飲食對線蟲脂質代謝、內質網壓力與免疫反應的調控

Abstract

飲食調控生物體內的代謝並且影響其生理現象。不正常的飲食與代謝異常息息相關，如可能誘導細胞產生壓力，造成肥胖、糖尿病以及心血管疾病等代謝相關疾病。然而，飲食如何調控代謝並且引發細胞內壓力以及其防禦機制仍尚未明確。在先前實驗中我們證明了餵食不同細菌食物，會造成線蟲脂質含量改變及內質網壓力。而藉由分析脂肪染色及伴隨蛋白hsp-4螢光表現，我們發現了不同的細菌食物可能會藉由調控線蟲體內的磷脂膽鹼及鞘脂代謝途徑來降低脂質含量並誘導內質網壓力。我們證明了飲食造成的內質網壓力需要透過三種典型路徑來活化，並且可能會受脂質不平衡或是蛋白質平衡異常所影響。此外，我們的RNA定序分析結果，表明了不同飲食會影響免疫相關基因表現，而我們透過病原菌感染實驗來觀察線蟲存活率，發現了不同的飲食可以改變線蟲對外來病菌的防禦力。綜合上述結果，本研究證明了細菌食物與宿主間對於宿主的脂質代謝、內質網壓力以及免疫反應等系統性的代謝調控。

Diets provide nutrients and energy to regulate cellular metabolisms and influence physiological processes in organisms. Imbalanced diets are associated with metabolic disturbance. For example, lipid disequilibrium caused by imbalanced diets can induce intracellular stress and cause numerous metabolic disorders, including obesity, diabetes and cardiovascular diseases. Nevertheless, how diets modulate cellular metabolism, and trigger cellular stress and defense mechanisms remain elucidated. My former lab members found that different bacterial diets cause lipid composition alteration and induce ER stress in C. elegans when assayed using ORO staining and hsp-4p::gfp reporter, respectively. Here, my work shows that different bacterial diets cause lipid composition alteration and induce ER stress response in C. elegans through modulating host PC and sphingolipid metabolism. My work demonstrates that the diet-mediated ER stress requires three canonical signaling pathways and can be induced through lipid disequilibrium or disturbed proteostasis. Furthermore, using the RNA-sequencing analysis of C. elegans fed different bacterial diets and the pathogen infection assays, my work showed that bacterial diets regulate innate immunity by, at least in part, controlling the defense gene transcription. Taken together, my work shows that bacterial diets regulate host lipid metabolism, ER stress and immune response as systemic metabolic alteration.