Division of Genetics, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Cutaneous Biology Research Center, Department of Dermatology and Cancer Center, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA; HCEMM-SU Translational Dermatology Research Group, Department of Physiology, Semmelweis University, 1085 Budapest Hungary; Department of Dermatology, Venereology, and Dermatooncology, Semmelweis University, 1085 Budapest Hungary.
Cell Rep. 2024 Jul 23;43(7):114393. doi: 10.1016/j.celrep.2024.114393. Epub 2024 Jun 28.
Vitamin D receptor (VDR) has been implicated in fatty liver pathogenesis, but its role in the regulation of organismal energy usage remains unclear. Here, we illuminate the evolutionary function of VDR by demonstrating that zebrafish Vdr coordinates hepatic and organismal energy homeostasis through antagonistic regulation of nutrient storage and tissue growth. Hepatocyte-specific Vdr impairment increases hepatic lipid storage, partially through acsl4a induction, while simultaneously diminishing fatty acid oxidation and liver growth. Importantly, Vdr impairment exacerbates the starvation-induced hepatic storage of systemic fatty acids, indicating that loss of Vdr signaling elicits hepatocellular energy deficiency. Strikingly, hepatocyte Vdr impairment diminishes diet-induced systemic growth while increasing hepatic and visceral fat in adult fish, revealing that hepatic Vdr signaling is required for complete adaptation to food availability. These data establish hepatocyte Vdr as a regulator of organismal energy expenditure and define an evolutionary function for VDR as a transcriptional effector of environmental nutrient supply.
维生素 D 受体（VDR）已被牵连到脂肪肝的发病机制中，但它在调节机体能量利用方面的作用仍不清楚。在这里，我们通过证明斑马鱼 Vdr 通过拮抗调节营养储存和组织生长来协调肝脏和机体的能量平衡，阐明了 VDR 的进化功能。肝细胞特异性 Vdr 损伤会增加肝脏脂质储存，部分是通过 acsl4a 的诱导，同时减少脂肪酸氧化和肝脏生长。重要的是，Vdr 损伤会加剧饥饿诱导的系统性脂肪酸在肝脏中的储存，表明 Vdr 信号的丧失会引发肝细胞能量不足。引人注目的是，肝细胞 Vdr 损伤会减少饮食诱导的全身生长，同时增加成年鱼的肝内和内脏脂肪，这表明肝 Vdr 信号对于完全适应食物供应是必需的。这些数据确立了肝细胞 Vdr 作为机体能量消耗的调节剂，并将 VDR 定义为环境营养供应的转录效应因子的进化功能。
