Dr. Weeks’ Comment: Did your statin drug deplete your fat soluble vitamins which protect the GI lining allowing for ulceration and inflammation of your guts?
re Zetia and absorption of fat soluble vitamins and nutrients
Drug companies claim (a lie!)
- Ezetimibe is a potent inhibitor of intestinal free cholesterol absorption that does not require exocrine pancreatic function for activity. Ezetimibe does not affect the absorption of triglyceride as a pancreatic lipase inhibitor (Orlistat) would, nor does it affect the absorption of vitamin A, D or taurocholate, as a bile acid sequestrant (cholestyramine) would.
That is implausible, Marty when you consider this research.
J Nutr. 2005 Oct;135(10):2305-12.
Carotenoid transport is decreased and expression of the lipid transporters SR-BI, NPC1L1, and ABCA1 is downregulated in Caco-2 cells treated with ezetimibe.
Data suggest that intestinal carotenoid absorption is a facilitated process. The present study was conducted to determine whether carotenoids and cholesterol share common pathways (transporters) for their intestinal absorption. Differentiated Caco-2 cells on membranes were incubated (16 h) with a carotenoid (1 micromol/L) with or without ezetimibe (EZ; Zetia, an inhibitor of cholesterol transport), and with or without antibodies against the receptors, cluster determinant 36 (CD36) and scavenger receptor class B, type I (SR-BI). Carotenoid transport in Caco-2 cells (cellular uptake + secretion) was decreased by EZ(10 mg/L) as follows: beta-carotene approximately alpha-carotene (50% inhibition) >> beta-cryptoxanthin approximately lycopene (20%) >> lutein:zeaxanthin (1:1)(7%).EZ reduced cholesterol transport by 31%, but not retinol transport. beta-Carotene transport was also inhibited by anti-SR-BI, but not by anti-CD36. The inhibitory effects of EZ and anti-SR-BI on beta-carotene transport were additive, indicating that they may have different targets. Finally, differentiated Caco-2 cells treated with EZ showed a significant decrease in mRNA expression for the surface receptors SR-BI, Niemann-Pick type C1 Like 1 protein (NPC1L1), and ATP-binding cassette transporter, subfamily A (ABCA1) and for the nuclear receptors retinoid acid receptor (RAR) gamma, sterol-regulatory element binding proteins (SREBP)-1 and -2, and liver X receptor (LXR) beta as assessed by real-time PCR analysis. The data indicate that 1) EZ is an inhibitor of carotenoid transport, an effect that decreases with increasing polarity of the carotenoid molecule, 2) SR-BI is involved in carotenoid transport, and 3) EZ may act, not only by interacting physically with cholesterol transporters as previously suggested, but also by downregulating expression of these proteins. The cellular uptake and efflux of carotenoids, like that of cholesterol, likely involve more than one transporter.
VIT D 3
J Steroid Biochem Mol Biol. 2019 Nov 1;197:105504. doi: 10.1016/j.jsbmb.2019.105504. [Epub ahead of print]
Inhibition of Niemann-Pick C1-like protein 1 by ezetimibe reduces uptake of deuterium-labeled vitamin D in mice.
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 D3 (vitamin D3-d3). Therefore, 30 male wild-type mice were randomly assigned into three groups and received diets with 25 μg/kg of vitamin D3-d3 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 ezetimibesignificantly reduced the concentrations of vitamin D3-d3 in the serum and tissues of mice. The magnitude of vitamin D3 reduction was comparable between the two ezetimibe groups. In comparison to the control group, mice treated with ezetimibe had lower concentrations of deuterated vitamin D3 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 D3 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 D3 in serum of these mice can not be explained by the expression levels of the key enzymes involved in vitamin Dhydroxylation.
Biochem Biophys Res Commun. 2017 Apr 29;486(2):476-480. doi: 10.1016/j.bbrc.2017.03.065. Epub 2017 Mar 16.
N-terminal domain of the cholesterol transporter Niemann-Pick C1-like 1 (NPC1L1) is essential for α-tocopherol transport.
