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As energy\u2010dense diet contributes to these disorders, this study investigates whether diet could impair vitamin D metabolism.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods and Results<\/jats:title><jats:p>Compared with control chow\u2010fed mice, high fat diet (HFD)\u2010fed mice show lower serum 25(OH)D<jats:sub>3<\/jats:sub> and 1,25(OH)<jats:sub>2<\/jats:sub>D<jats:sub>3<\/jats:sub> levels, lower hepatic vitamin D 25\u2010hydroxylase Cyp2r1 expression but comparable renal vitamin D metabolic enzymes expression. Time course studies show that after HFD feeding, the serum concentrations of cholesterol, triglycerides, fatty acids, glucose, and insulin elevate sequentially and before the reduction of hepatic Cyp2r1 expression and serum 25(OH)D<jats:sub>3<\/jats:sub> levels. Hepatic Cyp2r1 expression also reduces after consuming high fat and high sucrose diet. After high cholesterol diet feeding, serum total cholesterol rises and hepatic Cyp2r1 expression decreases ahead of the reduction of serum 25(OH)D<jats:sub>3<\/jats:sub>. In vitro studies demonstrate that high concentrations of cholesterol, glucose, and insulin significantly inhibit Cyp2r1expression in primary murine hepatocytes. Further studies show that dietary restriction in HFD\u2010fed mice ameliorates hypercholesterolemia, hyperglycemia, and hypertriglyceridemia, and elevates hepatic Cyp2r1 expression and serum 25(OH)D<jats:sub>3<\/jats:sub> level.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>These findings suggest that diet\u2010induced elevation of circulating cholesterol, glucose, and insulin reduces serum 25(OH)D<jats:sub>3<\/jats:sub> level through suppressing hepatic Cyp2r1 expression.<\/jats:p><\/jats:sec>","DOI":"10.1002\/mnfr.202100220","type":"journal-article","created":{"date-parts":[[2021,8,27]],"date-time":"2021-08-27T08:09:38Z","timestamp":1630051778000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["High Fat Diet and High Cholesterol Diet Reduce Hepatic Vitamin D\u201025\u2010Hydroxylase Expression and Serum 25\u2010Hydroxyvitamin D<sub>3<\/sub> Level through Elevating Circulating Cholesterol, Glucose, and Insulin Levels"],"prefix":"10.1002","volume":"65","author":[{"given":"Tengfei","family":"Zhu","sequence":"first","affiliation":[{"name":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences University of Chinese Academy of Sciences  Shanghai 200031 China"},{"name":"School of Public Health Shanghai Jiao Tong University School of Medicine  Shanghai 200025 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingyu","family":"Zhao","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences University of Chinese Academy of Sciences  Shanghai 200031 China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shu","family":"Zhuo","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Nutrition, Metabolism and Food Safety, 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