Inhibitory Effects of Japanese Herbal Medicines Sho-saiko-to and Juzen-taiho-to on Nonalcoholic Steatohepatitis in Mice

Yoshihisa Takahashi,Masato Watanabe,Toshio Fukusato,Arisa Kumagai,Hiroshi Uozaki,Yurie Soejima,Kalpana Ghoshal

doi:10.1371/journal.pone.0087279

Yoshihisa Takahashi, Masato Watanabe + Show 5 more

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https://doi.org/10.1371/journal.pone.0087279

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Journal: PloS one	Publication Date: Jan 22, 2014
Citations: 61	License type: CC BY 4.0

Affiliation: Teikyo University

Abstract

Although Japanese herbal medicines (JHMs) are widely used in Japan, only a few studies have investigated their effects on nonalcoholic steatohepatitis (NASH). In the present study, we examined the effect of 4 kinds of JHMs [sho-saiko-to (TJ-9), inchin-ko-to (TJ-135), juzen-taiho-to (TJ-48), and keishi-bukuryo-gan (TJ-25)] on a mouse model of NASH. Db/db mice were divided into 6 groups: control diet (control), methionine- and choline-deficient diet (MCD), and MCD diet supplemented with TJ-9, TJ-135, TJ-48, and TJ-25 (TJ-9, TJ-135, TJ-48, and TJ-25, respectively). All mice were sacrificed after 4 weeks of treatment, and biochemical, pathological, and molecular analyses were performed. Serum alanine aminotransferase levels and liver histology, including necroinflammation and fibrosis, were significantly alleviated in the TJ-9 and TJ-48 groups compared with the MCD group. The expression level of transforming growth factor (TGF)-β1 mRNA in the liver was significantly suppressed by TJ-48. Although the differences were not statistically significant, the expression levels of tumor necrosis factor (TNF)-α and interleukin (IL)-6 were lower, and those of peroxisome proliferators-activated receptor (PPAR)γ were higher in the TJ-9 and/or TJ-48 groups than in the MCD group. Similarly, even though the results were not statistically significant, malondialdehyde levels in liver tissues were lower in the TJ-9 and TJ-48 groups than in the MCD group. We showed that JHMs, especially TJ-9 and TJ-48, inhibited the necroinflammation and fibrosis in the liver of a mouse model of NASH, even though the mechanisms were not fully elucidated. Further studies are needed in the future to investigate the possibility of clinical application of these medicines in the treatment for NASH.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is a condition in which excessive fat accumulates in the liver of a patient who does not have a history of alcohol abuse
AST levels were significantly higher in the methionine- and choline-deficient diet (MCD) group than in the control group; they were lower in the TJ-9, TJ-48, and TJ-25 groups than in the MCD group, but the differences were not statistically significant
This study shows that Japanese herbal medicines (JHMs) significantly improved the serum ALT levels and liver histology, including the degree of fibrosis, in an animal model of nonalcoholic steatohepatitis (NASH)

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is a condition in which excessive fat accumulates in the liver of a patient who does not have a history of alcohol abuse. NASH is a progressive disease and may develop into liver cirrhosis or hepatocellular carcinoma [1,2]. The two-hit [5] or multiple-hit [6] hypotheses are generally advocated as the mechanisms underlying the pathogenesis of NAFLD/NASH. It is believed that fat accumulation in the liver is necessary for the occurrence of NAFLD, and further hits, such as oxidative stress, increase of inflammatory cytokines, or decrease of anti-inflammatory cytokines, are necessary for the development of the progressive NASH disease. Animal models are useful for elucidating the pathogenesis and for developing novel treatments for NASH. Several genetic and nutritional animal models of NAFLD/NASH have been proposed, these models do not replicate the full spectrum of the characteristics of human

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