A Hitchhiker Story? Exploring HDL as an Overlooked Vitamin D Carrier.

Background: Twenty-five-hydroxyvitamin D, used to assess vitamin status, is the primary circulating form of vitamin D having a half-life measured in weeks, and 1,25-dihydroxyvitamin D is the active metabolite having a half-life measured in hours. Although there has been a preponderance of research on the roles of the active metabolite in health, there remains a limited understanding of the transport of the true vitamin forms, ergocalciferol and cholecalciferol. Objective: This study proposes an alternative mechanism for vitamin D transport, hypothesizing that high-density lipoprotein (HDL) facilitates its movement from the intestine to the liver using cholesterol transporters. Methods: This perspective challenges the sole reliance on the classical chylomicron pathway, proposing an alternative mechanism based on vitamin D's striking structural similarity to cholesterol. Both are steroids sharing key features, suggesting analogous intestinal absorption and transport routes. Evidence indicates vitamin D utilizes known enteric cholesterol transporters for uptake. We hypothesize that high-density lipoprotein (HDL) functions as an important interorgan carrier, facilitating vitamin D's movement from the intestine to the liver, using shared cholesterol transporters. This proposed HDL-mediated delivery is particularly relevant given vitamin D-binding protein's lower affinity for vitamin D compared with 25-hydroxyvitamin D. Results: This mechanism offers a plausible explanation for observed correlations between vitamin D status (plasma 25-hydroxyvitamin D concentrations) and factors affecting HDL cholesterol concentration (HDLc). Modulators that increase HDLc (e.g., fibrates, oral contraceptives, and exercise) are associated with improved vitamin D status, whereas those that decrease HDLc or inhibit vitamin D absorption (e.g., smoking and ezetimibe) are linked to lower vitamin D status. Although current human data are largely correlative and confounded by numerous factors affecting vitamin D status, the consistent associations warrant further investigation into vitamin D's precise trafficking among lipoprotein fractions. Conclusions: Re-evaluating vitamin D's absorption and transport to include a role for HDL holds implications for optimizing vitamin D status.