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22.01.2019 | ORIGINAL ARTICLE

Inhibition of Niemann-Pick C1-Like 1 by Ezetimibe Reduces Dietary 5β,6β-Epoxycholesterol Absorption in Rats

verfasst von: Bungo Shirouchi, Yumiko Furukawa, Yuri Nakamura, Asuka Kawauchi, Katsumi Imaizumi, Hirosuke Oku, Masao Sato

Erschienen in: Cardiovascular Drugs and Therapy | Ausgabe 1/2019

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Abstract

Purpose

Oxycholesterols (OCs) are produced from cholesterol by oxidation of the steroidal backbone and side-chain. OCs are present in blood and evidence suggests their involvement in disease development and progression. However, limited information is available regarding the absorption mechanisms and relative absorption rates of dietary OCs. Although ezetimibe is known to inhibit intestinal cholesterol absorption via Niemann-Pick C1-Like 1 (NPC1L1), whether it also inhibits dietary OC absorption is unclear.

Methods

We investigated the effects of ezetimibe on OC absorption in rats fed an OC-rich diet containing 10 different OCs. We collected lymphatic fluid using permanent cannulation of the thoracic duct and quantified OC levels.

Results

Ezetimibe treatment significantly reduced the apparent absorption of 5β,6β-epoxycholesterol (5,6β-epoxy) and its levels in the proximal intestinal mucosa in OC-fed rats. Using in silico analyses, the binding energy of NPC1L1 N-terminal domain (NPC1L1-NTD) and 5,6β-epoxy was found to be similar to that of NPC1L1-NTD and cholesterol, suggesting that polar uncharged amino acids located in the steroidal part of 5,6β-epoxy were involved.

Conclusion

Our results indicate that ezetimibe-mediated inhibition of dietary OC absorption varies depending on the specific OC, and only the absorption of 5,6β-epoxy is significantly reduced.

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Vejux A, Lizard G. Cytotoxic effects of oxysterols associated with human diseases: induction of cell death (apoptosis and/or oncosis), oxidative and inflammatory activities, and phospholipidosis. Mol Asp Med. 2009;30:153–70.CrossRef

Zarrouk A, Vejux A, Mackrill J, et al. Involvement of oxysterols in age-related diseases and ageing processes. Ageing Res Rev. 2014;18:148–62.CrossRefPubMed

Kulig W, Cwiklik L, Jurkiewicz P, Rog T, Vattulainen I. Cholesterol oxidation products and their biological importance. Chem Phys Lipids. 2016;199:144–60.CrossRefPubMed

Sato M, Shirouchi B. Physiological significance of oxidized cholesterols. Oleoscience. 2012;12:115–23 (Article in Japanese).CrossRef

Paniangvait P, King AJ, Jones AD, German BG. Cholesterol oxides in foods of animal origin. J Food Sci. 1995;60:1159–74.CrossRef

van de Bovenkamp P, Kosmeijer-Schuil TG, Katan MB. Quantification of oxysterols in Dutch foods: egg products and mixed diets. Lipids. 1988;23:1079–85.CrossRefPubMed

Ichi I, Iwamoto M, Tomoyori H, Sato M, Ikeda I, Imaizumi K. Intake of oxycholesterols and oxyphytosterols in Japanese meals. J Jpn Soc Nutr Food Sci. 2005;58:145–9 (Article in Japanese).CrossRef

Emanuel HA, Hassel CA, Addis PB, Bergmann SD, Zavoral JH. Plasma cholesterol oxidation products (oxysterols) in human subjects fed a meal rich in oxysterols. J Food Sci. 1991;56:843–7.CrossRef

Clader JW. The discovery of ezetimibe: a view from outside the receptor. J Med Chem. 2004;47:1–9.CrossRefPubMed

10.

Garcia-Calvo M, Lisnock J, Bull HG, et al. The target of ezetimibe is Niemann-Pick C1-Like 1 (NPC1L1). Proc Natl Acad Sci U S A. 2005;102:8132–−7.CrossRefPubMedPubMedCentral

11.

Betters JL, Yu L. Transporters as drug targets: discovery and development of NPC1L1 inhibitors. Clin Pharmacol Ther. 2010;87:117–21.CrossRefPubMed

12.

Ge L, Wang J, Qi W, et al. The cholesterol absorption inhibitor ezetimibe acts by blocking the sterol-induced internalization of NPC1L1. Cell Metab. 2008;7:508–−19.CrossRefPubMed

13.

