{"doi":"10.1101/2023.06.27.23291942","title":"Critical Role for 24-Hydroxylation in Homeostatic Regulation of Vitamin D Metabolism","abstract":"ABSTRACT Context The body has evolved homeostatic mechanisms to maintain free levels of Ca +2 and 1,25-dihydroxyvitamin D [1,25(OH) 2 D] within narrow physiological ranges. Clinical guidelines emphasize important contributions of PTH in maintaining this homeostasis. Objective To investigate mechanisms of homeostatic regulation of vitamin D (VitD) metabolism and to apply mechanistic insights to improve clinical assessment of VitD status. Design Crossover clinical trial studying participants before and after VitD3-supplementation. Setting Community. Participants 11 otherwise healthy individuals with VitD-deficiency (25-hydroxyvitamin D [25(OH)D] ≤20 ng/mL). Interventions VitD3-supplements (50,000 IU once or twice a week depending on BMI, for 4-6 weeks) were administered to achieve 25(OH)D≥30 ng/mL. Results VitD3-supplementation significantly increased mean 25(OH)D by 2.7-fold and 24,25-dihydroxyvitamin D [24,25(OH) 2 D] by 4.3-fold. In contrast, mean levels of PTH, FGF23, and 1,25(OH) 2 D did not change. Mathematical modeling suggested that 24-hydroxylase activity was maximal for 25(OH)D≥50 ng/mL and achieved a minimum (∼90% suppression) with 25(OH)D<10-20 ng/mL. The 1,25(OH) 2 D/24,25(OH) 2 D ratio better predicted modeled 24-hydroxylase activity ( h ) (ρ=-0.85; p=0.001) compared to total plasma 25(OH)D (ρ=0.51; p=0.01) and the 24,25(OH) 2 D/25(OH)D ratio (ρ=0.37; p=0.3). Conclusions Suppression of 24-hydroxylase provides a first line of defense against symptomatic VitD-deficiency by decreasing metabolic clearance of 1,25(OH) 2 D. The 1,25(OH) 2 D/24,25(OH) 2 D ratio provides a useful index of VitD status since it incorporates 24,25(OH) 2 D levels and therefore, provides insight into 24-hydroxylase activity. When VitD availability is limited, this suppresses 24-hydroxylase activity – thereby decreasing the level of 24,25(OH) 2 D and increasing the 1,25(OH) 2 D/24,25(OH) 2 D ratio. Thus, an increased 1,25(OH) 2 D/24,25(OH) 2 D ratio signifies triggering of homeostatic regulation, which occurs at early stages of VitD-deficiency.","journal":"medRxiv","year":2023,"id":393420,"datarank":0.0,"base_score":0.0,"endowment":0.0,"self_citation_contribution":0.0,"citation_network_contribution":0.0,"self_endowment_contribution":0.0,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":4,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9512,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":25022,"name":"Elizabeth A. Streeten","orcid":"0000-0002-9771-6958","position":1,"is_corresponding":false},{"id":1167482,"name":"Hilary B. Whitlatch","orcid":"0000-0002-5770-6544","position":2,"is_corresponding":false},{"id":24828,"name":"May E. Montasser","orcid":"0000-0002-9558-5456","position":3,"is_corresponding":false},{"id":24946,"name":"Amber L. Beitelshees","orcid":null,"position":4,"is_corresponding":false},{"id":18626,"name":"Simeon I. Taylor","orcid":"0000-0001-7500-7854","position":5,"is_corresponding":false},{"id":1167481,"name":"Zhinous Shahidzadeh Yazdi","orcid":"0000-0003-1056-4523","position":0,"is_corresponding":true}],"reference_count":64,"raw_metadata":null,"created_at":"2026-07-19T01:19:05.913428Z","pmid":"37425945","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}