skeletal muscle, which are rich in this enzyme. During hydrolysis of the chylomicron triglycerides, a fraction of the vitamin D contained in the chylomicron can be taken up by these tissues. Uptake into adipose tissue and skeletal muscle accounts for the rapid postprandial disappearance of vitamin D from plasma and probably also explains why increased adiposity causes sequestering of vitamin D and is associated with lower 25OHD levels (Jones, 2008). What remains of the original chylomicron after lipolysis is a chylomicron remnant, a cholesterol-enriched, triglyceride-depleted particle that still contains a fraction of its vitamin D content.
Vitamin D, regardless of origin, is an inactive prohormone and must first be metabolized to its hormonal form before it can function. Once vitamin D enters the circulation from the skin or from the lymph, it is cleared by the liver or storage tissues within a few hours. The processes that follow are illustrated in Figure 3-3. Vitamin D is converted in the liver to 25OHD, a process carried out by a CYP enzyme that has yet to be fully defined but is likely CYP2R1 (Cheng et al., 2003). The crystal structure of CYP2R1 has been determined with vitamin D in the active site, and the enzyme has been shown to metabolize both vitamin D2 and vitamin D3 equally efficiently (Strushkevich et al., 2008). There is little, if any, feedback regulation of this enzyme. A large genome-wide association study of factors that might be determinants of the circulating 25OHD levels identified the human chromosomal 11p15 locus of CYP2R1 as a significant determinant, whereas the loci of the other enzymes purported to have 25-hydroxylase activity (e.g., CYP27A1 and CYP3A4) were not identified (Wang et al., 2010). The other determinants of serum 25OHD besides CYP2R1 have been reported to be DBP (also known as Gc protein), which has six common phenotypes (Laing and Cooke, 2005) as well as 7-dehydrocholesterol reductase and CYP24A1. Increasing intake of vitamin D results in higher blood levels of 25OHD, although perhaps not in a linear manner (Stamp et al., 1977; Clements et al., 1987).
At this point, 25OHD bound to DBP circulates in the blood stream and, when calcitriol is required due to a lack of calcium (or lack of phosphate), 25OHD is 1α-hydroxylated in the kidney to form calcitriol, the active form, by the 1α-hydroxylase enzyme (also known as CYP27B1) (Tanaka and DeLuca, 1983). This metabolic step is very tightly regulated by blood calcium and phosphate levels through PTH and the phosphaturic hormone, FGF23, and constitutes the basis of the vitamin D endocrine system that is central to maintaining calcium and phosphate homeostasis (see discussion below on functions and physiological actions). FGF23 acts by reducing the expression of renal sodium–phosphate transporters and reducing serum calcitriol levels.