Department of Medicine, Gifu University Graduate School of Medicine, Gifu, Japan.
BMC Cancer. 2011 Jun 28;11:281. doi: 10.1186/1471-2407-11-281.
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.
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.
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.
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.
肥胖症和相关的代谢异常，包括肝脏的炎症和脂质积累，在肝癌发生中起作用。脂肪细胞因子失衡，如血清脂联素水平降低，也与肥胖相关的肝肿瘤发生有关。在本研究中，我们研究了匹伐他汀——一种用于治疗高血脂的药物——对二乙基亚硝胺（DEN）诱导的 C57BL/KsJ-db/db（db/db）肥胖小鼠肝前病变发展的影响。
雄性 db/db 小鼠给予含 40ppm DEN 的自来水 2 周，随后给予含 1ppm 或 10ppm 匹伐他汀的饮食 14 周。
处死时，与未治疗组相比，10ppm 匹伐他汀喂养显著通过诱导细胞凋亡而抑制肝前恶性病变、细胞改变灶的发展，但抑制细胞增殖。匹伐他汀改善了肝脏脂肪变性，并激活了肝脏中的 AMPK-α 蛋白。它还降低了血清中的游离脂肪酸和氨基转移酶水平，同时增加了血清中脂联素的水平。匹伐他汀治疗降低了血清肿瘤坏死因子（TNF）-α水平和肝脏中 TNF-α和白细胞介素-6mRNA 的表达，表明脂肪过度沉积引起的慢性炎症得到了减轻。
匹伐他汀能有效抑制肥胖相关肝肿瘤发生的早期阶段，因此可能对肥胖个体的肝癌化学预防有用。
