MicroRNA 375 mediates palmitate-induced enteric neuronal damage and high-fat diet-induced delayed intestinal transit in mice.
MicroRNA 375 mediates palmitate-induced enteric neuronal damage and high-fat diet-induced delayed intestinal transit in mice.
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DOI：
10.1053/j.gastro.2013.10.053
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发表时间：
2014-02
期刊：
影响因子：
29.4
通讯作者：
Srinivasan S
中科院分区：
文献类型：
--
作者：
Nezami BG;Mwangi SM;Lee JE;Jeppsson S;Anitha M;Yarandi SS;Farris AB 3rd;Srinivasan S
高脂饮食(HFD)可导致严重的健康问题，包括胃肠道转运改变，其确切机制尚不清楚。一些microRNAs(MiRNAs)参与能量平衡、脂代谢和高脂饮食诱导的体重增加。我们研究了miRNAs在HFD引起的肠道神经系统损伤中的作用。雄性小鼠喂食高脂饮食(60%的卡路里来自脂肪)或常规饮食(18%的卡路里来自脂肪)，为期11周。正常饮食和HFD的小鼠被给予腹膜腔注射Mir375抑制剂或阴性对照。测量体重、食物摄入量、粪便指数和胃肠道转运(依文思蓝灌胃)。采用肠神经细胞系(IM-PEN)和原代肠道神经元进行体外研究。HFD延迟了肠道传输，这与结肠肌间神经元的凋亡增加和神经元丢失有关。喂食低棕榈酸高脂饮食的小鼠没有出现类似的表型。棕榈酸酯可引起肠神经细胞凋亡，并与线粒体功能障碍和内质网应激有关。棕榈酸酯在体外显著增加Mir375的表达；用Mir375抑制剂转染细胞可阻止棕榈酸酯诱导的肠神经细胞凋亡。在服用HFD的小鼠的肌间神经节中，Mir375的表达增加，并与包括PDK1在内的Mir375靶mRNAs水平的降低有关。全身注射Mir375抑制剂5周可防止HFD引起的肠道转运延迟和形态改变。HFD延缓结肠运输，部分原因是通过诱导肠神经细胞的凋亡。这种作用是由Mir375介导的，并与PDK1水平的降低有关。Mir375的作用靶点可能是增加肠道神经元的存活率和胃肠动力。
A high-fat diet (HFD) can cause serious health problems, including alteration of gastrointestinal transit, the exact mechanism of which is not clear. Several microRNAs (miRNAs) are involved in energy homeostasis, lipid metabolism, and HFD-induced weight gain. We investigated the role of miRNAs in HFD-induced damage to the enteric nervous system. Male mice were fed a HFD (60% calories from fat) or regular diets (18% calories from fat) for 11 weeks. Mice on regular diets and HFDs were given intraperitoneal injections of Mir375 inhibitor or a negative control. Body weights, food intake, stool indices, and gastrointestinal transit (following Evans blue gavage) were measured. An enteric neuronal cell line (IM-PEN) and primary enteric neurons were used for in vitro studies. A HFD delayed intestinal transit, which was associated with increased apoptosis and loss of neurons from colonic myenteric neurons. Mice fed a low-palmitate HFD did not develop a similar phenotype. Palmitate caused apoptosis of enteric neuronal cells associated with mitochondrial dysfunction and endoplasmic reticulum stress. Palmitate significantly increased the expression of Mir375 in vitro; transfection of cells with a Mir375 inhibitor prevented the palmitate-induced enteric neuronal cell apoptosis. Mir375 expression was increased in myenteric ganglia of mice fed HFD, and associated with decreased levels of Mir375 target mRNAs, including Pdk1. Systemic injection of a Mir375 inhibitor for 5 weeks prevented HFD-induced delays in intestinal transit and morphologic changes. HFD delay colonic transit, partly by inducing apoptosis in enteric neuronal cells. This effect is mediated by Mir375 and is associated with reduced levels of Pdk1. Mir375 might be targeted to increase survival of enteric neurons and gastrointestinal motility.
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影响因子：
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作者：
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通讯作者：
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