Vitamin D Receptor regulation of hepatic energy metabolism in zebrafish. Vitamin D Receptor regulation of hepatic energy metabolism in zebrafish

Vitamin D deficiency and mutations in Vitamin D Receptor (VDR) are associated with liver disease and obesity, but the functions of vitamin D signaling in metabolism are poorly understood. Though vitamin D signaling is best known for its functions in mineral homeostasis and skeleton calcification in terrestrial vertebrates, this is unlikely to be the evolutionary function of vitamin D signaling. We utilize tissue-specific genetic modulation of Vdr signaling to investigate the function of the vitamin D endocrine system in zebrafish. We find that hepatocyte Vdr regulates organismal response to nutritional cues and coordinates hepatic and organismal energy metabolism by balancing energy storage and tissue growth. Overall design: Comparative gene expression profiling analysis of RNA-seq data following hepatocyte-specific Vdr modulation in larval and adult zebrafish. fabp10a:dn-vdra and fabp10a:ca-vdra transgenes were used to achieve hepatocyte Vdr impairment or hyperactivation, respectively. Larval experiments were performed on sorted hepatocytes at 96 hours post fertilization (hpf) and reflect approximately 35 pooled fish per sample. Adult experiments were performed on dissected male liver collected at 4.5 months post fertilization (mpf) and are composed of 3 livers per sample. wild-type controls are included for each experiment. For larval fabp10a:dn-vdra, N = 4 wt, 4 dn-vdra. For fabp10a:ca-vdra, N = 4 wt, 3 ca-vdra. For adult fabp10a:dn-vdra, N = 4 wt, 4 dn-vdra.

维生素D缺乏与维生素D受体（Vitamin D Receptor, VDR）突变与肝脏疾病及肥胖密切相关，但维生素D信号通路在代谢调控中的功能尚不清楚。尽管维生素D信号通路以陆生脊椎动物中的矿物质稳态维持与骨骼矿化功能广为人知，但这并非维生素D信号通路演化起源的核心功能。本研究通过组织特异性基因调控手段操控Vdr信号通路，以探究斑马鱼体内维生素D内分泌系统的生理功能。研究发现，肝细胞Vdr可调控生物体对营养信号的响应，并通过平衡能量储存与组织生长，协调肝脏及整体的能量代谢。整体实验设计：对幼龄及成年斑马鱼实施肝细胞特异性Vdr调控后，对其RNA测序数据开展比较基因表达谱分析。分别采用fabp10a:dn-vdra与fabp10a:ca-vdra转基因品系，实现肝细胞Vdr功能抑制与过度激活。幼龄实验取材于受精后96小时（hpf）分选得到的肝细胞，每个样本约混合35条斑马鱼；成年实验取材于受精后4.5个月（mpf）解剖获取的雄性肝脏，每个样本包含3份肝脏组织。所有实验均设置野生型对照。其中幼龄fabp10a:dn-vdra组：野生型（wt）样本量N=4，dn-vdra组N=4；fabp10a:ca-vdra组：wt组N=4，ca-vdra组N=3；成年fabp10a:dn-vdra组：wt组N=4，dn-vdra组N=4。