Concurrent suppression of hyperlipidemia and intestinal polyp formation by NO-1886, increasing lipoprotein lipase activity in Min mice.

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.

• Authors: Naoko Niho, Michihiro Mutoh, Mami Takahashi, Kazuhiko Tsutsumi, Takashi Sugimura, Keiji Wakabayashi
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 102 Issue 8 Pg. 2970-4 (Feb 22 2005) ISSN: 0027-8424 [Print] United States
• PMID: 15710887 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anticarcinogenic Agents
• Benzamides
• Cholesterol, HDL
• Cholesterol, LDL
• Cholesterol, VLDL
• Hypolipidemic Agents
• Organophosphorus Compounds
• RNA, Messenger
• 4-diethoxyphosphorylmethyl-N-(4-bromo-2-cyanophenyl)benzamide
• Cyclooxygenase 2
• Prostaglandin-Endoperoxide Synthases
• Lipoprotein Lipase

Topics

• Animals
• Anticarcinogenic Agents (therapeutic use)
• Benzamides (therapeutic use)
• Cholesterol, HDL (blood)
• Cholesterol, LDL (blood)
• Cholesterol, VLDL (blood)
• Cyclooxygenase 2
• Female
• Hyperlipidemias (drug therapy)
• Hypolipidemic Agents (therapeutic use)
• Intestinal Polyps (prevention & control)
• Lipoprotein Lipase (genetics, metabolism)
• Mice
• Mice, Inbred C57BL
• Organophosphorus Compounds (therapeutic use)
• Prostaglandin-Endoperoxide Synthases (genetics)
• RNA, Messenger (analysis)