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We recently demonstrated that blood levels of 1,25-dihydroxyvitamin D [1,25(OH)<jats:sub>2<\/jats:sub>D, i.e. the active vitamin D] were significantly lower in non-survivors compared to survivors among sepsis patients. Unexpectedly, despite the well documented roles of 1,25(OH)<jats:sub>2<\/jats:sub>D in multiple biological functions such as regulation of immune responses, stimulation of antimicrobials, and maintenance of barrier function, 1,25(OH)<jats:sub>2<\/jats:sub>D supplementation failed to improve disease outcomes. These previous findings suggest that, in addition to 1,25(OH)<jats:sub>2<\/jats:sub>D deficiency, disorders leading to the 1,25(OH)<jats:sub>2<\/jats:sub>D deficiency also contribute to mortality among sepsis patients. Therefore, this study investigated the mechanisms leading to sepsis-associated 1,25(OH)<jats:sub>2<\/jats:sub>D deficiency.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We studied mechanisms known to regulate kidney 25-hydroxylvitamin D 1\u03b1-hydroxylase which physiologically catalyzes the conversion of 25(OH) D into 1,25(OH)<jats:sub>2<\/jats:sub>D. Such mechanisms included parathyroid hormone (PTH), insulin-like growth factor 1 (IGF-1), fibroblast growth factor 23 (FGF-23), and kidney function.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>We demonstrated in both human subjects and mice that sepsis-associated 1,25(OH)<jats:sub>2<\/jats:sub>D deficiency could not be overcome by increased production of PTH which stimulates 1\u03b1-hydroxylase. Further studies showed that this failure of PTH to maintain blood 1,25(OH)<jats:sub>2<\/jats:sub>D levels was associated with decreased blood levels of IGF-1, increased blood levels of FGF-23, and kidney failure. Since the increase in blood levels of FGF-23 is known to associate with kidney failure, we further investigated the mechanisms leading to sepsis-induced decrease in blood levels of IGF-1. Our data showed that blood levels of growth hormone, which stimulates IGF-1 production in liver, were increased but could not overcome the IGF-1 deficiency. Additionally, we found that the inability of growth hormone to restore the IGF-1 deficiency was associated with suppressed expression and signaling of growth hormone receptor in liver.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Because FGF-23 and IGF-1 have multiple biological functions besides their role in regulating kidney 1\u03b1-hydroxylase, our data suggest that FGF-23 and IGF-1 are warranted for further investigation as potential agents for the correction of 1,25(OH)<jats:sub>2<\/jats:sub>D deficiency and for the improvement of survival among sepsis patients.<\/jats:p><\/jats:sec>","DOI":"10.1186\/s12879-019-4529-7","type":"journal-article","created":{"date-parts":[[2019,12,2]],"date-time":"2019-12-02T14:06:14Z","timestamp":1575295574000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":20,"title":["Mechanistic study of the cause of decreased blood 1,25-Dihydroxyvitamin D in sepsis"],"prefix":"10.1186","volume":"19","author":[{"given":"Chih-Huang","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1492-9622","authenticated-orcid":false,"given":"Xiaolei","family":"Tang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samiksha","family":"Wasnik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohua","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jintao","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kin-Hing William","family":"Lau","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"H. 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