Xanthohumol ameliorates Diet-Induced Liver Dysfunction via Farnesoid X Receptor-Dependent and Independent Signaling

Area of Science:

• Hepatology and metabolic disease research.
• Pharmacology and natural product drug discovery.

Background:

• The farnesoid X receptor (FXR) is crucial for lipid and bile acid (BA) balance.
• FXR deficiency leads to liver steatosis, progressing to nonalcoholic steatohepatitis (NASH).
• Xanthohumol (XN), a hop compound, shows potential in mitigating metabolic syndrome.

Purpose of the Study:

• To investigate the therapeutic effects of XN on diet-induced liver injury in mice with FXR deficiency.
• To explore the underlying mechanisms of XN's action, including its impact on BA homeostasis and detoxification pathways.

Main Methods:

• Utilized wild-type (WT) and liver-specific FXR-null (FXR^Liver-/-) mice fed a high-fat diet (HFD).
• Administered XN or vehicle, followed by histological, lipid, BA, and gene expression analyses.
• Assessed liver damage, steatosis, BA concentrations, and the expression of key nuclear receptors (CAR, PXR, GR).

Main Results:

• XN treatment ameliorated hepatic steatosis and reduced BA concentrations in FXR^Liver-/- mice, particularly in males.
• XN upregulated the gene expression of constitutive androstane receptor (CAR), pregnane X receptor (PXR), and glucocorticoid receptor (GR) in the livers of FXR^Liver-/- mice.
• These findings suggest XN activates BA detoxification pathways, controlling BA levels in the absence of FXR.

Conclusions:

• XN ameliorates high-fat diet-induced liver dysfunction in mice with FXR deficiency.
• The protective effects of XN involve both FXR-dependent and independent signaling pathways.
• A sex-dependent relationship exists between FXR, lipids, and BAs, highlighting potential sex-specific therapeutic responses to XN.