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

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 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 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.

Vitamin D Modulates Intestinal Microbiota in Inflammatory Bowel Diseases

“…Cryptdins are antimicrobial peptides that are produced by Paneth cells, and their antimicrobial activity is important in reducing infection by pathogenic bacteria such as Listeria monocytogenes and Gram-negative bacteria [ 23 , 24 , 28 ]. Interestingly, both NOD2 [ 17 , 29 ] and ATG16L1 [ 30 ] are identified as the downstream target genes regulated by the transcriptional factor VDR. These studies suggest the unique roles of VDR as a genetic factor in IBD.…”

Impact of vitamin D deficiency on COVID-19

“…Epidemiological studies have exhibited a strong relationship between seasonal differences in nutrient D levels and the occurrence of varied infectious diseases, such as sepsis [9], respiratory infection [10], and seasonal influenza [11]. In addition to classic actions related to mineral homeostasis, vitamin D has pleiotropic physiological actions including immune system regulation [12]. Vitamin D can modulate the innate and adaptive immune responses [13].…”

Vitamin D: Promises on the Horizon and Challenges Ahead for Fighting Pancreatic Cancer

“…A wide variety of cells including gut epithelia, immune cells, and cancer cells express both CYP27B1 and VDR, which provides the molecular basis for 1,25(OH) 2 D to exert its multifunctional role in the human body ( Figure 1 ) [ 6 , 7 ]. 1,25(OH) 2 D ligand-activated VDR binds to more than 10,000 loci within the human genome, regulating the transcriptional expression of approximately 1000 target genes in many different cell types including epithelial cells, fibroblasts, and almost all the cells of the immune system [ 33 , 34 ]. Accumulating evidence shows that a low circulating 25(OH)D level is associated with an increased risk of developing several different diseases including those associated with chronic inflammation [ 35 , 36 ].…”