Silibinin, a commonly used therapeutic agent for non-alcohol fatty liver disease, functions through upregulating intestinal expression of fibroblast growth factor 15/19

Background and purpose: Silibinin is used to treat non-alcohol fatty liver disease (NAFLD) despite having rapid liver metabolism. Therefore, we investigated the role of the intestine in silibinin mechanism of action.

Experimental approach: NAFLD mice model was established by feeding them with a high-fat diet (HFD). Liver pathological were examined using H&E and oil red O staining. Tissue distribution of silibinin was detected by LC-MS/MS. SiRNA was employed for gene silencing and plasmid was used for gene overexpression. ChIP-qPCR assay was performed to detect the levels of histone acetylation. Recombinant adeno-associated virus 9-short hairpin-fibroblast growth factor (FGF)-15 and -farnesoid X receptor (FXR; NR1H4) were used to knockdown expression of FGF-15 and FXR.

Key results: Oral silibinin significantly reversed NAFLD in mice, although liver concentration was insufficient for reduction of lipid accumulation in hepatocytes. Among endogenous factors capable of reversing NAFLD, the expression of FGF-15 was selectively up-regulated by silibinin in ileum and colon of mice. When intestinal expression of FGF-15 was knocked down, protection of silibinin against lipid accumulation and injury of livers nearly disappeared. Silibinin could reduce activity of histone deacetylase 2 (HDAC2), enhance histone acetylation in the promoter region of FXR and consequently increase intestinal expression of FGF-15/19.

Conclusion and implications: Oral silibinin selectively promotes expression of FGF-15/19 in ileum by enhancing transcription of FXR via reduction of HDAC2 activity, and FGF-15/19 enters into circulation to exert anti-NAFLD action. As the site of action is the intestine this would explain the discrepancy between pharmacodynamics and pharmacokinetics of silibinin.

farnesoid X receptor; fibroblast growth factor 15/19; histone deacetylase 2; non‐alcoholic fatty liver disease; silibinin.