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 /Prox1-CreER 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.

中文翻译：

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降钙素受体样受体信号传导控制肠道淋巴神经支配和脂质摄取。

膳食脂肪的吸收需要复杂的神经内分泌介导的乳糜微粒通过肠细胞和肠淋巴管运输的调节。降钙素受体样受体 (Calcrl) 是一种 G 蛋白偶联受体，可将淋巴管生成配体肾上腺髓质素与辅助受体 RAMP2 或神经肽 CGRP 与辅助受体 RAMP1 结合。这种常见的 GPCR 通过淋巴管或肠神经支配控制脂质吸收的程度仍不清楚。我们使用淋巴管中 Calcrl 的条件性和诱导性遗传缺失来阐明该受体途径在高脂饮食条件下的病理生理学后果。在 Calcrl fl/fl /Prox1-CreER T2 小鼠中，膳食脂肪吸收效率低下加上淋巴管内皮连接改变导致过度，跨细胞脂质积累和肠细胞乳糜微粒加工异常和体重增加失败。有趣的是，Calcrl fl/fl /Prox1-CreER T2 动物表现出减少和杂乱无章的黏膜和黏膜下神经支配。一致地，具有 CGRP 辅助受体 RAMP1 遗传缺失的小鼠也表现出粘膜和粘膜下神经支配缺陷，证实了 Calcr1 在神经淋巴分泌轴中的 CGRP 偏向功能。因此，常见的 Calcrl 受体通过其在神经淋巴分泌串扰中的细胞特异性功能是脂质吸收的关键调节剂。CGRP 辅助受体 RAMP1 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 Calcr1 在神经淋巴分泌轴中的 CGRP 偏向功能。因此，常见的 Calcrl 受体通过其在神经淋巴分泌串扰中的细胞特异性功能是脂质吸收的关键调节剂。CGRP 辅助受体 RAMP1 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 Calcr1 在神经淋巴分泌轴中的 CGRP 偏向功能。因此，常见的 Calcrl 受体通过其在神经淋巴分泌串扰中的细胞特异性功能是脂质吸收的关键调节剂。