Dose‐dependent suppression of hyperlipidemia and intestinal polyp formation in Min mice by pioglitazone, a PPARγ ligand

Abstract

In our previous study, a peroxisome proliferator-activated receptor γ γ γ γ (PPARγ γ γ γ) 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 PPARγ γ γ γ 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 PPARγ γ γ γ agonist, pioglitazone, may thus be a promising candidate chemopreventive agent for colon cancer. onsumption of a high fat diet is epidemiologically related to the risk of colon cancer.

Suppressive Effect of Pioglitazone, a PPAR Gamma Ligand, on Azoxymethane-induced Colon Aberrant Crypt Foci in KK-AуMice

“…Pioglitazone also could effectively suppress intestinal polyp development in Min mice (Niho et al, 2003). Thus, pioglitazone might be a good candidate for a chemopreventive agent against obesity-associated colorectal cancer.…”

“…At the same time of first intraperitoneal injections, pioglitazone was administrated at concentrations of 400 or 800 ppm in basal diet. The dosage of pioglitazone was determined by our previous experiment (Niho et al, 2003). Food and water were available ad libitum.…”

“…Serum levels of triglycerides and total cholesterol were measured as reported (Niho et al, 2003). Serum levels of adiponectin, interleukin-1β (IL-1β), IL-6, MCP-1, leptin and insulin were measured using mouse adiponectin immunoassay (R&D systems, Inc., Minneapolis, MN, USA), mouse procarta® cytokine assay (Affymetrix, Inc., Santa Clara, CA, USA), a mouse leptin enzyme-linked immunosorbent assay kit (B-Bridge International, Inc., Cupertino, CA, USA) and a mouse insulin kit (Millipore Corp., Billerica, MA, USA).…”

“…Although side effects, such as weight gain, peripheral edema, precipitation of chronic heart failure and an increase in bone fractures limit widespread use of pioglitazone, pioglitazone is a useful antidiabetic drug, which is well tolerated in the majority of patients (Shah et al, 2010). Previously, we have reported that pioglitazone induced LPL and suppressed concurrently both hyperlipidemia and intestinal polyp formation in Apc-deficient Min mice, a model mouse for familial adenomatous polyposis (Niho et al, 2003). Thus, pioglitazone may be a potential chemopreventive agent against colorectal carcinogenesis.…”

Catalpa seed oil rich in 9t,11t,13c-conjugated linolenic acid suppresses the development of colonic aberrant crypt foci induced by azoxymethane in rats

“…Serum levels of triglycerides and cholesterol have been shown to be positively associated with colon carcinogenesis (38,39). Niho et al found that serum levels of triglycerides in Min mice are dramatically increased compared to the wild-type and the increase contributes to the growth of small intestinal polyps (40). They also demonstrated that a peroxisome proliferator-activated receptors (PPAR)Á ligand suppresses both serum triglyceride level and intestinal polyp formation in Min mice (40).…”