Interactions between nuclear receptors glucocorticoid receptor α and peroxisome proliferator-activated receptor α form a negative feedback loop.

Both nuclear receptors glucocorticoid receptor α (GRα) and peroxisome proliferator-activated receptor α (PPARα) are involved in energy and lipid metabolism, and possess anti-inflammation effects. Previous studies indicate that a regulatory loop may exist between them. In vivo and in vitro studies showed that glucocorticoids stimulate hepatic PPARα expression via GRα at the transcriptional level. This stimulation of PPARα by GRα has physiological relevance and PPARα is involved in many glucocorticoid-induced pathophysiological processes, including gluconeogenesis and ketogenesis during fasting, insulin resistance, hypertension and anti-inflammatory effects. PPARα also synergizes with GRα to promote erythroid progenitor self-renewal. As the feedback, PPARα inhibits glucocorticoid actions at pre-receptor and receptor levels. PPARα decreases glucocorticoid production through inhibiting the expression and activity of type-1 11β-hydroxysteroid dehydrogenase, which converts inactive glucocorticoids to active glucocorticoids at local tissues, and also down-regulates hepatic GRα expression, thus forming a complete and negative feedback loop. This negative feedback loop sheds light on prospective multi-drug therapeutic treatments in inflammatory diseases through a combination of glucocorticoids and PPARα agonists. This combination may potentially enhance the anti-inflammatory effects while alleviating side effects on glucose and lipid metabolism due to GRα activation. More investigations are needed to clarify the underlying mechanism and the relevant physiological or pathological significance of this regulatory loop.