Concomitant suppression of hyperlipidemia and intestinal polyp formation by increasing lipoprotein lipase activity in Apc-deficient mice.
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) alpha agonist, bezafibrate, or a PPARgamma agonist, pioglitazone, suppressed both hyperlipidemia and intestinal polyp formation in the mice, with induction of LPL mRNA. PPARalpha and PPARgamma 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. PPARalpha and PPARgamma agonists, as well as NO-1886, could be useful as chemopreventive agents for colon cancer.
Mutoh
Michihiro
M
Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Niho
Naoko
N
Wakabayashi
Keiji
K
D000367:Age Factors; D000818:Animals; D001549:Benzamides / Q000378:metabolism / Q000494:pharmacology; D001629:Bezafibrate / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D051546:Cyclooxygenase 2 / Q000378:metabolism; D017491:Genes, APC; D006801:Humans; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D007417:Intestinal Polyps / Q000378:metabolism / Q000517:prevention & control*; D008071:Lipoprotein Lipase / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D009943:Organophosphorus Compounds / Q000378:metabolism / Q000494:pharmacology; D047493:PPAR alpha / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D000077205:Pioglitazone; D045162:Thiazolidinediones / Q000008:administration & dosage / Q000378:metabolism / Q000494:pharmacology; D014280:Triglycerides / Q000097:blood / Q000378:metabolism
D001549:Benzamides; D008565:Membrane Proteins; D009943:Organophosphorus Compounds; D047493:PPAR alpha; D047495:PPAR gamma; D045162:Thiazolidinediones; D014280:Triglycerides; C082137:4-diethoxyphosphorylmethyl-N-(4-bromo-2-cyanophenyl)benzamide; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D008071:Lipoprotein Lipase; D000077205:Pioglitazone; D001629:Bezafibrate