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Raloxifene Ameliorates Liver Fibrosis of Nonalcoholic Steatohepatitis Induced by Choline-Deficient High-Fat Diet in Ovariectomized Mice

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Abstract

Background and Aim

The prevalence of nonalcoholic fatty liver disease (NAFLD) is higher in men than in women, but according to some epidemiological studies, this gender difference disappears after menopause. Estrogen therapy protects against NAFLD and nonalcoholic steatohepatitis (NASH) after menopause. We investigated the therapeutic effect of raloxifene, a second-generation selective estrogen-receptor modulator, on NASH induced by a choline-deficient high-fat (CDHF) diet in female ovariectomized (OVX) mice.

Methods

Seven-week-old female C57BL/6J mice were divided into three experimental groups as follows: (1) sham operation (SHAM group), (2) ovariectomy (OVX group), and (3) ovariectomy + raloxifene (intraperitoneal injection, 3 mg/kg body weight/day; OVX + RLX group). These three groups of mice were fed a CDHF diet for 8 weeks; choline-sufficient high-fat (CSHF) diet was used as control diet. Serum biochemical indicators of hepatic function and liver histological changes were evaluated.

Results

Compared with CSHF diet, ovariectomy enhances liver injury and fibrosis in CDHF diet-fed mice. Serum alanine aminotransferase (ALT) levels were significantly lower in the OVX + RLX group than in the OVX group. The OVX group developed extensive steatosis with inflammation and fibrosis. Lobular inflammatory scores and fibrosis staging in the OVX + RLX group were significantly lower than in the OVX group. Furthermore, the OVX + RLX group exhibited significantly higher expression of hepatic estrogen receptor-α, which was significantly lower in the OVX group than in the SHAM group.

Conclusions

Raloxifene may ameliorate progression of liver fibrosis of NASH induced by CDHF diet in ovariectomized female mice, and up-regulation of estrogen receptor-α may play an important role in the beneficial effects of raloxifene on NASH.

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Abbreviations

SERM:

Selective estrogen-receptor modulator

FFA:

Free fatty acids

CDHF:

Choline-deficient high-fat

CSHF:

Choline-sufficient high-fat

OVX:

Ovariectomized

NASH:

Nonalcoholic steatohepatitis

ALT:

Alanine aminotransferase

NAFLD:

Nonalcoholic fatty liver disease

AST:

Aspartate transaminase

SMA:

Smooth muscle actin

HSC:

Hepatic stellate cell

NAS:

NAFLD activity score

VLDL:

Very low-density lipoprotein

TGF:

Transforming growth factor

ER:

Estrogen receptor

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Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research (26460998) from the Ministry of Education, Culture, Sports, Science and Technology, Japan.

Conflict of interest

There is no conflict of interest with regard to this paper.

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Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan

    Fangqiong Luo, Masatoshi Ishigami, Koichi Achiwa, Yoji Ishizu, Teiji Kuzuya, Takashi Honda, Kazuhiko Hayashi, Tetsuya Ishikawa & Hidemi Goto

  2. Department of Internal Medicine, School of Medicine, Banbuntane Hotokukai Hospital, Fujita Health University, Nagoya, Japan

    Yoshiaki Katano

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  1. Fangqiong Luo
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Correspondence to Masatoshi Ishigami.

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Luo, F., Ishigami, M., Achiwa, K. et al. Raloxifene Ameliorates Liver Fibrosis of Nonalcoholic Steatohepatitis Induced by Choline-Deficient High-Fat Diet in Ovariectomized Mice. Dig Dis Sci 60, 2730–2739 (2015). https://doi.org/10.1007/s10620-015-3660-6

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  • DOI: https://doi.org/10.1007/s10620-015-3660-6

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