Vitamin D2, also known as ergocalciferol, is produced in plants. Vitamin D3 and vitamin D2 are both absorbed from the diet and are equally effective once converted into active hydroxylated forms. The balance between UVB-dependent endogenously synthesized vitamin D3 and the absorption of dietary forms of vitamin D becomes crucial in certain situations. Individuals with higher melanin content in their skin who live at higher latitudes convert less 7-dehydrocholesterol to vitamin D3 and therefore rely more on vitamin supplements or dietary sources of vitamin D, such as milk. Institutionalized elderly patients who stay indoors and avoid dairy products are especially at risk of developing vitamin D deficiency.

In the bloodstream, vitamin D is transported from the skin to the liver. Dietary vitamin D reaches the liver either directly through transport in the portal circulation or indirectly via chylomicrons. In the liver, vitamin D is hydroxylated at the 25-carbon position, resulting in the formation of 25-hydroxyvitamin D. The hepatic 25-hydroxylase enzyme is constantly expressed and not regulated, so the levels of circulating 25-hydroxyvitamin D indicate the amount of precursor available for hydroxylation. Due to its relatively long half-life in the circulation (2-3 weeks), measuring 25-hydroxyvitamin D levels is used to assess an individual's vitamin D status.

Further hydroxylation of 25-hydroxyvitamin D occurs in the proximal tubule of the kidney. Hydroxylation at the 1α position generates 1,25-dihydroxyvitamin D, which is the most active form of vitamin D. Hydroxylation at the 24 position produces 24,25-dihydroxyvitamin D, which does not play a significant biological role and serves as an inactivation pathway.

The activity of renal 1α-hydroxylase, the enzyme responsible for hydroxylation at the 1α position, is tightly regulated by various factors. Parathyroid hormone (PTH) and hypophosphatemia are the primary inducers of 1α-hydroxylase activity, leading to increased levels of 1,25-dihydroxyvitamin D. Conversely, elevated levels of calcium and 1,25-dihydroxyvitamin D inhibit the enzyme. Fibroblast growth factor (FGF)23, a key regulator of phosphorus metabolism, also inhibits 1α-hydroxylase activity. The reduction of FGF23 levels likely mediates the impact of hypophosphatemia on the production of 1,25-dihydroxyvitamin D.
Fig. 40.5 ). Vitamin D2 (ergocalciferol) is produced in plants. Vitamin D3 and to a lesser extent vitamin D2 are absorbed from the diet and are equally effective after conversion to active hydroxylated forms. The balance between UVB-dependent endogenously synthesized vitamin D3 and absorption of the dietary forms of vitamin D becomes important in certain situations. Individuals with higher melanin content in skin who live at higher latitudes convert less 7-dehydrocholesterol to vitamin D3 and thus are more dependent on vitamin supplements or dietary sources of vitamin D (natural or fortified, e.g., milk). Institutionalized elderly patients who stay indoors and avoid dairy products are particularly at risk for development of vitamin D deficiency.
Vitamin D is transported in blood from the skin to the liver. Dietary vitamin D reaches the liver directly via transport in the portal circulation and indirectly via chylomicrons (see
Fig. 40.6 ). In the liver, vitamin D is hydroxylated at the 25-carbon position to yield 25-hydroxyvitamin D. The hepatic 25-hydroxylase is constitutively expressed and unregulated, so circulating levels of 25-hydroxyvitamin D reflect the amount of precursor available for 25-hydroxylation. For this reason, and because of its relatively long half-life in the circulation (2–3 weeks), measurement of 25-hydroxyvitamin D levels is used to assess vitamin D status.
25-Hydroxyvitamin D undergoes further hydroxylation in the proximal tubule of the kidney (see
Figs.
40.5 40.6).
Hydroxylation at the 1α position generates 1,25-dihydroxyvitamin D, the most active form of vitamin D. Hydroxylation at the 24 position generates 24,25-dihydroxyvitamin D, which does not play a major biological role and serves as an inactivation pathway.
Renal 1α-hydroxylase is tightly regulated by a number of factors (
Fig. 40.7). PTH and hypophosphatemia are the primary inducers of 1α-hydroxylase activity, resulting in 25(OH)D3 1˜-hydroxylase 1,25(OH)2D3 25(OH)D3 CYP27B1 FGFRKIotho •Fig. 40.7 Regulationof1α-hydroxylasegene(CYP27B1) expressionintheproximaltubule,showingstimulationbyPTHandinhibitionbyFGF23and1,25-dihydroxyvitaminD.Hypophosphatemiaprobablystimulates1α-hydroxylasebyreducingFGF23levelsatleastinpart.
increased levels of 1,25-dihydroxyvitamin D. Conversely, [Ca++] and 1,25-dihydroxyvitamin D, the enzyme product, inhibit it. Fibroblast growth factor (FGF)23, a major regulator of Pi metabolism (see later), also represses 1α-hydroxylase activity; a reduction of FGF23 levels likely mediates the effect of hypophosphatemia on 1,25-dihydroxyvitamin D production at least in part.