Abstract
Epidemiologically, a high-fat diet is associated with the risk of colon cancer. In addition, serum levels of triglycerides (TGs) and cholesterol have been demonstrated to be positively associated with colon carcinogenesis. We recently found that an age-dependent hyperlipidemic state (high serum TG levels) exists in Apc-deficient mice, an animal model for human familial adenomatous polyposis. The mRNA levels of lipoprotein lipase (LPL), which catalyzes TG hydrolysis, were shown to be downregulated in the liver and intestines of mice. Moreover, treatment with a peroxisome proliferator-activated receptor (PPAR) α agonist, bezafibrate, or a PPARγ agonist, pioglitazone, suppressed both hyperlipidemia and intestinal polyp formation in the mice, with induction of LPL mRNA. PPARα and PPARγ agonists are reported to exert anti-proliferative and pro-apoptotic effects in cancer cells. One compound that also increases LPL expression levels but does not possess PPAR agnostic activity is NO-1886. When given at 400 or 800 ppm in the diet, it suppresses both hyperlipidemia and intestinal polyp formation in Apc-deficient mice, with elevation of LPL mRNA. In conclusion, a decrease in serum lipid levels by increasing LPL activity may contribute to a reduction in intestinal polyp formation with Apc deficiency. PPARα and PPARγ agonists, as well as NO-1886, could be useful as chemopreventive agents for colon cancer.
References
Agarwal, B., Rao, C.V., Bhendwal, S., Ramey, W.R., Shirin, H., Reddy, B.S., and Holt, P.R. (1999). Lovastatin augments sulindac-induced apoptosis in colon cancer cells and potentiates chemopreventive effects of sulindac. Gastroenterology117, 838–847.10.1016/S0016-5085(99)70342-2Search in Google Scholar
Bruce, W.R., Wolever, T.M., and Giacca, A. (2000). Mechanisms linking diet and colorectal cancer: the possible role of insulin resistance. Nutr. Cancer37, 19–26.10.1207/S15327914NC3701_2Search in Google Scholar
Corpet, D.E. and Pierre, F. (2003). Point: from animal models to prevention of colon cancer. Systematic review of chemoprevention in min mice and choice of the model system. Cancer Epidemiol. Biomarkers Prev.12, 391–400.Search in Google Scholar
Doi, M., Kondo, Y., and Tsutsumi, K. (2003). Lipoprotein lipase activator NO-1886 (ibrolipim) accelerates the mRNA expression of fatty acid oxidation-related enzymes in rat liver. Metabolism52, 1547–1550.10.1016/j.metabol.2003.07.007Search in Google Scholar
DuBois, R.N., Radhika, A., Reddy, B.S., and Entingh, A.J. (1996). Increased cyclooxygenase-2 levels in carcinogen-induced rat colonic tumors. Gastroenterology110, 1259–1262.10.1053/gast.1996.v110.pm8613017Search in Google Scholar
Fodde, R., Edelmann, W., Yang, K., van Leeuwen, C., Carlson, C., Renault, B., Breukel, C., Alt, E., Lipkin, M., Khan, P.M., and Kucherlapati, R. (1994). A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. Proc. Natl. Acad. Sci. USA91, 8969–8973.10.1073/pnas.91.19.8969Search in Google Scholar
Gehrisch, S. (1999). Common mutations of the lipoprotein lipase gene and their clinical significance. Curr. Atheroscler. Rep.1, 70–78.10.1007/s11883-999-0052-4Search in Google Scholar
Goldberg, I.J. (1996). Lipoprotein lipase and lipolysis: central roles in lipoprotein metabolism and atherogenesis. J. Lipid Res.37, 693–707.10.1016/S0022-2275(20)37569-6Search in Google Scholar
