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Open Access Highly Accessed Research article

Pitavastatin suppresses diethylnitrosamine-induced liver preneoplasms in male C57BL/KsJ-db/db obese mice

Masahito Shimizu1*, Yoichi Yasuda1, Hiroyasu Sakai1, Masaya Kubota1, Daishi Terakura1, Atsushi Baba1, Tomohiko Ohno1, Takahiro Kochi1, Hisashi Tsurumi1, Takuji Tanaka2 and Hisataka Moriwaki1

Author Affiliations

1 Department of Medicine, Gifu University Graduate School of Medicine, Gifu, Japan

2 Department of Oncologic Pathology, Kanazawa Medical University, Ishikawa, Japan

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BMC Cancer 2011, 11:281  doi:10.1186/1471-2407-11-281

Published: 28 June 2011

Abstract

Background

Obesity and related metabolic abnormalities, including inflammation and lipid accumulation in the liver, play a role in liver carcinogenesis. Adipocytokine imbalances, such as decreased serum adiponectin levels, are also involved in obesity-related liver tumorigenesis. In the present study, we examined the effects of pitavastatin - a drug used for the treatment of hyperlipidemia - on the development of diethylnitrosamine (DEN)-induced liver preneoplastic lesions in C57BL/KsJ-db/db (db/db) obese mice.

Methods

Male db/db mice were administered tap water containing 40 ppm DEN for 2 weeks and were subsequently fed a diet containing 1 ppm or 10 ppm pitavastatin for 14 weeks.

Results

At sacrifice, feeding with 10 ppm pitavastatin significantly inhibited the development of hepatic premalignant lesions, foci of cellular alteration, as compared to that in the untreated group by inducing apoptosis, but inhibiting cell proliferation. Pitavastatin improved liver steatosis and activated the AMPK-α protein in the liver. It also decreased free fatty acid and aminotransferases levels, while increasing adiponectin levels in the serum. The serum levels of tumor necrosis factor (TNF)-α and the expression of TNF-α and interleukin-6 mRNAs in the liver were decreased by pitavastatin treatment, suggesting attenuation of the chronic inflammation induced by excess fat deposition.

Conclusions

Pitavastatin is effective in inhibiting the early phase of obesity-related liver tumorigenesis and, therefore, may be useful in the chemoprevention of liver cancer in obese individuals.