Leptin activation of mTOR pathway in intestinal epithelial cell triggers lipid droplet formation, cytokine production and increased cell proliferation.
Leptin activation of mTOR pathway in intestinal epithelial cell triggers lipid droplet formation, cytokine production and increased cell proliferation.
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DOI：
10.1080/15384101.2015.1041684
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发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Bozza PT
中科院分区：
文献类型：
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作者：
Fazolini NP;Cruz AL;Werneck MB;Viola JP;Maya-Monteiro CM;Bozza PT
越来越多的证据表明，肥胖和增强的炎症反应是发展结肠癌的诱发条件。肥胖与高水平的循环瘦素有关。瘦素是一种脂肪细胞因子，由脂肪组织分泌并调节免疫反应和炎症。脂滴（LD）是参与脂质代谢和炎症介质产生的细胞器，并且在人结肠癌中观察到LD数量增加。瘦素以PI 3 K/mTOR途径依赖的方式诱导巨噬细胞中LD的形成。此外，mTOR是一种丝氨酸/苏氨酸激酶，在细胞生长中起关键作用，并且在肿瘤中经常改变。因此，我们研究了瘦素在肠上皮细胞（IEC-6细胞）的mTOR通路的调节和脂质代谢和炎症表型的调节中的作用。我们发现，瘦素促进LD形成的剂量和时间依赖性增强。LD的生物发生伴随着这些细胞中CXCL 1/CINC-1、CCL 2/MCP-1和TGF-β的产生增加以及考克斯-2表达增加。我们证明瘦素诱导STAT 3和AKT的磷酸化增加以及剂量和时间依赖性mTORC激活，下游蛋白P70 S6 K蛋白的磷酸化增强。雷帕霉素预处理可显著抑制IEC-6细胞LD形成、考克斯-2和TGF-β的产生。此外，瘦素能够刺激上皮细胞增殖的mTOR依赖的方式。我们的结论是，瘦素调节脂质代谢，细胞因子的产生和肠细胞的增殖，通过一种机制，在很大程度上依赖于激活的mTOR通路，从而表明瘦素诱导的mTOR激活可能有助于肥胖相关的增强结肠癌的易感性。
Accumulating evidence suggests that obesity and enhanced inflammatory reactions are predisposing conditions for developing colon cancer. Obesity is associated with high levels of circulating leptin. Leptin is an adipocytokine that is secreted by adipose tissue and modulates immune response and inflammation. Lipid droplets (LD) are organelles involved in lipid metabolism and production of inflammatory mediators, and increased numbers of LD were observed in human colon cancer. Leptin induces the formation of LD in macrophages in a PI3K/mTOR pathway-dependent manner. Moreover, the mTOR is a serine/threonine kinase that plays a key role in cellular growth and is frequently altered in tumors. We therefore investigated the role of leptin in the modulation of mTOR pathway and regulation of lipid metabolism and inflammatory phenotype in intestinal epithelial cells (IEC-6 cells). We show that leptin promotes a dose- and time-dependent enhancement of LD formation. The biogenesis of LD was accompanied by enhanced CXCL1/CINC-1, CCL2/MCP-1 and TGF-β production and increased COX-2 expression in these cells. We demonstrated that leptin-induced increased phosphorylation of STAT3 and AKT and a dose and time-dependent mTORC activation with enhanced phosphorilation of the downstream protein P70S6K protein. Pre-treatment with rapamycin significantly inhibited leptin effects in LD formation, COX-2 and TGF-β production in IEC-6 cells. Moreover, leptin was able to stimulate the proliferation of epithelial cells on a mTOR-dependent manner. We conclude that leptin regulates lipid metabolism, cytokine production and proliferation of intestinal cells through a mechanism largely dependent on activation of the mTOR pathway, thus suggesting that leptin-induced mTOR activation may contribute to the obesity-related enhanced susceptibility to colon carcinoma.