Narushima K, Takada T, Yamanashi Y, Suzuki H. Niemann-pick C1-like 1 mediates alpha-tocopherol transport. Mol Pharmacol. 2008;74:42–9.CrossRefPubMed

14.

Takada T, Yamanashi Y, Konishi K, et al. NPC1L1 is a key regulator of intestinal vitamin K absorption and a modulator of warfarin therapy. Sci Transl Med. 2015;7:275ra23.CrossRefPubMed

15.

Osada K, Sasaki E, Sugano M. Lymphatic absorption of oxidized cholesterol in rats. Lipids. 1994;29:555–9.CrossRefPubMed

16.

Tomoyori H, Carvajal O, Nakayama M, et al. Lymphatic transport of dietary cholesterol oxidation products, cholesterol and triacylglycerols in rats. Biosci Biotechnol Biochem. 2002;66:828–−34.CrossRefPubMed

17.

Staprans I, Pan XM, Rapp JH, Moser AH, Feingold KR. Ezetimibe inhibits the incorporation of dietary oxidized cholesterol into lipoproteins. J Lipid Res. 2006;47:2575–80.CrossRefPubMed

18.

Tso P. Gastrointestinal digestion and absorption of lipid. Adv Lipid Res. 1985;21:143–86.CrossRefPubMed

19.

Carey MC, Hernell O. Digestion and absorption of fat. Semin Gastrointest Dis. 1992;3:189–208.

20.

Shirouchi B, Kawamura S, Matsuoka R, et al. Dietary guar gum reduces lymph flow and diminishes lipid transport in thoracic duct-cannulated rats. Lipids. 2011;46:789–93.CrossRefPubMed

21.

Shirouchi B, Nakamura Y, Furukawa Y, et al. Ezetimibe inhibits lymphatic transport of esterified cholesterol but not free cholesterol in thoracic lymph duct-cannulated rats. Cardiovasc Drugs Ther. 2012;26:427–31.CrossRefPubMed

22.

Matsuoka R, Shirouchi B, Kawamura S, et al. Dietary egg white protein inhibits lymphatic lipid transport in thoracic lymph duct-cannulated rats. J Agric Food Chem. 2014;62:10694–700.CrossRefPubMed

23.

Bang HJ, Arakawa C, Takada M, Sato M, Imaizumi K. A comparison of the potential unfavorable effects of oxycholesterol and oxyphytosterol in mice: different effects, on cerebral 24S-hydroxychoelsterol and serum triacylglycerols levels. Biosci Biotechnol Biochem. 2008;72:3128–33.CrossRefPubMed

24.

American Institute of Nutrition. Report of the American Institute of Nurtition ad hoc committee on standards for nutritional studies. J Nutr. 1977;107:1340–8.CrossRef

25.

Shirouchi B, Kashima K, Horiuchi Y, et al. 27-Hydroxycholesterol suppresses lipid accumulation by down-regulating lipogenic and adipogenic gene expression in 3T3-L1 cells. Cytotechnology. 2017;69:485–92.CrossRefPubMed

26.

Zhang JH, Ge L, Qi W, et al. The N-terminal domain of NPC1L1 protein binds cholesterol and plays essential roles in cholesterol uptake. J Biol Chem. 2011;286:25088–97.CrossRefPubMedPubMedCentral

27.

Sánchez R, Sali A. Comparative protein structure modeling. Introduction and practical examples with modeller. Methods Mol Biol. 2000;143:97–129.PubMed

28.

Oku H, Inafuku M, Ishikawa T, Takamine T, Ishmael M, Fukuta M. Molecular cloning and biochemical characterization of isoprene synthases from the tropical trees Ficus virgata, Ficus septica, and Casuarina equisetifolia. J Plant Res. 2015;128:849–61.CrossRefPubMed

29.

Morris GM, Huey R, Lindstrom W, et al. AutoDock4 and AutoDockTools4: automated docking with selective receptor flexibility. J Comput Chem. 2009;30:2785–91.CrossRefPubMedPubMedCentral

30.

Kitaura K, Sawai T, Asada T, Nakano T, Uebayasi M. Pair interaction molecular orbital method: an approximate computational method for molecular interactions. Chem Phys Lett. 1999;312:319–24.CrossRef

31.

Kitaura K, Ikeo E, Asada T, Nakano T, Uebayasi M. Fragment molecular orbital method: an approximate computational method for large molecules. Chem Phys Lett. 1999;313:701–6.CrossRef

32.