Jackson, L., Wahli, W., Michalik, L., Watson, S.A., Morris, T., Anderton, K., Bell, D.R., Smith, J.A., Hawkey, C.J., and Bennett, A.J. (2003). Potential role for peroxisome proliferator activated receptor (PPAR) in preventing colon cancer. Gut52, 1317–1322.10.1136/gut.52.9.1317Search in Google Scholar PubMed PubMed Central
Jarvinen, R., Knekt, P., Hakulinen, T., Rissanen, H., and Heliovaara, M. (2001). Dietary fat, cholesterol and colorectal cancer in a prospective study. Br. J. Cancer85, 357–361.10.1054/bjoc.2001.1906Search in Google Scholar PubMed PubMed Central
Lefebvre, A.M., Chen, I., Desreumaux, P., Najib, J., Fruchart, J.C., Geboes, K., Briggs, M., Heyman, R., and Auwerx, J. (1998). Activation of the peroxisome proliferator-activated receptor promotes the development of colon tumors in C57BL/6J-APCMin/+ mice. Nat. Med.4, 1053–1057.10.1038/2036Search in Google Scholar PubMed
Le Marchand, L., Wilkens, L.R., Kolonel, L.N., Hankin, J.H., and Lyu, L.C. (1997). Associations of sedentary lifestyle, obesity, smoking, alcohol use, and diabetes with the risk of colorectal cancer. Cancer Res.57, 4787–4794.Search in Google Scholar
McKeown-Eyssen, G.E. (1994). Epidemiology of colorectal cancer revisited: are serum triglycerides and/or plasma glucose associated with risk? Cancer Epidemiol. Biomark. Prev.3, 687–695.Search in Google Scholar
Mead, J.R., Irvine, S.A., and Ramji, D.P. (2002). Lipoprotein lipase: structure, function, regulation, and role in disease. J. Mol. Med.80, 753–769.10.1007/s00109-002-0384-9Search in Google Scholar PubMed
Moser, A.R., Pitot, H.C., and Dove, W.F. (1990). A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science247, 322–324.10.1126/science.2296722Search in Google Scholar PubMed
Niho, N., Takahashi, M., Kitamura, T., Shoji, Y., Itoh, M., Noda, T., Sugimura, T., and Wakabayashi, K. (2003a). Concomitant suppression of hyperlipidemia and intestinal polyp formation in Apc-deficient mice by peroxisome proliferator-activated receptor ligands. Cancer Res.63, 6090–6095.Search in Google Scholar
Niho, N., Takahashi, M., Shoji, Y., Takeuchi, Y., Matsubara, S., Sugimura, T., and Wakabayashi, K. (2003b). Dose-dependent suppression of hyperlipidemia and intestinal polyp formation in Min mice by pioglitazone, a PPARγ ligand. Cancer Sci.94, 960–964.10.1111/j.1349-7006.2003.tb01385.xSearch in Google Scholar PubMed
Niho, N., Mutoh, M., Takahashi, M., Tsutsumi, K., Sugimura, T., and Wakabayashi, K. (2005). Concurrent suppression of hyperlipidemia and intestinal polyp formation by NO-1886, increasing lipoprotein lipase activity in Min mice. Proc. Natl. Acad. Sci. USA102, 2970–2974.10.1073/pnas.0500153102Search in Google Scholar PubMed PubMed Central
Oshima, M., Oshima, H., Kitagawa, K., Kobayashi, M., Itakura, C., and Taketo, M. (1995). Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene. Proc. Natl. Acad. Sci. USA92, 4482–4486.10.1073/pnas.92.10.4482Search in Google Scholar PubMed PubMed Central
Quesada, C.F., Kimata, H., Mori, M., Nishimura, M., Tsuneyoshi, T., and Baba, S. (1998). Piroxicam and acarbose as chemopreventive agents for spontaneous intestinal adenomas in APC gene 1309 knockout mice. Jpn. J. Cancer Res.89, 392–396.10.1111/j.1349-7006.1998.tb00576.xSearch in Google Scholar PubMed PubMed Central
