Phellopterin from angelica dahurica is a natural antagonist of glucocorticoid receptors regulating lipid and cholesterol metabolism

Phellopterin, a compound isolated from Angelica dahurica, has broad-spectrum metabolic modulatory activities, including anti-inflammatory and lipid-lowering effects. However, its molecular pharmacological mechanism and direct target are not fully understood. Glucocorticoids (GCs) have been identified as important risk factors for metabolic syndromes such as obesity, hyperlipidemia and fatty liver. Here, we sought to study whether phellopterin can ameliorate the lipid dysregulation induced by dexamethasone, a potent synthetic GC and whether phellopterin is an antagonist of the Glucocorticoid Receptor (GR). We found that phellopterin inhibited dexamethasone-induced adipocyte lipid accumulation in vitro. Mechanistically, cellular thermal shift assays combined with luciferase reporter assays confirmed that phellopterin could bind to GR and inhibit GR activation in vitro. In vivo, phellopterin counteracted dexamethasone-driven hyperlipidemia and lipid accumulation in hepatocytes and adipocytes in C57BL/6J mice. Mechanistically, phellopterin inhibited GR-induced expression of genes involved in lipid synthesis, metabolism, and Cholesterol biosynthesis. These findings indicate that phellopterin has GR antagonist activity in vitro and in vivo, and reveal the molecular mechanism underlying phellopterin's lipid-lowering effect. Phellopterin may serve as a promising candidate for treating glucocorticoid-associated disorders such as Cushing syndrome and metabolic syndromes.

Antagonist; Glucocorticoid receptor; Hyperlipidemia; Metabolic disorders; Phellopterin.