Aberrant Fat Metabolism in Caenorhabditis elegans Mutants with Defects in the Defecation Motor Program

The molecular mechanisms by which dietary fatty acids are absorbed by the intestine, and the way in which the process is regulated are poorly understood. In a genetic screen for mutations affecting fat accumulation in the intestine of Caenorhabditis elegans, nematode worms, we have isolated mutations in the aex-5 gene, which encodes a Kex2/subtilisin-family, Ca2+-sensitive proprotein convertase known to be required for maturation of certain neuropeptides, and for a discrete step in an ultradian rhythmic phenomenon called the defecation motor program. We demonstrate that aex-5 mutants have markedly lower steady-state levels of fat in the intestine, and that this defect is associated with a significant reduction in the rate at which labeled fatty acid derivatives are taken up from the intestinal lumen. Other mutations affecting the defecation motor program also affect steady-state levels of triglycerides, suggesting that the program is required per se for the proper accumulation of neutral lipids. Our results suggest that an important function of the defecation motor program in C. elegans is to promote the uptake of an important class of dietary nutrients. They also imply that modulation of the program might be one way in which worms adjust nutrient uptake in response to altered metabolic status.肠道对膳食脂肪酸的吸收分子机制，以及该过程的调控方式，目前仍未得到充分阐明。本研究以影响秀丽隐杆线虫（Caenorhabditis elegans，一种线虫）肠道脂肪积累的突变为靶标开展遗传筛选，成功分离获得aex-5基因的突变体。该基因编码一种Kex2/枯草杆菌蛋白酶家族（Kex2/subtilisin-family）的钙离子敏感性前蛋白转化酶（Ca2+-sensitive proprotein convertase），已知其参与部分神经肽（neuropeptides）的成熟过程，并参与被称为排便运动程序（defecation motor program）的超昼夜节律现象（ultradian rhythmic phenomenon）中的特定步骤。研究表明，aex-5突变体的肠道稳态脂肪水平显著降低，且该缺陷与标记脂肪酸衍生物（labeled fatty acid derivatives）从肠腔（intestinal lumen）的摄取速率显著降低密切相关。其他影响排便运动程序的突变同样会改变甘油三酯（triglycerides）的稳态水平，提示该程序本身对于中性脂质（neutral lipids）的正常积累是必需的。本研究结果显示，秀丽隐杆线虫的排便运动程序的一项重要功能是促进一类重要膳食营养素的摄取；同时该结果也暗示，对该程序的调控或许是线虫根据代谢状态变化调节营养摄取的途径之一。