Improvement of hyperlipidemia by indomethacin in Min mice.
Apc gene-deficient Min and Apc(1309) mice feature a hyperlipidemic state with a markedly low expression level of lipoprotein lipase (LPL) compared to their wild-type counterparts. We previously showed that induction of LPL mRNA by peroxisome proliferator-activated receptor (PPAR) alpha and gamma agonists or an LPL selective inducer suppresses both high serum lipid levels and intestinal polyp formation in these model animals. Since the general cyclooxygenase inhibitor, indomethacin, is known to suppress intestinal tumor development, but not to affect serum lipids, its influence in Min mice was here investigated. Treatment with 2.5, 5 and 10 ppm indomethacin in the diet for 14 weeks from 6 weeks of age caused significant dose-dependent reduction in serum triglycerides, along with a reduction in the numbers of intestinal polyps to 25% of the untreated control value. LPL mRNA levels in the liver were slightly increased by indomethacin treatment. We further performed oligonucleotide microarray analysis and quantitative PCR analysis and found 8 lipid metabolism-related genes, regulated by sterol regulatory element binding protein-1c, to be modulated by indomethacin-treatment in the Min mouse liver. Furthermore, TNFalpha was downregulated. These results indicate that indomethacin might suppress intestinal tumor formation together with a hyperlipidemic state by regulating LPL and other lipid metabolic factors.
Niho
Naoko
N
Cancer Prevention Basic Research Project, National Cancer Center Research Institute, Chuo-ku, Tokyo, Japan.
Mutoh
Michihiro
M
Komiya
Masami
M
Ohta
Tsutomu
T
Sugimura
Takashi
T
Wakabayashi
Keiji
K
D000818:Animals; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D018076:DNA, Complementary / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006949:Hyperlipidemias / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology* / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D007213:Indomethacin / Q000494:pharmacology*; D008071:Lipoprotein Lipase / Q000097:blood* / Q000187:drug effects / Q000235:genetics; D008099:Liver / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D016133:Polymerase Chain Reaction; D012333:RNA, Messenger / Q000378:metabolism; D051780:Sterol Regulatory Element Binding Protein 1 / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood*
D016861:Cyclooxygenase Inhibitors; D018076:DNA, Complementary; D000960:Hypolipidemic Agents; D012333:RNA, Messenger; D051780:Sterol Regulatory Element Binding Protein 1; D014280:Triglycerides; D008071:Lipoprotein Lipase; D007213:Indomethacin