Kaerophyllin Suppresses Hepatic Stellate Cell Activation by Apoptotic Bodies and Ameliorates Hepatic Fibrosis in Rats

Hepatocyte apoptosis is a central feature of many liver diseases, leading to liver inflammation and fibrosis. In this study, we screened potential drugs inhibiting hepatic stellate cell (HSC) migration induced by hepatocyte apoptotic bodies (ABs) and evaluated the in vivo therapeutic effects in a rat model of hepatic fibrosis induced by thioacetamide (TAA). Rat HSCs were exposed to UV-irradiated hepatocyte ABs or TNF-α to investigate the anti-fibrotic effects of kaerophyllin. Liver fibrosis was induced by TAA injection into rats twice weekly for 6 weeks. Kaerophyllin (10 or 30mg/kg) or curcumin (150mg/kg, as a positive control) was given by gavage twice daily for 4 weeks starting 2 weeks after TAA injection. Kaerophyllin (α-(trans-3,4-dimethoxybenzylidene)-β-(3,4-methylenedioxy-benzyl)-γ-butyrolactone, a lignan isolated from a Chinese herb Bupleurum scorzonerifolium by bioactivity-guided fractionation) attenuated ABs- and TNF-α-induced HSC migration, protein levels of collagen I and α-SMA, and the mRNA levels of ICAM-1, MCP-1 and IL-1β genes, but elevated PPAR-γ luciferase activity. Furthermore, kaerophyllin reduced TNF-α- and ABs-induced NF-κB luciferase activity with decreased IκB phosphorylation and p65 nuclear translocation. In TAA rats, kaerophyllin and curcumin treatment significantly protected liver from injury by reducing serum AST and ALT levels, and improved the histological architecture and fibrosis score. In addition, kaerophyllin treatment suppressed α-SMA protein expression, and mRNA levels of collagen I, TIMP-1, TNF-α, IL-1β and MCP-1 genes in TAA rats. Our results demonstrated that kaerophyllin protected the rat liver from TAA-caused injury and fibrogenesis by suppressing hepatic inflammation and inhibiting HSC activation.

Keywords: hepatic stellate cells, liver fibrosis, kaerophyllin, inflammation, Bupleurum scorzonerifolium

Acknowledgement: This work was supported by the National Science Council and the National Research Institute of Chinese Medicine in Taiwan.

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