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High-fat diet enhances stemness and tumorigenicity of intestinal progenitors

机译：高脂饮食可增强肠道祖细胞的干性和致瘤性

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摘要

Little is known about how pro-obesity diets regulate tissue stem and progenitor cell function. Here we show that high-fat diet (HFD)-induced obesity augments the numbers and function of Lgr5(+) intestinal stem cells of the mammalian intestine. Mechanistically, a HFD induces a robust peroxisome proliferator-activated receptor delta (PPAR-delta) signature in intestinal stem cells and progenitor cells (non-intestinal stem cells), and pharmacological activation of PPAR-delta recapitulates the effects of a HFD on these cells. Like a HFD, ex vivo treatment of intestinal organoid cultures with fatty acid constituents of the HFD enhances the self-renewal potential of these organoid bodies in a PPAR-delta-dependent manner. Notably, HFD- and agonist-activated PPAR-delta signalling endow organoid-initiating capacity to progenitors, and enforced PPAR-delta signalling permits these progenitors to form in vivo tumours after loss of the tumour suppressor Apc. These findings highlight how diet-modulated PPAR-delta activation alters not only the function of intestinal stem and progenitor cells, but also their capacity to initiate tumours.
机译：关于肥胖饮食如何调节组织干和祖细胞功能知之甚少。在这里，我们表明，高脂饮食（HFD）引起的肥胖症会增加哺乳动物肠道Lgr5（+）肠道干细胞的数量和功能。从机理上讲，HFD会在肠道干细胞和祖细胞（非肠道干细胞）中诱导强大的过氧化物酶体增殖物激活受体δ（PPAR-delta）签名，并且PPAR-δ的药理学激活概括了HFD对这些细胞的作用。像HFD一样，用HFD的脂肪酸成分对肠道类器官培养物进行离体处理，可以以PPAR-δ依赖性方式增强这些类器官的自我更新能力。值得注意的是，HFD和激动剂激活的PPAR-δ信号传递赋予祖细胞类器官起始能力，而强制的PPAR-δ信号传递使这些祖细胞在肿瘤抑制因子Apc丧失后形成体内肿瘤。这些发现突显了饮食调节的PPAR-δ激活如何不仅改变肠道干细胞和祖细胞的功能，而且改变它们引发肿瘤的能力。

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  • 来源
    《Nature》 |2016年第7592期|53-58|共6页
  • 作者

    Beyaz Semir; Mana Miyeko D.; Roper Jatin; Kedrin Dmitriy; Saadatpour Assieh; Hong Sue Jean; Bauer-Rowe Khristian E.; Xifaras Michael E.; Akkad Adam; Arias Erika; Pinello Luca; Katz Yarden; Shinagare Shweta; Abu-Remaileh Monther; Mihaylova Maria M.; Lamming Dudley W.; Dogum Rizkullah; Guo Guoji; Bell George W.; Selig Martin; Nielsen G. Petur; Gupta Nitin; Ferrone Cristina R.; Deshpande Vikram; Yuan Guo-Cheng; Orkin Stuart H.; Sabatini David M.; Yilmaz Oemer H.;

  • 作者单位

    MIT, Dept Biol, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA|Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol,Howard Hughes Med Inst,Harvard, 44 Binney St, Boston, MA 02115 USA;

    MIT, Dept Biol, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA;

    MIT, Dept Biol, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA|Tufts Med Ctr, Div Gastroenterol, Boston, MA 02111 USA|Tufts Med Ctr, Mol Oncol Res Inst, Boston, MA 02111 USA;

    MIT, Dept Biol, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA|Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA|Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA|Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA|Harvard Univ, Sch Med, Boston, MA 02114 USA;

    Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA|Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA;

    MIT, Dept Biol, Howard Hughes Med Inst, Whitehead Inst Biomed Res, 77 Massachusetts Ave, Cambridge, MA 02142 USA;

    MIT, Dept Biol, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA;

    MIT, Dept Biol, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA;

    MIT, Dept Biol, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA;

    MIT, Dept Biol, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA;

    Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA|Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA;

    Broad Inst Harvard & MIT, Cambridge, MA 02142 USA;

    MIT, Dept Biol, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA;

    MIT, Dept Biol, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA|MIT, Dept Biol, Howard Hughes Med Inst, Whitehead Inst Biomed Res, 77 Massachusetts Ave, Cambridge, MA 02142 USA;

    MIT, Dept Biol, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA|MIT, Dept Biol, Howard Hughes Med Inst, Whitehead Inst Biomed Res, 77 Massachusetts Ave, Cambridge, MA 02142 USA;

    Univ Wisconsin, Dept Med, Madison, WI 53705 USA;

    MIT, Dept Biol, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA;

    Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol,Howard Hughes Med Inst,Harvard, 44 Binney St, Boston, MA 02115 USA;

    MIT, Dept Biol, Howard Hughes Med Inst, Whitehead Inst Biomed Res, 77 Massachusetts Ave, Cambridge, MA 02142 USA;

    Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA|Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA|Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA|Harvard Univ, Sch Med, Boston, MA 02114 USA;

    Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA|Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA|Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA|Harvard Univ, Sch Med, Boston, MA 02114 USA;

    Univ Mississippi, Med Ctr, Div Digest Dis, Jackson, MS 39216 USA;

    Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA|Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA|Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA|Harvard Univ, Sch Med, Boston, MA 02114 USA;

    Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA|Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA|Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA|Harvard Univ, Sch Med, Boston, MA 02114 USA;

    Dana Farber Canc Inst, Dept Biostat & Computat Biol, Boston, MA 02115 USA|Harvard Univ, TH Chan Sch Publ Hlth, Boston, MA 02115 USA;

    Boston Childrens Hosp, Div Hematol Oncol, Boston, MA 02115 USA|Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Pediat Oncol,Howard Hughes Med Inst,Harvard, 44 Binney St, Boston, MA 02115 USA;

    MIT, Dept Biol, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA|MIT, Dept Biol, Howard Hughes Med Inst, Whitehead Inst Biomed Res, 77 Massachusetts Ave, Cambridge, MA 02142 USA|Broad Inst Harvard & MIT, Cambridge, MA 02142 USA;

    MIT, Dept Biol, David H Koch Inst Integrat Canc Res, 77 Massachusetts Ave, Cambridge, MA 02139 USA|Massachusetts Gen Hosp, Dept Pathol, Boston, MA 02114 USA|Massachusetts Gen Hosp, Dept Gastroenterol, Boston, MA 02114 USA|Massachusetts Gen Hosp, Dept Surg, Boston, MA 02114 USA|Harvard Univ, Sch Med, Boston, MA 02114 USA|Broad Inst Harvard & MIT, Cambridge, MA 02142 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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