Dose-dependent suppression of hyperlipidemia and intestinal polyp formation in Min mice by pioglitazone, a PPAR gamma ligand.
In our previous study, a peroxisome proliferator-activated receptor gamma (PPAR gamma) agonist, pioglitazone, suppressed both hyperlipidemia and intestinal polyp formation in Apc(1309) mice at doses of 100 and 200 ppm in the diet. In contrast, it has been reported that doses of 1500 or 2000 ppm of another PPAR gamma agonist, troglitazone, enhanced colon polyp development in Min mice. In the present study, we therefore investigated the effects of a wide range of pioglitazone doses on both hyperlipidemia and intestinal polyp formation in Min mice. Serum triglycerides and very low density lipoprotein (VLDL) cholesterol in the basal diet group were elevated to levels 13-15 times higher than those in the wild-type counterparts at 20 weeks of age. They were reduced dose-dependently by treatment with 100, 200, 400 and 1600 ppm pioglitazone from 6-20 weeks of age with suppression to almost the wild-type level at the highest dose. Moreover, up-regulation of the liver mRNA levels for lipoprotein lipase (LPL) was evident in the pioglitazone-treated animals. Dose-dependent reduction of intestinal polyps was observed in Min mice given 100-1600 ppm for 14 weeks, total numbers being decreased to 63-9% of the control value. A suppressive effect of pioglitazone on colon polyp formation was also found. The PPAR gamma agonist, pioglitazone, may thus be a promising candidate chemopreventive agent for colon cancer.
Niho
Naoko
N
Cancer Prevention Basic Research Project, National Cancer Center Research Institute, Chuo-ku, Tokyo 104-0045. nniho@gan2.ncc.go.jp
Takahashi
Mami
M
Shoji
Yutaka
Y
Takeuchi
Yoshito
Y
Matsubara
Satoshi
S
Sugimura
Takashi
T
Wakabayashi
Keiji
K
D000818:Animals; D008078:Cholesterol, LDL / Q000097:blood / Q000235:genetics; D003111:Colonic Polyps / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D017491:Genes, APC; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D044483:Intestinal Polyposis / Q000097:blood / Q000188:drug therapy* / Q000473:pathology; D008024:Ligands; D008071:Lipoprotein Lipase / Q000378:metabolism; D008099:Liver / Q000201:enzymology; D008297:Male; 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*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D045162:Thiazolidinediones / Q000627:therapeutic use*; D014157:Transcription Factors / Q000819:agonists*; D014280:Triglycerides / Q000097:blood
D008078:Cholesterol, LDL; D007004:Hypoglycemic Agents; D008024:Ligands; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D045162:Thiazolidinediones; D014157:Transcription Factors; D014280:Triglycerides; D008071:Lipoprotein Lipase; D000077205:Pioglitazone