Ishikawa T, Ishikura T, Kuwata K. Theoretical study of the prion protein based on the fragment molecular orbital method. J Comput Chem. 2009;30:2594–601.CrossRefPubMed

33.

Ponder JW, Case DA. Force fields for protein simulations. Adv Protein Chem. 2003;66:27–85.CrossRefPubMed

34.

Yanai H. Statcel 3–the useful add-in software forms on excel, 3rd ed. Tokyo: OMS; 2011.

35.

Bosner MS, Lange LG, Stenson WF, Ostlund RE Jr. Percent cholesterol absorption in normal women and men quantified with dual stable isotopic tracers and negative ion mass spectrometry. J Lipid Res. 1999;40:302–8.PubMed

36.

Smith LL, Kulig MJ, Miiller D, Ansari GAS. Sterol metabolism. 44. Oxidation of cholesterol by dioxygen species. J Am Chem Soc. 1978;100:6206–11.CrossRef

37.

Baumgartner S, Mensink RP, Haenen GR, et al. The effects of vitamin E or lipoic acid supplementation on oxyphytosterols in subjects with elevated oxidative stress: a randomized trial. Sci Rep. 2017;7:15288.CrossRefPubMedPubMedCentral

38.

Mitton JR, Scholan NA, Boyd GS. The oxidation of cholesterol in rat liver sub-cellular particles. The cholesterol-7-alpha-hydroxylase enzyme system. Eur J Biochem. 1971;20:569–79.CrossRefPubMed

39.

Aringer L, Eneroth P. Formation and metabolism in vitro of 5,6-epoxides of cholesterol and beta-sitosterol. J Lipid Res. 1974;15:389–98.PubMed

40.

Peng SK, Taylor CB, Tham P, Werthessen NT, Mikkelson B. Effect of auto-oxidation products from cholesterol on aortic smooth muscle cells: an in vitro study. Arch Pathol Lab Med. 1978;102:57–61.PubMed

41.

Sevanian A, Peterson AR. Cholesterol epoxide is a direct-acting mutagen. Proc Natl Acad Sci U S A. 1984;81:4198–202.CrossRefPubMedPubMedCentral

42.

Sevanian A, Berliner J, Peterson H. Uptake, metabolism, and cytotoxicity of isomeric cholesterol-5,6-epoxides in rabbit aortic endothelial cells. J Lipid Res. 1991;32:147–55.PubMed

43.

Terunuma S, Kumata N, Osada K. Ezetimibe impairs uptake of dietary cholesterol oxidation products and reduces alterations in hepatic cholesterol metabolism and antioxidant function in rats. Lipids. 2013;48:587–95.CrossRefPubMed

44.

Deushi M, Osaka M, Nakano K, Osada K, Egashira K, Yoshida M. Ezetimibe reduced hepatic steatosis induced by dietary oxysterols in nonhuman primates. FEBS Open Bio. 2016;6:1008–15.CrossRefPubMedPubMedCentral

45.

Sato K, Nakano K, Katsuki S, et al. Dietary cholesterol oxidation products accelerate plaque destabilization and rupture associated with monocyte infiltration/activation via the MCP-1-CCR2 pathway in mouse brachiocephalic arteries: therapeutic effects of ezetimibe. J Atheroscler Thromb. 2012;19:986–98.CrossRefPubMed

Titel: Inhibition of Niemann-Pick C1-Like 1 by Ezetimibe Reduces Dietary 5β,6β-Epoxycholesterol Absorption in Rats
verfasst von: Bungo Shirouchi
Yumiko Furukawa
Yuri Nakamura
Asuka Kawauchi
Katsumi Imaizumi
Hirosuke Oku
Masao Sato
Publikationsdatum: 22.01.2019
Verlag: Springer US
Erschienen in: Cardiovascular Drugs and Therapy / Ausgabe 1/2019
Print ISSN: 0920-3206
Elektronische ISSN: 1573-7241
DOI: https://doi.org/10.1007/s10557-019-06854-4

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Springer Medizin

Inhibition of Niemann-Pick C1-Like 1 by Ezetimibe Reduces Dietary 5β,6β-Epoxycholesterol Absorption in Rats

Abstract

Purpose

Methods

Results

Conclusion

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Springer Medizin

Abstract

Purpose

Methods

Results

Conclusion

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