Both cholesterol and α-tocopherol are essential lipophilic nutrients for humans and animals. Although cholesterol in excess causes severe problems such as coronary heart disease, it is a necessary component of cell membranes and is the precursor for the biosynthesis of steroid hormones and bile acids. Niemann-Pick C1-like 1 (NPC1L1) is a cholesterol transporter that is highly expressed in the small intestine and liver in humans and plays an important role in cholesterol homeostasis. Cholesterol promotes NPC1L1 endocytosis, which is an early step in cholesterol uptake. Furthermore, α-tocopherol is the most active form of vitamin E, and sufficient amounts of vitamin E are critical for health. It has been reported that NPC1L1 mediates α-tocopherol absorption; however, the mechanisms underlying this process are unknown. In this study, we found that treatment of cells that stably express NPC1L1-GFP with α-tocopherol promotes NPC1L1 endocytosis, and the NPC1L1 inhibitor, ezetimibe, efficiently prevents the α-tocopherol-induced endocytosis of NPC1L1. Cholesterol binding to the N-terminal domain (NTD) of NPC1L1 (NPC1L1-NTD) is essential for NPC1L1-mediated cholesterol absorption. We found that α-tocopherol competitively binds NPC1L1-NTD with cholesterol. Furthermore, when cells stably expressed NPC1L1ΔNTD-GFP, α-tocopherol could not induce the endocytosis of NPC1L1ΔNTD. Taken together, these results demonstrate that NPC1L1 recognizes α-tocopherol via its NTD and mediates α-tocopherol uptake through the same mechanism as cholesterol absorption.
Biopharm Drug Dispos. 2017 May;38(4):280-289. doi: 10.1002/bdd.2059. Epub 2017 Jan 20.
Inhibitory effect of ezetimibe can be prevented by an administration interval of 4 h between α-tocopherol and ezetimibe.
Tocopherol is used not only as an ethical drug but also as a supplement. In 2008, it was reported that α-tocopherol is partly transported via an intestinal cholesterol transporter, Niemann-Pick C1-Like 1 (NPC1L1). Ezetimibe, a selective inhibitor of NPC1L1, is administered for a long time to inhibit cholesterol absorption and there is a possibility that the absorption of α-tocopherol is also inhibited by ezetimibe. This study investigated the influence of ezetimibe on the absorption of α-tocopherol with single administration and long-term administration. An approach to avoid its undesirable consequence was also examined. α-Tocopherol (10 mg/kg) and ezetimibe(0.1 mg/kg) were administered to rats, and the plasma concentration profiles of α-tocopherol and tissue concentrations were investigated. The plasma concentration of α-tocopherol was decreased by the combination use of ezetimibe in the case of concurrent single administration. On the other hand, inhibition of the absorption of α-tocopherol was prevented by an administration interval of 4 h. In a group of rats administered for 2 months with a 4 h interval, not only the plasma concentration but also the liver concentration was increased compared with those in a group with concurrent combination intake of α-tocopherol and ezetimibe.The absorption of α-tocopherol was inhibited by ezetimibe.The inhibitory effect of ezetimibe can be prevented by an administration interval of 4 h, although ezetimibe is a medicine of enterohepatic circulation. Attention should be paid to the use of ezetimibe and components of NPC1L1 substrates such as α-tocopherol.
Sci Transl Med. 2015 Feb 18;7(275):275ra23. doi: 10.1126/scitranslmed.3010329.
NPC1L1 is a key regulator of intestinal vitamin K absorption and a modulator of warfarin therapy.
Vitamin K (VK) is a micronutrient that facilitates blood coagulation. VK antagonists, such as warfarin, are used in the clinic to prevent thromboembolism. Because VK is not synthesized in the body, its intestinal absorption is crucial for maintaining whole-body VK levels. However, the molecular mechanism of this absorption is unclear. We demonstrate that Niemann-Pick C1-like 1 (NPC1L1) protein, a cholesterol transporter, plays a central role in intestinal VK uptake and modulates the anticoagulant effect of warfarin. In vitro studies using NPC1L1-overexpressing intestinal cells and in vivo studies with Npc1l1-knockout mice revealed that intestinal VK absorption is NPC1L1-dependent and inhibited by ezetimibe, an NPC1L1-selective inhibitor clinically used for dyslipidemia. In addition, in vivo pharmacological studies demonstrated that the coadministration of ezetimibe and warfarin caused a reduction in hepatic VK levels and enhanced the pharmacological effect of warfarin. Adverse events caused by the coadministration of ezetimibe and warfarin were rescued by oral VK supplementation, suggesting that the drug-drug interaction effects observed were the consequence of ezetimibe-mediated VK malabsorption.This mechanism was supported by a retrospective evaluation of clinical data showing that, in more than 85% of warfarin-treated patients, the anticoagulant activity was enhanced by cotreatment with ezetimibe. Our findings provide insight into the molecular mechanism of VK absorption. This new drug-drug interaction mechanism between ezetimibe (a cholesterol transport inhibitor) and warfarin (a VK antagonist and anticoagulant) could inform clinical care of patients on these medications, such as byaltering the kinetics of essential, fat-soluble vitamins.