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

Both nuclear receptors glucocorticoid receptor alpha (GR alpha) and peroxisome proliferator-activated receptor alpha (PPAR alpha) 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 PPAR alpha expression via GR alpha at the transcriptional level. This stimulation of PPAR alpha by GR alpha has physiological relevance and PPAR alpha is involved in many glucocorticoid-induced pathophysiological processes, including gluconeogenesis and ketogenesis during fasting, insulin resistance, hypertension and anti-inflammatory effects. PPAR alpha also synergizes with GR alpha to promote erythroid progenitor self-renewal. As the feedback, PPAR alpha inhibits glucocorticoid actions at pre-receptor and receptor levels. PPAR alpha decreases glucocorticoid production through inhibiting the expression and activity of type-1 11 beta-hydroxysteroid dehydrogenase, which converts inactive glucocorticoids to active glucocorticoids at local tissues, and also down-regulates hepatic GR alpha 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 PPAR alpha agonists. This combination may potentially enhance the anti-inflammatory effects while alleviating side effects on glucose and lipid metabolism due to GR alpha activation. More investigations are needed to clarify the underlying mechanism and the relevant physiological or pathological significance of this regulatory loop.

Automated summary

There is a regulatory loop between glucocorticoid receptor alpha and peroxisome proliferator-activated receptor alpha, which affects energy and lipid metabolism and has anti-inflammatory effects.