Concomitant suppression of hyperlipidemia and intestinal polyp formation in Apc-deficient mice by peroxisome proliferator-activated receptor ligands.
Concomitant suppression of hyperlipidemia and intestinal polyp formation in Apc-deficient mice by peroxisome proliferator-activated receptor ligands.
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发表时间：
2003-09
期刊：
影响因子：
11.2
通讯作者：
N. Niho;Mami Takahashi;T. Kitamura;Y. Shoji;M. Itoh;T. Noda;T. Sugimura;K. Wakabayashi
中科院分区：
文献类型：
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作者：
N. Niho;Mami Takahashi;T. Kitamura;Y. Shoji;M. Itoh;T. Noda;T. Sugimura;K. Wakabayashi
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候选肿瘤预防剂，已被证明可以降低血清甘油三酯水平。在本研究中，我们评估了 Apc 缺陷小鼠（人类家族性腺瘤性息肉病模型动物）的高脂血症，并检查了吡格列酮和苯扎贝特（分别为 PPARγ 和 PPARα 激动剂）对高脂血症和肠息肉病的影响。测量了 6 至 15 周龄的 Apc(1309) 小鼠和 Min 小鼠的血清脂质水平。尽管 6 周时 Apc(1309) 和野生型小鼠的血清甘油三酯和胆固醇水平较低，但到 12 周龄时，Apc(1309) 小鼠的甘油三酯升高了 10 倍，而野生型小鼠则不然。胆固醇也显着增加，并且在老年 Apc(1309) 小鼠的肝脏中观察到明显的小叶中心限制性脂肪变性。在 15 周龄的 Min 小鼠中也观察到了类似的结果。此外，Apc(1309) 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 吡格列酮或苯扎贝特治疗 Apc(1309) 小鼠 6 周，导致血清甘油三酯和胆固醇呈剂量依赖性下降，同时肠息肉数量减少至对照值的 67%。本研究清楚地证明了 Apc 基因缺陷小鼠的高脂血症状态以及 PPARα 和 PPARgamma 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的发展有关。
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.