Vitamin D (Calciferol) Functions

Vitamins >> Vitamin D (Calciferol) Functions

Activation of Vitamin D

Vitamin D itself is biologically inactive, and it must be metabolized to its biologically active forms. After it is consumed in the diet or synthesized in the skin, vitamin D enters the circulation and is transported to the liver. In the liver, vitamin D is hydroxylated to form 25-hydroxyvitamin D [25(OH)D], the major circulating form of vitamin D. Increased exposure to sunlight or increased intake of vitamin D increases serum levels of 25(OH)D, making the serum 25(OH)D concentration a useful indicator of vitamin D nutritional status. In the kidney and other tissues, the 25(OH)D3-1-hydroxylase enzyme catalyzes a second hydroxylation of 25(OH)D, resulting in the formation of 1alpha,25-dihydroxyvitamin D [1,25(OH)2D]—the most potent form of vitamin D. Most of the physiological effects of vitamin D in the body are related to the activity of 1,25(OH)2D.

Mechanisms of Action

Many of the biological effects of 1,25(OH)2D are mediated through a nuclear transcription factor known as the vitamin D receptor (VDR). Upon entering the nucleus of a cell, 1,25(OH)2D associates with the VDR and promotes its association with the retinoic acid X receptor (RXR). In the presence of 1,25(OH)2D the VDR/RXR complex binds small sequences of DNA known as vitamin D response elements (VDREs), and initiates a cascade of molecular interactions that modulate the transcription of specific genes. More than 50 genes in tissues throughout the body are known to be regulated by 1,25(OH)2D. Some physiological responses to 1,25(OH)2D occur too rapidly to be acting through gene transcription, suggesting that their may be also be a receptor for 1,25(OH)2D on the outer membrane of cells.

Calcium Balance

Maintenance of serum calcium levels within a narrow range is vital for normal functioning of the nervous system, as well as for bone growth, and maintenance of bone density. Vitamin D is essential for the efficient utilization of calcium by the body. The parathyroid glands sense serum calcium levels, and secrete parathyroid hormone (PTH) if calcium levels drop too low. Elevations in PTH increase the activity of 25(OH)D3-1-hydroxylase enzyme in the kidney, resulting in increased production of 1,25(OH)2D. Increasing 1,25(OH)2D production results in changes in gene expression that normalize serum calcium by 1) increasing the absorption of dietary calcium, 2) increasing the mobilization of calcium from bone into the circulation, and 3) increasing the reabsorption of calcium filtered by the kidneys.

Cell Differentiation

Cells that are dividing rapidly are said to be proliferating. Differentiation results in the specialization of cells for specific functions. In general, differentiation of cells leads to a decrease in proliferation. While cellular proliferation is essential for growth and wound healing, uncontrolled proliferation of cells with certain mutations may lead to diseases like cancer. The active form of vitamin D, 1,25(OH)2D, inhibits proliferation and stimulates the differentiation of cells.

Immunity

Vitamin D in the form of 1,25(OH)2D is a potent immune system modulator. The VDR is expressed by most cells of the immune system, including T cells and antigen-presenting cells, such as dendritic cells and macrophages. Macrophages also produce the 25(OH)D3-1-hydroxylase enzyme that converts 25(OH)D to 1,25(OH)2D. There is considerable scientific evidence that 1,25(OH)2D has a variety of effects on immune system function that may enhance innate immunity and inhibit the development of autoimmunity.

Insulin Secretion

The VDR is expressed by insulin secreting cells of the pancreas, and the results of animal studies suggest that 1,25(OH)2D plays a role in insulin secretion under conditions of increased insulin demand. Limited data in humans suggests that insufficient vitamin D levels may have an adverse effect on insulin secretion and glucose tolerance in type 2 diabetes (noninsulin-dependent diabetes mellitus; NIDDM).

Blood Pressure Regulation

The renin-angiotensin system plays an important role in the regulation of blood pressure. Renin is an enzyme that catalyzes the cleavage (splitting) of a small peptide (Angiotensin I) from a larger protein (angiotensinogen) produced in the liver. Angiotensin converting enzyme (ACE) catalyzes the cleavage of angiotensin I to form angiotensin II, a peptide that can increase blood pressure by inducing the constriction of small arteries and increasing sodium and water retention. The rate of angiotensin II synthesis is dependent on renin. Recent research in mice lacking the gene encoding the VDR, indicates that 1,25(OH)2D decreases the expression of the gene encoding renin through its interaction with the VDR. Since inappropriate activation of the renin-angiotensin system is thought to play a role in some forms of human hypertension, adequate vitamin D levels may be important for decreasing the risk of high blood pressure.