Vitamin D Receptor regulation of hepatic and organismal energy metabolism

Abstract

Epidemiological and experimental studies have demonstrated a role for vitamin D and its effector Vitamin D Receptor (VDR) in the pathogenesis of metabolic disorders such as non-alcoholic fatty liver disease (NAFLD) and obesity, but the functions of VDR signaling in the regulation of energy metabolism remain unknown. Here, we employ an evolutionary perspective to provide insight into the functions of VDR in metabolic homeostasis and disease. The canonical function of VDR signaling is to regulate mineral homeostasis and skeletal health in terrestrial vertebrates, but the functions of VDR signaling in more basal vertebrates are not understood. We demonstrate that vdr mutation in zebrafish diminishes organismal growth while increasing hepatic and visceral fat accumulation, highlighting a central role for Vdr in the regulation of zebrafish energy balance. Using genetic impairment of hepatocyte Vdr in zebrafish larvae, we demonstrate that loss of hepatic Vdr signaling restricts liver growth and stimulates hepatic steatosis. Strikingly, the hepatic lipid accumulation induced by Vdr impairment is prevented by high-fat diet feeding, suggesting that the loss of Vdr signaling elicits a starvation-like metabolic program marked by increased energy storage at the expense of liver growth. Using RNA-sequencing, we demonstrate that Vdr impairment elicits a transcriptional signature of reduced fatty acid oxidation alongside elevated hepatic uptake and activation of fatty acids. Further, we illuminate overexpression of the acyl-CoA synthetase Acsl4a as a downstream consequence of Vdr impairment that contributes to hepatic steatosis. In adult fish, impairment specifically of hepatocyte Vdr drives hepatic and visceral fat accumulation. Strikingly, the loss of hepatic Vdr signaling attenuates diet-induced organismal weight gain, illustrating the requirement for hepatocyte Vdr to fully adapt to fluctuations in nutrient availability. Collectively, our work demonstrates that hepatocyte Vdr antagonistically regulates energy storage and tissue growth in zebrafish. Because vitamin D is an environmentally available ligand that governs organismal energy expenditure, we postulate an evolutionary function for zebrafish Vdr as a sensor and effector of nutrient abundance. Finally, we use this framework to interpret the impacts of vitamin D signaling on mammalian metabolism, reasoning that these effects reflect the ancestral role for VDR in nutrient sensing.