University of Cologne, Faculty of Mathematics and Natural Sciences, Cluster of Excellence Cellular Stress Responses in Aging-associated Diseases (CECAD), Joseph-Stelzmann-Strasse 26, 50931 Cologne, Germany; Institute for Genetics, Faculty of Mathematics and Natural Sciences, University of Cologne, Cologne, Germany.
Department of Human Genetics, University of Utah School of Medicine, Salt Lake City, UT 84112-5330, USA.
Cell Rep. 2024 Sep 24;43(9):114693. doi: 10.1016/j.celrep.2024.114693. Epub 2024 Sep 4.
Nutrient digestion, absorption, and export must be coordinated in the gut to meet the nutritional needs of the organism. We used the Drosophila intestine to characterize the mechanisms that coordinate the fate of dietary lipids. We identified enterocytes specialized in absorbing and exporting lipids to peripheral organs. Distinct hepatocyte-like cells, called oenocytes, communicate with these enterocytes to adjust intestinal lipid storage and export. A single transcription factor, Drosophila hepatocyte nuclear factor 4 (dHNF4), supports this gut-liver axis. In enterocytes, dHNF4 maximizes dietary lipid export by preventing their sequestration in cytoplasmic lipid droplets. In oenocytes, dHNF4 promotes the expression of the insulin antagonist ImpL2 to activate Foxo and suppress lipid retention in enterocytes. Disruption of this switch between lipid storage and export is associated with intestinal inflammation, suggesting a lipidic origin for inflammatory bowel diseases. These studies establish dHNF4 as a central regulator of intestinal metabolism and inter-organ lipid trafficking.
肠道必须协调营养消化、吸收和输出，以满足机体的营养需求。我们利用果蝇肠道来描述协调膳食脂质命运的机制。我们鉴定出了专门吸收和向外周器官输出脂质的肠细胞。被称为成脂细胞的独特肝细胞样细胞与这些肠细胞进行通讯，以调节肠道脂质储存和输出。一种称为果蝇肝细胞核因子 4 (dHNF4) 的单一转录因子支持这个肠-肝轴。在肠细胞中，dHNF4 通过防止其被细胞质脂滴隔离来最大程度地促进膳食脂质的输出。在成脂细胞中，dHNF4 促进胰岛素拮抗剂 ImpL2 的表达，以激活 Foxo 并抑制肠细胞中的脂质保留。这种脂质储存和输出之间的转换的破坏与肠道炎症有关，这表明炎症性肠病具有脂质起源。这些研究确立了 dHNF4 作为肠道代谢和器官间脂质运输的中央调节剂。
