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Transporters for the Intestinal Absorption of Cholesterol, Vitamin E, and Vitamin K

View Article: PubMed Central - PubMed

ABSTRACT

Humans cannot synthesize fat-soluble vitamins such as vitamin E and vitamin K. For this reason, they must be obtained from the diet via intestinal absorption. As the deficiency or excess of these vitamins has been reported to cause several types of diseases and disorders in humans, the intestinal absorption of these nutrients must be properly regulated to ensure good health. However, the mechanism of their intestinal absorption remains poorly understood. Recent studies on cholesterol using genome-edited mice, genome-wide association approaches, gene mutation analyses, and the development of cholesterol absorption inhibitors have revealed that several membrane proteins play crucial roles in the intestinal absorption of cholesterol. Surprisingly, detailed analyses of these cholesterol transporters have revealed that they can also transport vitamin E and vitamin K, providing clues to uncover the molecular mechanisms underlying the intestinal absorption of these fat-soluble vitamins. In this review, we focus on the membrane proteins (Niemann-Pick C1 like 1, scavenger receptor class B type I, cluster of differentiation 36, and ATP-binding cassette transporter A1) that are (potentially) involved in the intestinal absorption of cholesterol, vitamin E, and vitamin K and discuss their physiological and pharmacological importance. We also discuss the related uncertainties that need to be explored in future studies.

No MeSH data available.


Related in: MedlinePlus

Proposed mechanism of the drug interaction between ezetimibe and warfarin.Vitamin K (VK) is absorbed by NPC1L1 in the intestine and then circulates through the vitamin K cycle in the liver. In this cycle, vitamin K activates clotting factors and regulates blood coagulation. When warfarin, an anticoagulant drug that inhibits the vitamin K cycle, and ezetimibe, an NPC1L1 inhibitor clinically used for dyslipidemia, are administered together, the anticoagulant effect of warfarin is apparently enhanced by the ezetimibe-related reduction in vitamin K absorption.
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Figure 5: Proposed mechanism of the drug interaction between ezetimibe and warfarin.Vitamin K (VK) is absorbed by NPC1L1 in the intestine and then circulates through the vitamin K cycle in the liver. In this cycle, vitamin K activates clotting factors and regulates blood coagulation. When warfarin, an anticoagulant drug that inhibits the vitamin K cycle, and ezetimibe, an NPC1L1 inhibitor clinically used for dyslipidemia, are administered together, the anticoagulant effect of warfarin is apparently enhanced by the ezetimibe-related reduction in vitamin K absorption.

Mentions: Based on reports showing that anticoagulant activity is enhanced in patients taking warfarin in combination with ezetimibe43), the ezetimibe package insert warns that caution should be exercised when ezetimibe is co-administered with warfarin41). However, the mechanism of the warfarin-ezetimibe interaction was not clear. The results of vitamin K1 absorption studies (Fig. 3), together with the fact that clotting factors are activated in the liver through the cyclic conversion of hepatic vitamin K (vitamin K cycle)44), led to the hypothesis that the inhibition of vitamin K absorption by ezetimibe would apparently enhance the inhibitory effect of warfarin on the activation of clotting factors. To test this hypothesis, the effect of ezetimibe on anticoagulant activities and on hepatic vitamin K levels in Wistar rats treated with (or without) warfarin was examined42). The anticoagulant effect of warfarin was reflected in the extension of prothrombin time. Consistent with a previous case report in humans43), prothrombin time in rats co-treated with warfarin and ezetimibe (co-treatment group) was significantly longer than that in rats treated with warfarin alone (warfarin alone group) (Fig. 4A). Analysis of the hepatic vitamin K1 level in these rats showed that the liver vitamin K1 concentration in the co-treatment group was significantly lower than that in the warfarin alone group (Fig. 4B). In addition, vitamin K1 rescue experiments revealed that restoration of the hepatic vitamin K1 level by oral vitamin K1 supplementation canceled the extension of prothrombin time observed in the co-treatment group (Fig. 4). Taken together with the observation that the co-administration of ezetimibe did not result in significant changes in the hepatic warfarin concentration in rats, these data suggest that the effect of the drug interaction between ezetimibe and warfarin is mediated by the decrease in the hepatic vitamin K level, which is caused by ezetimibe-mediated vitamin K1 malabsorption (Fig. 5).


