Niho Naoko, Takahashi Mami, Kitamura Tomohiro, Shoji Yutaka, Itoh Masaki, Noda Tetsuo, Sugimura Takashi, Wakabayashi Keiji
Cancer Prevention Division, National Cancer Center Research Institute, Tokyo, Japan.
Cancer Res. 2003 Sep 15;63(18):6090-5.
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.
流行病学研究表明结肠癌与高脂血症呈正相关。此外，过氧化物酶体增殖物激活受体（PPAR）α和γ配体产生的信号被认为是潜在的肿瘤预防剂，已被证明可降低血清甘油三酯水平。在本研究中，我们评估了Apc基因缺陷小鼠（人类家族性腺瘤性息肉病的模型动物）的高脂血症情况，并分别研究了PPARγ激动剂吡格列酮和PPARα激动剂苯扎贝特对高脂血症和肠道息肉病的影响。测量了6至15周龄的Apc(1309)小鼠和Min小鼠的血脂水平。虽然6周龄时Apc(1309)小鼠和野生型小鼠的血清甘油三酯和胆固醇水平都很低，但到12周龄时，Apc(1309)小鼠的甘油三酯升高了10倍，而野生型小鼠则没有。胆固醇也显著增加，在老年Apc(1309)小鼠的肝脏中观察到明显的小叶中央局限性脂肪变性。15周龄的Min小鼠也有类似的发现。此外，Apc(1309)小鼠和Min小鼠肝脏和小肠中的脂蛋白脂肪酶mRNA水平低于野生型小鼠。从6周龄开始，用100和200 ppm的吡格列酮或苯扎贝特治疗Apc(1309)小鼠6周，可使血清甘油三酯和胆固醇呈剂量依赖性降低，同时肠道息肉数量减少至对照值的67%。本研究清楚地证明了Apc基因缺陷小鼠存在高脂血症状态，以及PPARα和PPARγ配体抑制高脂血症和息肉形成的潜力。因此，这些小鼠的高脂血症可能与其肠道病变发展有关。
