Nongenomic Activities of Vitamin D

Abstract

Vitamin D shows a variety of pleiotropic activities which cannot be fully explained by the stimulation of classic pathway- and vitamin D receptor (VDR)-dependent transcriptional modulation. Thus, existence of rapid and nongenomic responses to vitamin D was suggested. An active form of vitamin D (calcitriol, 1,25(OH)2D3) is an essential regulator of calcium–phosphate homeostasis, and this process is tightly regulated by VDR genomic activity. However, it seems that early in evolution, the production of secosteroids (vitamin-D-like steroids) and their subsequent photodegradation served as a protective mechanism against ultraviolet radiation and oxidative stress. Consequently, direct cell-protective activities of vitamin D were proven. Furthermore, calcitriol triggers rapid calcium influx through epithelia and its uptake by a variety of cells. Subsequently, protein disulfide-isomerase A3 (PDIA3) was described as a membrane vitamin D receptor responsible for rapid nongenomic responses. Vitamin D was also found to stimulate a release of secondary massagers and modulate several intracellular processes—including cell cycle, proliferation, or immune responses—through wingless (WNT), sonic hedgehog (SSH), STAT1-3, or NF-kappaB pathways. Megalin and its coreceptor, cubilin, facilitate the import of vitamin D complex with vitamin-D-binding protein (DBP), and its involvement in rapid membrane responses was suggested. Vitamin D also directly and indirectly influences mitochondrial function, including fusion–fission, energy production, mitochondrial membrane potential, activity of ion channels, and apoptosis. Although mechanisms of the nongenomic responses to vitamin D are still not fully understood, in this review, their impact on physiology, pathology, and potential clinical applications will be discussed.

Vitamin D3 Metabolism and Its Role in Temporomandibular Joint Osteoarthritis and Autoimmune Thyroid Diseases

“…Vitamin D 3 is a pro-hormone, but it was initially categorized as a vitamin, because it can be absorbed from dietary products, mainly oily fish, fish oil, dairy products, meat, eggs and some mushrooms. Nevertheless, the main source of vitamin D 3 in humans is biosynthesis from 7-dehydrocholesterol in the course of photochemical reaction within the human skin [ 28 ].…”

Reply to Pluta, R. Comment on “Minich et al. Is Melatonin the “Next Vitamin D”?: A Review of Emerging Science, Clinical Uses, Safety, and Dietary Supplements. Nutrients 2022, 14, 3934”

“…Our suggestion is not that one replaces the other, but that there may be some similarities in function. Furthermore, our intention in this review article was to provide a survey of multiple areas of clinical concern related to how melatonin and vitamin D may be involved in foundational mechanisms associated with a broad spectrum of disease pathologies, including their (1) anti-inflammatory activities [ 15 ]; (2) antioxidant potential [ 16 ]; and (3) mitochondrial regulation [ 17 ].…”

Vitamin D3 and Omega-3 Fatty Acids: A New Approach for Cardiovascular Prevention

“…2 The mechanism requires the vitamin D-induced upregulation of genes involved in antioxidant response through vitamin D receptor-mediated genomic pathways with additional activation of nuclear-factorerythroid 2-related factor 2 (Nrf2). 3 Vitamin D3 also has an indirect impact on mitochondria function; indeed, transcriptomic analyses focused on mitochondrial genes showed that vitamin D3 inhibits the expression of several genes involved in oxidative processes and upregulates genes involved in reactive oxygen species defense by Nrf2. 3 Furthermore, in a study using diabetic rats, vitamin D3 injection resulted in the inhibition of nicotinamide adenine dinucleotide phosphate oxidase synthesis in the aorta.…”