Transporters for the Intestinal Absorption of Cholesterol, Vitamin E, and Vitamin K
Proposed mechanism of the drug interaction between ezetimibe and warfarin.Vitamin K (VK) is absorbed by NPC1L1 in the intestine and then circulates through the vitamin K cycle in the liver. In this cycle, vitamin K activates clotting factors and regulates blood coagulation. When warfarin, an anticoagulant drug that inhibits the vitamin K cycle, and ezetimibe, an NPC1L1 inhibitor clinically used for dyslipidemia, are administered together, the anticoagulant effect of warfarin is apparently enhanced by the ezetimibe-related reduction in vitamin K absorption.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5392472&req=5

Figure 5: Proposed mechanism of the drug interaction between ezetimibe and warfarin.Vitamin K (VK) is absorbed by NPC1L1 in the intestine and then circulates through the vitamin K cycle in the liver. In this cycle, vitamin K activates clotting factors and regulates blood coagulation. When warfarin, an anticoagulant drug that inhibits the vitamin K cycle, and ezetimibe, an NPC1L1 inhibitor clinically used for dyslipidemia, are administered together, the anticoagulant effect of warfarin is apparently enhanced by the ezetimibe-related reduction in vitamin K absorption.
Mentions: Based on reports showing that anticoagulant activity is enhanced in patients taking warfarin in combination with ezetimibe43), the ezetimibe package insert warns that caution should be exercised when ezetimibe is co-administered with warfarin41). However, the mechanism of the warfarin-ezetimibe interaction was not clear. The results of vitamin K1 absorption studies (Fig. 3), together with the fact that clotting factors are activated in the liver through the cyclic conversion of hepatic vitamin K (vitamin K cycle)44), led to the hypothesis that the inhibition of vitamin K absorption by ezetimibe would apparently enhance the inhibitory effect of warfarin on the activation of clotting factors. To test this hypothesis, the effect of ezetimibe on anticoagulant activities and on hepatic vitamin K levels in Wistar rats treated with (or without) warfarin was examined42). The anticoagulant effect of warfarin was reflected in the extension of prothrombin time. Consistent with a previous case report in humans43), prothrombin time in rats co-treated with warfarin and ezetimibe (co-treatment group) was significantly longer than that in rats treated with warfarin alone (warfarin alone group) (Fig. 4A). Analysis of the hepatic vitamin K1 level in these rats showed that the liver vitamin K1 concentration in the co-treatment group was significantly lower than that in the warfarin alone group (Fig. 4B). In addition, vitamin K1 rescue experiments revealed that restoration of the hepatic vitamin K1 level by oral vitamin K1 supplementation canceled the extension of prothrombin time observed in the co-treatment group (Fig. 4). Taken together with the observation that the co-administration of ezetimibe did not result in significant changes in the hepatic warfarin concentration in rats, these data suggest that the effect of the drug interaction between ezetimibe and warfarin is mediated by the decrease in the hepatic vitamin K level, which is caused by ezetimibe-mediated vitamin K1 malabsorption (Fig. 5).

View Article: PubMed Central - PubMed

ABSTRACT

Humans cannot synthesize fat-soluble vitamins such as vitamin E and vitamin K. For this reason, they must be obtained from the diet via intestinal absorption. As the deficiency or excess of these vitamins has been reported to cause several types of diseases and disorders in humans, the intestinal absorption of these nutrients must be properly regulated to ensure good health. However, the mechanism of their intestinal absorption remains poorly understood. Recent studies on cholesterol using genome-edited mice, genome-wide association approaches, gene mutation analyses, and the development of cholesterol absorption inhibitors have revealed that several membrane proteins play crucial roles in the intestinal absorption of cholesterol. Surprisingly, detailed analyses of these cholesterol transporters have revealed that they can also transport vitamin E and vitamin K, providing clues to uncover the molecular mechanisms underlying the intestinal absorption of these fat-soluble vitamins. In this review, we focus on the membrane proteins (Niemann-Pick C1 like 1, scavenger receptor class B type I, cluster of differentiation 36, and ATP-binding cassette transporter A1) that are (potentially) involved in the intestinal absorption of cholesterol, vitamin E, and vitamin K and discuss their physiological and pharmacological importance. We also discuss the related uncertainties that need to be explored in future studies.

No MeSH data available.


Related in: MedlinePlus