Cui Mingxue, Wang Yi, Cavaleri Jonathon, Kelson Taylor, Teng Yudong, Han Min
Howard Hughes Medical Institute and Department of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder, Colorado 80309.
Howard Hughes Medical Institute and Department of Molecular, Cellular and Developmental Biology, University of Colorado at Boulder, Colorado 80309
Genetics. 2017 Feb;205(2):775-785. doi: 10.1534/genetics.116.194282. Epub 2016 Dec 14.
Our understanding of the cellular mechanisms by which animals regulate their response to starvation is limited, despite the strong relevance of the problem to major human health issues. The L1 diapause of Caenorhabditis elegans, where first-stage larvae arrest in response to a food-less environment, is an excellent system to study this mechanism. We found, through genetic manipulation and lipid analysis, that biosynthesis of ceramide, particularly those with longer fatty acid side chains, critically impacts animal survival during L1 diapause. Genetic interaction analysis suggests that ceramide may act in both insulin-IGF-1 signaling (IIS)-dependent and IIS-independent pathways to affect starvation survival. Genetic and expression analyses indicate that ceramide is required for maintaining the proper expression of previously characterized starvation-responsive genes, genes that are regulated by the IIS pathway and tumor suppressor Rb, and genes responsive to pathogen. These findings provide an important insight into the roles of sphingolipid metabolism, not only in starvation response, but also in aging and food-response-related human health problems.
尽管动物如何调节其对饥饿的反应这一问题与人类重大健康问题密切相关，但我们对其细胞机制的了解仍然有限。秀丽隐杆线虫的L1滞育，即第一阶段幼虫在无食物环境中停滞发育，是研究这一机制的绝佳系统。我们通过基因操作和脂质分析发现，神经酰胺的生物合成，特别是那些具有较长脂肪酸侧链的神经酰胺，对L1滞育期间的动物存活至关重要。基因相互作用分析表明，神经酰胺可能在依赖胰岛素-IGF-1信号通路（IIS）和不依赖IIS的途径中发挥作用，以影响饥饿存活。基因和表达分析表明，神经酰胺是维持先前鉴定的饥饿反应基因、受IIS途径和肿瘤抑制因子Rb调控的基因以及对病原体有反应的基因正常表达所必需的。这些发现不仅为鞘脂代谢在饥饿反应中的作用，也为其在衰老和与食物反应相关的人类健康问题中的作用提供了重要见解。
