Farnesoid X receptor (FXR) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. Similar to other nuclear receptors, when activated, FXR translocates to the cell nucleus, forms a dimer and binds to hormone response elements on DNA, which up- or down-regulates the expression of certain genes. FXR is a nuclear receptor activated by bile acids. Chenodeoxycholic acid and other bile acids are natural ligands for FXR. Bile acids are the end products of cholesterol metabolism. Subsequently, bile acids return to the liver to complete their enterohepatic circulation. On its activation by bile acids, FXR regulates bile acid synthesis, conjugation, transport, and various aspects of lipid and glucose metabolism. Besides, Polyunsaturated fatty acids (PUFA) and intermediates of the bile acid synthetic pathways, are the FXR ligands and modulators.

One of the primary functions of FXR activation is the suppression of cholesterol 7 alpha-hydroxylase (CYP7A1). CYP7A1 is the rate-limiting enzyme in bile acid synthesis from cholesterol. FXR is also important in regulation of hepatic triglyceride levels.Specifically, FXR activation suppresses lipogenesis and promotes free fatty acid oxidation by PPARα activation. What’s more, activation of FXR in diabetic mice reduces plasma glucose and improves insulin sensitivity, whereas inactivation of FXR has the opposite effect.

Fargesone A is a potent and selective FXR agonist.

Fargesone A is a natural product that can be found in the flower buds of Magnolia fargesii. Sporadic studies reported that Fargesone A showed weak Ca²⁺ antagonistic and anti-inflammatory activities. What’s more, Fargesone A is a potent and selective FXR novel agonist. The agonistic effect of Fargesone A on FXR is through direct binding to the same OCA-binding pocket of FXR. Therefore, Fargesone A alleviates hepatocyte disorders in an FXR-dependent manner in human liver WRL68 cells. Moreover, treated of bile duct ligation (BDL)-induced liver disorder with Fargesone A ameliorates pathological features in mice.

All in all, Fargesone A is a potent and selective FXR agonist that ameliorates liver inflammation and fibrosis in the BDL mouse model.

References:

[1] Claudel T, et, al. Arterioscler Thromb Vasc Biol. 2005 Oct;25(10):2020-30.

[2] Guo F, et, al. JACS Au. 2022 Dec 7;2(12):2830-2838.