Concomitant suppression of hyperlipidemia and intestinal polyp formation in Apc-deficient mice by peroxisome proliferator-activated receptor ligands.

Epidemiological studies have shown a positive association of colon cancer with hyperlipidemia. Furthermore, signaling generated by peroxisome proliferator-activated receptor (PPAR) alpha and gamma ligands, suggested to be candidate tumor preventive agents, has been shown to lower serum triglyceride levels. In the present study, we assessed hyperlipidemia in Apc-deficient mice, model animals for human familial adenomatous polyposis, and examined the effects of pioglitazone and bezafibrate, respectively, PPARgamma and PPARalpha agonists, on both hyperlipidemia and intestinal polyposis. Serum lipid levels in Apc(1309) mice and Min mice from 6 to 15 weeks of age were measured. Although serum levels of triglyceride and cholesterol were low in both Apc(1309) and wild-type mice at 6 weeks, triglycerides were elevated 10-fold in Apc(1309) mice by the age of 12 weeks but not in their wild-type counterparts. Cholesterol was also increased significantly, and marked centrilobular-restricted steatosis was observed in the livers of aged Apc(1309) mice. Similar findings were observed for Min mice at 15 weeks of age. Moreover, lipoprotein lipase mRNA levels in the liver and small intestine of Apc(1309) and Min mice were demonstrated to be lower than those in wild-type mice. Treatment of Apc(1309) mice with 100 and 200 ppm pioglitazone or bezafibrate for 6 weeks from 6 weeks of age caused dose-dependent reduction in serum triglycerides and cholesterol, along with reduction in the numbers of intestinal polyps to 67% of the control value. The present study clearly demonstrated a hyperlipidemic state in Apc gene-deficient mice and a potential of PPARalpha and PPARgamma ligands to suppress both hyperlipidemia and polyp formation. Hyperlipidemia in these mice may thus be associated with their intestinal lesion development.

[1]  P. Watkins,et al.  Mouse Very Long-chain Acyl-CoA Synthetase in X-linked Adrenoleukodystrophy* , 2002, The Journal of Biological Chemistry.

[2]  Y. Kawahito,et al.  Expression of Peroxisome Proliferator-Activated Receptor γ in Renal Cell Carcinoma and Growth Inhibition by Its Agonists , 2001 .

[3]  B. Spiegelman,et al.  Adipose Expression of the Phosphoenolpyruvate Carboxykinase Promoter Requires Peroxisome Proliferator-activated Receptor γ and 9-cis-Retinoic Acid Receptor Binding to an Adipocyte-specific Enhancer in Vivo* , 1999, The Journal of Biological Chemistry.

[4]  B. Spiegelman,et al.  Effects of ligand activation of peroxisome proliferator-activated receptor gamma in human prostate cancer. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[5]  J Auwerx,et al.  The peroxisome proliferator activated receptors (PPARS) and their effects on lipid metabolism and adipocyte differentiation. , 1996, Biochimica et biophysica acta.

[6]  T. Barton,et al.  Changes in serum lipids related to the presence of experimental colon cancer. , 1987, British Journal of Cancer.

[7]  J. Auwerx,et al.  Activation of the peroxisome proliferator-activated receptor γ promotes the development of colon tumors in C57BL/6J-APCMin/+ mice , 1998, Nature Medicine.

[8]  M Oshima,et al.  Loss of Apc heterozygosity and abnormal tissue building in nascent intestinal polyps in mice carrying a truncated Apc gene. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[9]  B. Spiegelman,et al.  Terminal differentiation of human liposarcoma cells induced by ligands for peroxisome proliferator-activated receptor gamma and the retinoid X receptor. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[10]  T. Wolever,et al.  Mechanisms Linking Diet and Colorectal Cancer: The Possible Role of Insulin Resistance , 2000, Nutrition and cancer.

[11]  T. Noda,et al.  Inhibitory effects of mofezolac, a cyclooxygenase-1 selective inhibitor, on intestinal carcinogenesis. , 2002, Carcinogenesis.

[12]  J. Reddy,et al.  Hepatocellular and Hepatic Peroxisomal Alterations in Mice with a Disrupted Peroxisomal Fatty Acyl-coenzyme A Oxidase Gene* , 1996, The Journal of Biological Chemistry.

[13]  G. Atsumi,et al.  Magnitude of Peroxisome Proliferator-Activated Receptor-γ Activation is Associated With Important and Seemingly Opposite Biological Responses in Breast Cancer Cells , 2001, Journal of Investigative Medicine.

[14]  M. Mcentee,et al.  Discordant effect of aspirin and indomethacin on intestinal tumor burden in Apc(Min/+)mice. , 2000, Prostaglandins, leukotrienes, and essential fatty acids.

[15]  Y. Ohkura,et al.  New water-soluble hydrogen donors for the enzymatic photometric determination of hydrogen peroxide. II. N-ethyl-N-(2-hydroxy-3-sulfopropyl)aniline derivatives. , 1982 .

[16]  Takuji Tanaka,et al.  Ligands for peroxisome proliferator-activated receptors alpha and gamma inhibit chemically induced colitis and formation of aberrant crypt foci in rats. , 2001, Cancer research.

