J Steroid Biochem Mol Biol 2020 03 1;197:105504. Epub 2019 Nov 1.
Institute of Agricultural and Nutritional Sciences, Martin Luther University Halle-Wittenberg, Germany; Competence Cluster of Cardiovascular Health and Nutrition (nutriCARD), Halle-Jena-Leipzig, Germany. Electronic address:
For a long time, orally ingested vitamin D was assumed to enter the body exclusively via simple passive diffusion. Recent data from in vitro experiments have described Niemann-Pick C1-like protein 1 (Npc1l1) as an important sterol transporter for vitamin D absorption. However, short-term applications of ezetimibe, which inhibits Npc1l1, were not associated with reduced vitamin D uptake in animals and humans. The current study aimed to elucidate the effect of long-term inhibition of Npc1l1 by ezetimibe on the uptake and storage of orally administered triple deuterated vitamin D (vitamin D-d). Therefore, 30 male wild-type mice were randomly assigned into three groups and received diets with 25 μg/kg of vitamin D-d that contained 0 (control group), 50 or 100 mg/kg ezetimibe for six weeks. Mice fed diets with 50 or 100 mg/kg ezetimibe had lower circulating levels of cholesterol than control mice (-12 %, -15 %, P < 0.01). In contrast, the concentrations of 7-dehydrocholesterol in serum (P < 0.001) and liver (P < 0.05) were higher in mice treated with ezetimibe than in control mice, indicating an increased sterol synthesis to compensate for cholesterol reduction. Long-term application of ezetimibe significantly reduced the concentrations of vitamin D-d in the serum and tissues of mice. The magnitude of vitamin D reduction was comparable between the two ezetimibe groups. In comparison to the control group, mice treated with ezetimibe had lower concentrations of deuterated vitamin D compared with the control group in serum (62 %, P < 0.001), liver (79 %, P < 0.001), kidney (54 %, P < 0.001), adipose tissues (55 %, P < 0.001) and muscle (41 %, P < 0.001). Surprisingly, the serum concentration of deuterated 25-hydroxyvitamin D was higher in the group fed 100 mg/kg ezetimibe than in the control group (P < 0.05). The protein expression of the vitamin D hydroxylases Cyp2r1, Cyp27a1, Cyp3a11, Cyp24a1 and Cyp2j3 in liver and Cyp27b1 and Cyp24a1 in kidney remained largely unaffected by ezetimibe. To conclude, Npc1l1 appears to be crucial for the uptake of orally ingested vitamin D because long-term inhibition of Npc1l1 by ezetimibe strongly reduced the levels of deuterium-labeled vitamin D in the body; the observed rise in deuterated 25-hydroxyvitamin D in serum of these mice can not be explained by the expression levels of the key enzymes involved in vitamin D hydroxylation.