高胆固醇饮食与癌症有关,原来是“干细胞”在捣鬼!
2018/02/09
众所周知,不健康饮食会增加患各种疾病的风险。其中,高胆固醇饮食被证实与结肠癌风险升高有关。那么,这背后的机制是怎样的呢?来自美国的一个科学家小组于近日找到了答案!


图片来源:Cell Stem Cell(DOI: http://dx.doi.org/10.1016/j.stem.2017.12.017)

“虽然先前已有研究建立了胆固醇与结肠癌之间的联系,但其背后的机制一直不得而知。发现胆固醇会影响肠道干细胞的生长,我们感到非常兴奋。”加州大学洛杉矶分校的Peter Tontonoz教授说。

1月25日,在线发表于 Cell Stem Cell上题为“Phospholipid Remodeling and Cholesterol Availability Regulate Intestinal Stemness and Tumorigenesis”的论文中,Peter Tontonoz教授带领的研究小组发现,提高小鼠的胆固醇水平会促使肠道干细胞分裂得更快,从而使肿瘤形成的速度快了100倍。


A pale-blue stain shows stem cells multiplying in a mouse's intestine. Credit: Tontonoz lab/UCLA

具体来说,在一些小鼠中,科学家们通过在它们的饮食中引入更多的胆固醇增加肠道干细胞中的这类物质;而在另一些小鼠中,研究人员是通过改变调节磷脂(phospholipids,细胞膜中脂肪的主要类型)的一个基因——Lpcat3,从而使得细胞自己产生更多的胆固醇。研究结果显示,这两组小鼠的肠道干细胞增殖能力都增加了。


图片来源:Cell Stem Cell

Tontonoz教授解释道:“当小鼠的胆固醇水平升高后,它们的细胞分裂得更快,这导致肠道中的组织扩张,以及肠道变长(lengthen)。这些变化显著加快了结肠中肿瘤形成的速度。

此外,该研究中,科学家们还鉴定出了一个可作为结肠癌治疗新药物靶点的分子通路。据悉,未来,他们将进一步探索,是否这一分子通路在加速其他癌症的生长中也扮演着类似的角色。

参考资料:

Study could explain link between high-cholesterol diet and colon cancer

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  • Phospholipid Remodeling and Cholesterol Availability Regulate Intestinal Stemness and Tumorigenesis

    Adequate availability of cellular building blocks, including lipids, is a prerequisite for cellular proliferation, but excess dietary lipids are linked to increased cancer risk. Despite these connections, specific regulatory relationships between membrane composition, intestinal stem cell (ISC) proliferation, and tumorigenesis are unclear. We reveal an unexpected link between membrane phospholipid remodeling and cholesterol biosynthesis and demonstrate that cholesterol itself acts as a mitogen for ISCs. Inhibition of the phospholipid-remodeling enzyme Lpcat3 increases membrane saturation and stimulates cholesterol biosynthesis, thereby driving ISC proliferation. Pharmacologic inhibition of cholesterol synthesis normalizes crypt hyperproliferation in Lpcat3-deficient organoids and mice. Conversely, increasing cellular cholesterol content stimulates crypt organoid growth, and providing excess dietary cholesterol or driving endogenous cholesterol synthesis through SREBP-2 expression promotes ISC proliferation in vivo. Finally, disruption of Lpcat3-dependent phospholipid and cholesterol homeostasis dramatically enhances tumor formation in Apcmin mice. These findings identify a critical dietary-responsive phospholipid-cholesterol axis regulating ISC proliferation and tumorigenesis.

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