Laboratory of Endocrinology and Metabolism, Department of Endocrinology, West China Hospital, Sichuan University, 610041, Chengdu, China.
Department of Endocrinology and Metabolism, the Third Affiliated Hospital of Zunyi Medical University (the First People's Hospital of Zunyi), 563002, Zunyi, China.
Rev Endocr Metab Disord. 2022 Oct;23(5):893-903. doi: 10.1007/s11154-022-09725-w. Epub 2022 Apr 27.
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.
核受体糖皮质激素受体 α (GRα) 和过氧化物酶体增殖物激活受体 α (PPARα) 都参与能量和脂质代谢，并具有抗炎作用。先前的研究表明它们之间可能存在一个调节回路。体内和体外研究表明，糖皮质激素通过 GRα 在转录水平上刺激肝 PPARα 的表达。GRα 对 PPARα 的这种刺激具有生理相关性，PPARα 参与许多糖皮质激素诱导的病理生理过程，包括禁食时的糖异生和酮体生成、胰岛素抵抗、高血压和抗炎作用。PPARα 还与 GRα 协同作用促进红系祖细胞自我更新。作为反馈，PPARα 在受体前和受体水平抑制糖皮质激素的作用。PPARα 通过抑制 1 型 11β-羟类固醇脱氢酶的表达和活性来减少糖皮质激素的产生，该酶将无活性的糖皮质激素转化为局部组织中的活性糖皮质激素，同时还下调肝 GRα 的表达，从而形成一个完整的负反馈回路。这个负反馈回路为通过糖皮质激素和 PPARα 激动剂联合治疗炎症性疾病提供了潜在的多药物治疗方法。这种组合可能会增强抗炎作用，同时减轻由于 GRα 激活而对葡萄糖和脂质代谢产生的副作用。需要进一步的研究来阐明这种调节回路的潜在机制及其相关的生理或病理意义。
