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Concurrent suppression of hyperlipidemia and intestinal polyp formation by NO-1886, increasing lipoprotein lipase
Naoko Niho1, Michihiro Mutoh, Mami Takahashi
1Cancer Prevention Basic Research Project, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Abstract:
We have previously reported a hyperlipidemic state in two strains of Apc-deficient mice, Min and Apc(1309), associated with low expression levels of lipoprotein lipase (LPL) in the liver and small intestine, and enforced induction of LPL mRNA by peroxisome proliferator-activated receptor (PPAR)alpha and PPARgamma agonists clearly suppressed hyperlipidemia and intestinal polyp formation in these mice. Meanwhile, a compound, NO-1886, has been shown to increase LPL mRNA and protein levels but not to possess PPARalpha and PPARgamma agonistic activity. In this study, therefore, the effects of NO-1886 on hyperlipidemia and intestinal polyp formation were investigated in Min mice. Administration of 400 and 800 ppm NO-1886 in the diet for 13 weeks from 7 weeks of age caused a reduction of serum triglycerides to 39% and 31% of the untreated value, respectively, and the values for very low-density lipoprotein cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol were improved almost to the wild-type level with a corresponding elevation of the LPL mRNA. Moreover, total numbers of intestinal polyps in the groups receiving NO-1886 at 400 and 800 ppm were decreased to 48% and 42% of the control value, respectively. We also found that NO-1886 suppressed cyclooxygenase-2 transcriptional promoter activity in a reporter gene assay and reduced cyclooxygenase-2 mRNA levels in the small intestine of Min mice. These results indicate that suppression of serum lipid levels by increasing LPL activity may contribute to a reduction of intestinal polyp formation with Apc-deficiency, and NO-1886 and its derivatives could be useful as chemopreventive agents for colon cancer.
Insights
The compound NO-1886 effectively reduced hyperlipidemia and intestinal polyps in Apc-deficient mice by increasing lipoprotein lipase (LPL) levels. This suggests NO-1886 and its derivatives may serve as chemopreventive agents for colon cancer.
Area of Science:
- Biochemistry
- Genetics
- Oncology
Background:
- Apc-deficient mice (Min and Apc(1309)) exhibit hyperlipidemia linked to low lipoprotein lipase (LPL) expression.
- Peroxisome proliferator-activated receptor (PPAR) agonists reduce hyperlipidemia and polyps in these mice by inducing LPL mRNA.
Purpose of the Study:
- To investigate the effects of NO-1886, a compound that increases LPL without PPAR agonism, on hyperlipidemia and intestinal polyp formation in Min mice.
Main Methods:
- Min mice were fed diets containing 400 or 800 ppm NO-1886 for 13 weeks.
- Serum lipid levels, LPL mRNA, and intestinal polyp counts were analyzed.
- Cyclooxygenase-2 (COX-2) transcriptional activity and mRNA levels were assessed.
Main Results:
- NO-1886 significantly reduced serum triglycerides, LDL, and HDL cholesterol levels.
- LPL mRNA levels were elevated, correlating with lipid improvements.
- Intestinal polyp numbers were decreased in NO-1886 treated groups.
- NO-1886 suppressed COX-2 transcriptional activity and mRNA levels.
Conclusions:
- Increased LPL activity by NO-1886 contributes to reduced intestinal polyps in Apc-deficient mice.
- NO-1886 and its derivatives show potential as chemopreventive agents for colon cancer.