[17]  B. Spiegelman,et al.  APC-dependent suppression of colon carcinogenesis by PPARγ , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[18]  I. Sakurabayashi,et al.  Improved enzymatic method for determining free fatty acids in serum, with use of 3-octenoic acid. , 1990, Clinical chemistry.

[19]  W. Richmond.  Preparation and properties of a cholesterol oxidase from Nocardia sp. and its application to the enzymatic assay of total cholesterol in serum. , 1973, Clinical chemistry.

[20]  G. McKeown-Eyssen.  Epidemiology of colorectal cancer revisited: are serum triglycerides and/or plasma glucose associated with risk? , 1994, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[21]  S. Rockman,et al.  Id2 is a target of the beta-catenin/T cell factor pathway in colon carcinoma. , 2001, The Journal of biological chemistry.

[22]  S. Hirohashi,et al.  Transactivation of the multidrug resistance 1 gene by T-cell factor 4/beta-catenin complex in early colorectal carcinogenesis. , 2000, Cancer research.

[23]  Y. Ohkura,et al.  New water-soluble hydrogen donors for the enzymatic spectrophotometric determination of hydrogen peroxide , 1982 .

[24]  T. Okumura,et al.  Activation of PPARγ inhibits cell growth and induces apoptosis in human gastric cancer cells , 1999 .

[25]  D. Brackett,et al.  Therapeutic treatment of DMBA-induced mammary tumors with PPAR ligands. , 2001, Anticancer research.

[26]  K. Kinzler,et al.  Erratum: Multiple Intestinal Neoplasia Caused By a Mutation in the Murine Homolog of the APC Gene , 1992, Science.

[27]  Samuel Singer,et al.  Differentiation and reversal of malignant changes in colon cancer through PPARγ , 1998, Nature Medicine.

[28]  R. Hammer,et al.  Overproduction of cholesterol and fatty acids causes massive liver enlargement in transgenic mice expressing truncated SREBP-1a. , 1996, The Journal of clinical investigation.

[29]  J Auwerx,et al.  PPARalpha and PPARgamma activators direct a distinct tissue‐specific transcriptional response via a PPRE in the lipoprotein lipase gene. , 1996, The EMBO journal.

[30]  S. Baba,et al.  Piroxicam and Acarbose as Chemopreventive Agents for Spontaneous Intestinal Adenomas in APC Gene 1309 Knockout Mice , 1998, Japanese journal of cancer research : Gann.

[31]  J. G. Alvarez,et al.  Activators of the nuclear receptor PPARγ enhance colon polyp formation , 1998, Nature Medicine.

[32]  C. Rao,et al.  Lovastatin augments sulindac-induced apoptosis in colon cancer cells and potentiates chemopreventive effects of sulindac. , 1999, Gastroenterology.

[33]  H. Pitot,et al.  A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. , 1990, Science.

[34]  P. Knekt,et al.  Dietary fat, cholesterol and colorectal cancer in a prospective study , 2001, British Journal of Cancer.

[35]  M. Sporn,et al.  A New Ligand for the Peroxisome Proliferator-Activated Receptor-γ (PPAR-γ), GW7845, Inhibits Rat Mammary Carcinogenesis , 1999 .

[36]  S. Narumiya,et al.  Role of the prostaglandin E receptor subtype EP1 in colon carcinogenesis. , 1999, Cancer research.

[37]  T. Wang,et al.  Gastrin is a downstream target of the b-catenin/Tcf-4 signaling pathway which mediates growth in the APCmin−/+ model of intestinal polyposis , 2000 .

[38]  R Fodde,et al.  A targeted chain-termination mutation in the mouse Apc gene results in multiple intestinal tumors. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[39]  B. Spiegelman,et al.  PPARγ: a Nuclear Regulator of Metabolism, Differentiation, and Cell Growth* , 2001, The Journal of Biological Chemistry.

[40]  L. Chao,et al.  Adipose tissue is required for the antidiabetic, but not for the hypolipidemic, effect of thiazolidinediones. , 2000, The Journal of clinical investigation.

[41]  J. Lehmann,et al.  Peroxisome Proliferator-activated Receptors α and γ Are Activated by Indomethacin and Other Non-steroidal Anti-inflammatory Drugs* , 1997, The Journal of Biological Chemistry.

[42]  Paul Polakis,et al.  The metalloproteinase matrilysin is a target of β-catenin transactivation in intestinal tumors , 1999, Oncogene.

[43]  Y. Momose,et al.  Activation of human peroxisome proliferator-activated receptor (PPAR) subtypes by pioglitazone. , 2000, Biochemical and biophysical research communications.

[44]  H. Kawamata,et al.  Expression of peroxisome proliferator-activated receptor gamma and the growth inhibitory effect of its synthetic ligands in human salivary gland cancer cell lines. , 2002, International journal of oncology.

[45]  S. Ishihara,et al.  Peroxisome proliferator-activated receptor γ ligand-induced growth inhibition of human hepatocellular carcinoma , 2001, British Journal of Cancer.