Rosen, E.D. and Spiegelman, B.M. (2001). PPARγ: a nuclear regulator of metabolism, differentiation, and cell growth. J. Biol. Chem.276, 37731–37734.10.1074/jbc.R100034200Search in Google Scholar PubMed
Ross, S.E., Hemati, N., Longo, K.A., Bennett, C.N., Lucas, P.C., Erickson, R.L., and MacDougald, O.A. (2000). Inhibition of adipogenesis by Wnt signaling. Science289, 950–953.10.1126/science.289.5481.950Search in Google Scholar PubMed
Sakamoto, J., Kimura, H., Moriyama, S., Odaka, H., Momose, Y., Sugiyama, Y., and Sawada, H. (2000). Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone. Biochem. Biophys. Res. Commun.278, 704–711.10.1006/bbrc.2000.3868Search in Google Scholar PubMed
Sano, H., Kawahito, Y., Wilder, R.L., Hashiramoto, A., Mukai, S., Asai, K., Kimura, S., Kato, H., Kondo, M., and Hla, T. (1995). Expression of cyclooxygenase-1 and -2 in human colorectal cancer. Cancer Res.55, 3785–3789.Search in Google Scholar
Schoonjans, K., Peinado-Onsurbe, J., Lefebvre, A.M., Heyman, R.A., Briggs, M., Deeb, S., Staels, B., and Auwerx, J. (1996a). PPAR and PPAR activators direct a distinct tissue-specific transcriptional response via a PPRE in the lipoprotein lipase gene. EMBO J.15, 5336–5348.10.1002/j.1460-2075.1996.tb00918.xSearch in Google Scholar
Schoonjans, K., Staels, B., and Auwerx, J. (1996b). The peroxisome proliferator activated receptors (PPARs) and their effects on lipid metabolism and adipocyte differentiation. Biochim. Biophys. Acta1302, 93–109.10.1016/0005-2760(96)00066-5Search in Google Scholar
Semenkovich, C.F., Chen, S.H., Wims, M., Luo, C.C., Li, W.H., and Chan, L. (1989). Lipoprotein lipase and hepatic lipase mRNA tissue specific expression, developmental regulation, and evolution. J. Lipid Res.30, 423–431.10.1016/S0022-2275(20)38369-3Search in Google Scholar
Tanaka, T., Kohno, H., Yoshitani, S., Takashima, S., Okumura, A., Murakami, A., and Hosokawa, M. (2001). Ligands for peroxisome proliferator-activated receptors inhibit chemically induced colitis and formation of aberrant crypt foci in rats. Cancer Res.61, 2424–2428.Search in Google Scholar
Tettey, J.N., Maggs, J.L., Rapeport, W.G., Pirmohamed, M., and Park, B.K. (2001). Enzyme-induction dependent bioactivation of troglitazone and troglitazone quinone in vivo. Chem. Res. Toxicol.14, 965–974.10.1021/tx0001981Search in Google Scholar
Tsujii, M., Kawano, S., Tsuji, S., Sawaoka, H., Hori, M., and DuBois, R.N. (1998). Cyclooxygenase regulates angiogenesis induced by colon cancer cells. Cell93, 705–716.10.1016/S0092-8674(00)81433-6Search in Google Scholar
Tsutsumi, K., Inoue, Y., Shima, A., Iwasaki, K., Kawamura, M., and Murase, T. (1993). The novel compound NO-1886 increases lipoprotein lipase activity with resulting elevation of high density lipoprotein cholesterol, and long-term administration inhibits atherogenesis in the coronary arteries of rats with experimental atherosclerosis. J. Clin. Invest.92, 411–417.10.1172/JCI116582Search in Google Scholar
Williams, C.S., Luongo, C., Radhika, A., Zhang, T., Lamps, L.W., Nanney, L.B., Beauchamp, R.D., and DuBois, R.N. (1996). Elevated cyclooxygenase-2 levels in Min mouse adenomas. Gastroenterology111, 1134–1140.10.1016/S0016-5085(96)70083-5Search in Google Scholar
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