title: Concomitant suppression of hyperlipidemia and intestinal polyp formation in Apc-deficient mice by peroxisome proliferator-activated receptor ligands.
abstract: 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, PPARgamma and PPARalpha agonists, on both hyperlipidemia and intestinal polyposis. Serum lipid levels in Apc(1309) mice and Min mice from 6 to 15 weeks of age were measured. Although serum levels of triglyceride and cholesterol were low in both Apc(1309) and wild-type mice at 6 weeks, triglycerides were elevated 10-fold in Apc(1309) 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 Apc(1309) 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 Apc(1309) and Min mice were demonstrated to be lower than those in wild-type mice. 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 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 PPARalpha and PPARgamma ligands to suppress both hyperlipidemia and polyp formation. Hyperlipidemia in these mice may thus be associated with their intestinal lesion development.
authors.affiliation: Cancer Prevention Division, National Cancer Center Research Institute, Tokyo, Japan. nniho@gan2.ncc.go.jp
authors.forename: Naoko
authors.initials: N
authors.lastname: Niho
authors.forename: Mami
authors.initials: M
authors.lastname: Takahashi
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kitamura
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Shoji
authors.forename: Masaki
authors.initials: M
authors.lastname: Itoh
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.forename: Takashi
authors.initials: T
authors.lastname: Sugimura
authors.forename: Keiji
authors.initials: K
authors.lastname: Wakabayashi
mesh_terms: D000367:Age Factors; D000818:Animals; D001629:Bezafibrate / Q000494:pharmacology*; D002784:Cholesterol / Q000097:blood; D005230:Fatty Acids, Nonesterified / Q000097:blood; D017491:Genes, APC / Q000502:physiology*; D006949:Hyperlipidemias / Q000097:blood / Q000150:complications / Q000188:drug therapy* / Q000235:genetics; D044483:Intestinal Polyposis / Q000097:blood / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics; D007421:Intestine, Small / Q000201:enzymology; D008024:Ligands; D008071:Lipoprotein Lipase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D000077205:Pioglitazone; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists*; D045162:Thiazolidinediones / Q000494:pharmacology*; D014157:Transcription Factors / Q000819:agonists*; D014280:Triglycerides / Q000097:blood
chemical_list: D005230:Fatty Acids, Nonesterified; D008024:Ligands; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D014280:Triglycerides; D002784:Cholesterol; D008071:Lipoprotein Lipase; D000077205:Pioglitazone; D001629:Bezafibrate