Vitamin D-regulated Gene Expression Profiles: Species-specificity and Cell-specific Effects on Metabolism and Immunity

Abstract

Abstract Vitamin D has pleiotropic physiological actions including immune system regulation, in addition to its classical role in calcium homeostasis. Hormonal 1,25-dihydroxyvitamin D (1,25D) signals through the nuclear vitamin D receptor, and large-scale expression profiling has provided numerous insights into its diverse physiological roles. To obtain a comprehensive picture of vitamin D signaling, we analyzed raw data from 94 (80 human, 14 mouse) expression profiles of genes regulated by 1,25D or its analogs. This identified several thousand distinct genes directly or indirectly up- or downregulated in a highly cell-specific manner in human cells using a 1.5-fold cut-off. There was significant overlap of biological processes regulated in human and mouse but minimal intersection between genes regulated in each species. Disease ontology clustering confirmed roles for 1,25D in immune homeostasis in several human cell types, and analysis of canonical pathways revealed novel and cell-specific roles of vitamin D in innate immunity. This included cell-specific regulation of several components of Nucleotide-binding Oligomerization Domain-like (NOD-like) pattern recognition receptor signaling, and metabolic events controlling innate immune responses. Notably, 1,25D selectively enhanced catabolism of branched-chain amino acids (BCAAs) in monocytic cells. BCAA levels regulate the major metabolic kinase mammalian Target of Rapamycin (mTOR), and pretreatment with 1,25D suppressed BCAA-dependent activation of mTOR signaling. Furthermore, ablation of BCAT1 expression in monocytic cells blocked 1,25D-induced increases in autophagy marker LAMP1. In conclusion, the data generated represents a powerful tool to further understand the diverse physiological roles of vitamin D signaling and provides multiple insights into mechanisms of innate immune regulation by 1,25D.