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Reverse Yeast Two-hybrid System to Identify Mammalian Nuclear Receptor Residues that Interact with Ligands and/or Antagonists
Published on: November 15, 2013
Interactions between nuclear receptors glucocorticoid receptor α and peroxisome proliferator-activated receptor α
Hongjiao Gao1,2, Yujue Li1, Xiang Chen3
1Laboratory of Endocrinology and Metabolism, Department of Endocrinology, West China Hospital, Sichuan University, 610041, Chengdu, China.
Abstract:
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.
Insights
Glucocorticoid receptor alpha (GRα) and peroxisome proliferator-activated receptor alpha (PPARα) form a negative feedback loop regulating metabolism and inflammation. This interaction offers potential for combined therapies in inflammatory diseases.
Area of Science:
- Endocrinology
- Molecular Biology
- Metabolic Research
Background:
- Glucocorticoid receptor alpha (GRα) and peroxisome proliferator-activated receptor alpha (PPARα) are key regulators of energy and lipid metabolism with anti-inflammatory properties.
- Previous research suggests a potential regulatory interaction between GRα and PPARα.
Purpose of the Study:
- To investigate the regulatory loop between GRα and PPARα in metabolic and inflammatory processes.
- To elucidate the mechanisms underlying their interaction and its physiological relevance.
Main Methods:
- In vivo and in vitro studies were employed to examine the transcriptional regulation of PPARα by GRα.
- Analysis of glucocorticoid production, 11β-hydroxysteroid dehydrogenase activity, and hepatic GRα expression was performed.
Main Results:
- Glucocorticoids stimulate hepatic PPARα expression via GRα transcriptionally.
- PPARα negatively feedbacks by inhibiting glucocorticoid production and down-regulating hepatic GRα expression, establishing a complete negative feedback loop.
- PPARα synergizes with GRα in erythroid progenitor self-renewal and influences glucocorticoid-induced pathophysiological conditions.
Conclusions:
- The identified negative feedback loop between GRα and PPARα is crucial for metabolic homeostasis and inflammation control.
- Combination therapy with glucocorticoids and PPARα agonists may enhance anti-inflammatory effects while mitigating metabolic side effects.
- Further research is needed to fully understand the mechanisms and significance of this regulatory axis.
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