| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2004: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Research Abstract |
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.
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