively involved in the GR-regulated gene transcription. We will identify coregulators that act with GR to specifically exert metabolic or inflammatory responses. This will allow us to target specific coregulators to dissociate the anti-inflammatory functions of glucocorticoids from the adverse metabolic effects. Finally, we aim to elucidate the metabolic functions of angiopoietin-like 4 (Angptl4), a GR primary target gene, which encodes a secreted protein that inhibits extracellular lipoprotein lipase. We have found that Angptl4 also promotes intracellular lipolysis in adipocytes. The mechanism underlying such Angptl4 action and its effect in the regulation of glucose homeostasis are currently being investigated in our laboratory.