Silybin Alleviates Hepatic Steatosis and Fibrosis in NASH Mice by Inhibiting Oxidative Stress and Involvement with the Nf-κB Pathway.

Abstract

BACKGROUND AND AIM:

Silybin is the major biologically active compound of silymarin, the standardized extract of the milk thistle (Silybum marianum). Increasing numbers of studies have shown that silybin can improve nonalcoholic steatohepatitis (NASH) in animal models and patients; however, the mechanisms underlying silybin's actions remain unclear.

METHODS:

Male C57BL/6 mice were fed a methionine-choline deficient (MCD) diet for 8 weeks to induce the NASH model, and silybin was orally administered to the NASH mice. The effects of silybin on lipid accumulation, hepatic fibrosis, oxidative stress, inflammation-related gene expression and nuclear factor kappa B (NF-κB) activities were evaluated by biochemical analysis, immunohistochemistry, immunofluorescence, quantitative real-time PCR and western blot.

RESULTS:

Silybin treatment significantly alleviated hepatic steatosis, fibrosis and inflammation in MCD-induced NASH mice. Moreover, silybin inhibited HSC activation and hepatic apoptosis and prevented the formation of MDBs in the NASH liver. Additionally, silybin partly reversed the abnormal expression of lipid metabolism-related genes in NASH. Further study showed that the nuclear factor erythroid 2-related factor 2 (Nrf2) signaling pathway played important roles in the silybin-derived antioxidant effect, as evidenced by the upregulation of Nrf2 target genes in the silybin treatment group. In addition, silybin significantly downregulated the expression of inflammation-related genes and suppressed the activity of NF-κB signaling.

CONCLUSIONS:

Silybin was effective in preventing the MCD-induced increases in hepatic steatosis, fibrosis and inflammation. The effect was related to alteration of lipid metabolism-related gene expression, activation of the Nrf2 pathway and inhibition of the NF-κB signaling pathway in the NASH liver.

• Authors: Qiang Ou, Yuanyuan Weng, Siwei Wang, Yajuan Zhao, Feng Zhang, Jianhua Zhou, Xiaolin Wu
• Journal: Digestive diseases and sciences (Dig Dis Sci) Vol. 63 Issue 12 Pg. 3398-3408 (12 2018) ISSN: 1573-2568 [Electronic] United States
• PMID: 30191499 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Phytogenic
• NF-E2-Related Factor 2
• NF-kappa B
• Nfe2l2 protein, mouse
• Silybin

Topics

• Animals
• Antineoplastic Agents, Phytogenic (pharmacology)
• Apoptosis (drug effects)
• Disease Models, Animal
• Fatty Liver (drug therapy, metabolism)
• Gene Expression (drug effects)
• Lipid Metabolism (drug effects, genetics)
• Liver Cirrhosis (drug therapy, metabolism)
• Mice
• Mice, Inbred C57BL
• NF-E2-Related Factor 2 (metabolism)
• NF-kappa B (metabolism)
• Non-alcoholic Fatty Liver Disease (metabolism, prevention & control)
• Oxidative Stress (drug effects)
• Silybin (pharmacology)
• Treatment Outcome