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[Cancer Research 63, 6090-6095, September 15, 2003]
© 2003 American Association for Cancer Research

Epidemiology and Prevention

Concomitant Suppression of Hyperlipidemia and Intestinal Polyp Formation in Apc-deficient Mice by Peroxisome Proliferator-activated Receptor Ligands1

Naoko Niho2, Mami Takahashi, Tomohiro Kitamura, Yutaka Shoji, Masaki Itoh, Tetsuo Noda, Takashi Sugimura and Keiji Wakabayashi

Cancer Prevention Division, National Cancer Center Research Institute, Tokyo 104-0045 [N. N., M. T., T. K., Y. S., T. S., K. W.]; Cell Biology Department, Cancer Institute, Tokyo 170-8455 [M. I., T. N.]; Oncology Department, Jikei University School of Medicine, Tokyo 105-8461 [M. I.]; and The Core Research for Evolutional Science and Technology Program, Japan Science and Technology Corporation, Kawaguchi 332-0012 [T. N.], Japan

Epidemiological studies have shown a positive association of colon cancer with hyperlipidemia. Furthermore, signaling generated by peroxisome proliferator-activated receptor (PPAR) {alpha} and {gamma} ligands, suggested to be candidate tumor preventive agents, has been shown to lower serum triglyceride levels. In the present study, we assessed hyperlipidemia in Apc-deficient mice, model animals for human familial adenomatous polyposis, and examined the effects of pioglitazone and bezafibrate, respectively, PPAR{gamma} and PPAR{alpha} agonists, on both hyperlipidemia and intestinal polyposis. Serum lipid levels in Apc1309 mice and Min mice from 6 to 15 weeks of age were measured. Although serum levels of triglyceride and cholesterol were low in both Apc1309 and wild-type mice at 6 weeks, triglycerides were elevated 10-fold in Apc1309 mice by the age of 12 weeks but not in their wild-type counterparts. Cholesterol was also increased significantly, and marked centrilobular-restricted steatosis was observed in the livers of aged Apc1309 mice. Similar findings were observed for Min mice at 15 weeks of age. Moreover, lipoprotein lipase mRNA levels in the liver and small intestine of Apc1309 and Min mice were demonstrated to be lower than those in wild-type mice. Treatment of Apc1309 mice with 100 and 200 ppm pioglitazone or bezafibrate for 6 weeks from 6 weeks of age caused dose-dependent reduction in serum triglycerides and cholesterol, along with reduction in the numbers of intestinal polyps to 67% of the control value. The present study clearly demonstrated a hyperlipidemic state in Apc gene-deficient mice and a potential of PPAR{alpha} and PPAR{gamma} ligands to suppress both hyperlipidemia and polyp formation. Hyperlipidemia in these mice may thus be associated with their intestinal lesion development.




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