Relationship between the mechanism for hyperlipidemia and intestinal polyp formation in Apc knockout mice

Apc基因敲除小鼠高脂血症机制与肠息肉形成的关系

• 批准号: 15590360
• 负责人: TAKAHASHI Mami
• 金额: $ 2.3万
• 依托单位: National Cancer Center
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2003
• 资助国家: 日本
• 起止时间: 2003 至 2004
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15590360/
• 关键词: Apc knockoutmouse; Hyperlipidemia; Intestinalpolyp; Lipoprotein lipase; Triglyceride; PPARα; PPARγ; Pioglitazone; ベザフィブレート

An age-dependent hyperlipidemic state in Ape-deficient mice was shown, and involvement of hyperlipidemia in intestinal polyp formation was examined using anti-hyperlipidemic agents. It was demonstrated that levels of serum triglycerides(TG) in Apc-deficient mice were markedly increased at 15-20 weeks of age. Then, the effects of a PPAR alpha ligand, bezafibrate, and a PPAR gamma ligand, pioglitazone, on both hyperlipidemia and intestinal polyp development in Apc-deficient mice, Apc^<1309> mice, were examined. Treatment of Apc^<1309> mice with 100 and 200 ppm pioglitazone or bezafibrate for 6 weeks from 6 weeks of age caused dose-dependent reduction in serum TG, along with a decrease in the numbers of intestinal polyps. When Min mice were treated with 100-1600 ppm pioglitazone for 14 weeks, a decrease of serum TG and polyp numbers was similarly observed to 7% and 9% of the untreated values, respectively, at the highest dose. Moreover, lipoprotein lipase(LPL) mRNA levels in the liver and small intestine of Apc^<1309> and Min mice were up-regulated by treatment with pioglitazone. Thus, the present study demonstrated that 100-1,600 ppm of pioglitazone can suppress both hyperlipidemia and polyp formation in Apc gene-deficient mice, so this PPAR gamma ligand might be a good candidate chemopreventive agent for colon cancer. In addition, it was shown that a LPL-selective activator, NO-1886,also suppressed both serum lipid levels and polyp formation in Min mice, suggesting that lowered activity of LPL in Apc-deficient mice may contribute to hyperlipidemia and polyp formation. These anti-hyperlipidemic agents might be good candidate chemopreventive agents for colon cancer.

在Ape缺陷小鼠中显示出年龄依赖性高脂血症状态，并且使用抗高脂血症剂检查高脂血症在肠息肉形成中的参与。结果表明，Apc缺陷小鼠血清甘油三酯（TG）水平在15-20周龄时显著升高。然后，检查了PPARa配体苯扎贝特和PPARy配体吡格列酮对Apc缺陷小鼠Apc +/-小鼠中的高脂血症和肠息肉发展的影响<1309>。从<1309>6周龄开始用100和200 ppm吡格列酮或苯扎贝特治疗Apc^小鼠6周，导致血清TG剂量依赖性降低，沿着肠息肉数量减少。当Min小鼠接受100-1600 ppm吡格列酮治疗14周时，在最高剂量下，同样观察到血清TG和息肉数量分别下降至未治疗值的7%和9%。此外，Apc^和Min小鼠肝脏和小肠中的脂蛋白脂酶（LPL）mRNA水平<1309>通过吡格列酮治疗上调。因此，本研究表明，100- 1，600 ppm的吡格列酮可以抑制Apc基因缺陷小鼠的高脂血症和息肉形成，因此这种PPAR γ配体可能是结肠癌的良好候选化学预防剂。此外，研究表明，LPL选择性激活剂NO-1886也可抑制Min小鼠的血清脂质水平和息肉形成，这表明APC缺陷小鼠中LPL活性降低可能有助于高脂血症和息肉形成。这些抗高血脂药物可能是结肠癌化学预防的良好候选药物。

项目成果

Concurrent suppression of hyperlipidemia and intestinal polyp formation by NO-1886, increasing lipoprotein lipase activity in Min mice

• DOI: 10.1073/pnas.0500153102
• 发表时间: 2005-02-22
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Niho, N;Mutoh, M;Wakabayashi, K
• 通讯作者: Wakabayashi, K

Niho, N., et al.: "Dose-dependent suppression of hyperlipidemia and intestinal polyp formation in Min mice by pioglitazone, a PPARγ ligand."Cancer Sci.. 94. 960-964 (2003)

Niho, N., 等人：“吡格列酮（PPARγ 配体）对 Min 小鼠高脂血症和肠息肉形成的剂量依赖性抑制。”Cancer Sci.. 94. 960-964 (2003)

Dose-dependent suppression of hyperlipidemia and intestinal polyp formation in Min mice by pioglitazone, α PPARg ligand.

吡格列酮、α PPARg 配体对 Min 小鼠高脂血症和肠息肉形成的剂量依赖性抑制。

• 发表时间: 2003
• 期刊: Cancer Sci. Vol.94
• 作者: Niho;N.;et al.
• 通讯作者: et al.

Dose-dependent suppression of hyperlipidemia and intestinal polyp formation in Min mice by pioglitazone, a PPARg ligand.

PPARg 配体吡格列酮对 Min 小鼠高脂血症和肠息肉形成的剂量依赖性抑制。

• 发表时间: 2003
• 期刊: Cancer Sci. 94
• 作者: Niho;N.;et al.
• 通讯作者: et al.

Niho, N., et al.: "Concomitant suppression of hyperlipidemia and intestinal polyp formation in Apc deficient mice by PPAR ligands."Cancer Res.. 63. 6090-6095 (2003)

Niho, N., 等人：“PPAR 配体在 Apc 缺陷小鼠中同时抑制高脂血症和肠息肉形成。”Cancer Res.. 63. 6090-6095 (2003)