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)␣ and PPAR␥ 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 PPAR␣ and PPAR␥ 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.

Inhibition of Intestinal Polyp Formation by Pitavastatin, a HMG-CoA Reductase Inhibitor

“…Hyperlipidemia has also been indicated to be positively associated with colon carcinogenesis (3,4). We have reported Apc deficient, Min and Apc 1309 mice, which developed a large number of intestinal polyps showed the hyperlipidemic state (5)(6)(7). Interestingly, improvement of hyperlipidemic state by peroxisome proliferator-activated receptor (PPAR) a and g agonists and a selective LPL-inducing agent, NO-1886, which does not possess PPARs agonistic activity, suppressed intestinal polyp formation in Min mice.…”

Differential Effects of Lipoprotein Lipase on Tumor Necrosis Factor-α and Interferon-γ-mediated Gene Expression in Human Endothelial Cells

“…In mouse models of adenomatous polyposis such as Min and APC 1309 age-dependent hyperlipidemia, increased intestinal polyp formation and down-regulation of LPL was reported (14). Administration of NO-1886, a compound known to increase LPL mRNA and protein levels, resulted in concurrent suppression of hyperlipidemia, cyclooxygenase-2 levels, and intestinal polyp formation (15).…”

Susceptibility of Snark‐deficient mice to azoxymethane‐induced colorectal tumorigenesis and the formation of aberrant crypt foci

“…(8)(9)(10)(11)(12)(13)(14)(15)(16)(17) We suspected that the metabolic disorders in Snark-deficient mice might be correlated with tumorigenesis. Furthermore, SNARK activity is reportedly upregulated under genotoxic stresses in some cell culture systems, suggesting the potential roles of SNARK in cellular stress responses.…”