Calcitonin-Receptor-Like Receptor Signaling Governs Intestinal Lymphatic Innervation and Lipid Uptake
Calcitonin-Receptor-Like Receptor Signaling Governs Intestinal Lymphatic Innervation and Lipid Uptake
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DOI：
10.1021/acsptsci.8b00061
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发表时间：
2019-04-12
影响因子：
--
通讯作者：
Caron, Kathleen M.
中科院分区：
文献类型：
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作者：
Davis, Reema B.;Ding, Shengli;Caron, Kathleen M.
膳食脂肪的吸收需要复杂的神经内分泌介导的调节乳糜微粒通过肠细胞和肠淋巴管的运输。降钙素受体样受体（Calcrl）是一种G蛋白偶联受体，可以结合淋巴管生成配体肾上腺髓质素与辅助受体RAMP 2，或神经肽CGRP与辅助受体RAMP 1。这种常见的GPCR在多大程度上控制脂质吸收通过神经或肠神经支配仍然不清楚。我们使用条件性和诱导性遗传缺失的Calcrl在hatics，以阐明该受体途径的病理生理后果的条件下，高脂饮食。在Calcrl（fl/fl）/Prox 1-CreER（T2）小鼠中，膳食脂肪的低效吸收加上淋巴管内皮连接的改变导致过度的跨细胞脂质积累和异常的肠细胞乳糜微粒加工以及体重增加失败。有趣的是，Calcrl（fl/fl）/ProxlCreER（T2）动物显示粘膜和粘膜下神经支配减少和紊乱。一致的是，CGRP辅助受体RAMP 1基因缺失的小鼠也表现出粘膜和粘膜下神经支配缺陷，证实了Calcrl在神经淋巴分泌轴中的CGRP偏向功能。因此，共同的钙受体是一个关键的调节脂质吸收通过其细胞特异性功能的神经淋巴分泌串扰。
The absorption of dietary fat requires complex neuroendocrine-mediated regulation of chylomicron trafficking through enterocytes and intestinal lymphatic vessels. Calcitonin-receptor-like receptor (Calcrl) is a G protein-coupled receptor that can bind either a lymphangiogenic ligand adrenomedullin, with coreceptor RAMP2, or the neuropeptide CGRP, with coreceptor RAMP1. The extent to which this common GPCR controls lipid absorption via lymphatics or enteric innervation remains unclear. We used conditional and inducible genetic deletion of Calcrl in lymphatics to elucidate the pathophysiological consequences of this receptor pathway under conditions of high-fat diet. Inefficient absorption of dietary fat coupled with altered lymphatic endothelial junctions in Calcrl(fl/fl)/Prox1-CreER(T2) mice results in excessive, transcellular lipid accumulation and abnormal enterocyte chylomicron processing and failure to gain weight. Interestingly, Calcrl(fl/fl)/Prox1CreER(T2) animals show reduced and disorganized mucosal and submucosal innervation. Consistently, mice with genetic loss of the CGRP coreceptor RAMP1 also displayed mucosal and submucosal innervation deficits, substantiating the CGRP-biased function of Calcrl in the neurolymphocrine axis. Thus, the common Calcrl receptor is a critical regulator of lipid absorption through its cell-specific functions in neurolymphocrine crosstalk.