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Digestive Diseases and Sciences

, Volume 60, Issue 9, pp 2730–2739 | Cite as

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

  • Fangqiong Luo
  • Masatoshi Ishigami
  • Koichi Achiwa
  • Yoji Ishizu
  • Teiji Kuzuya
  • Takashi Honda
  • Kazuhiko Hayashi
  • Tetsuya Ishikawa
  • Yoshiaki Katano
  • Hidemi Goto
Original Article

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.

Keywords

Nonalcoholic steatohepatitis Raloxifene Ovariectomy Estrogen 

Abbreviation

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

Notes

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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Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Fangqiong Luo
    • 1
  • Masatoshi Ishigami
    • 1
  • Koichi Achiwa
    • 1
  • Yoji Ishizu
    • 1
  • Teiji Kuzuya
    • 1
  • Takashi Honda
    • 1
  • Kazuhiko Hayashi
    • 1
  • Tetsuya Ishikawa
    • 1
  • Yoshiaki Katano
    • 2
  • Hidemi Goto
    • 1
  1. 1.Department of Gastroenterology and HepatologyNagoya University Graduate School of MedicineNagoyaJapan
  2. 2.Department of Internal Medicine, School of Medicine, Banbuntane Hotokukai HospitalFujita Health UniversityNagoyaJapan

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