The combination of ezetimibe and ursodiol promotes fecal sterol excretion and reveals a G5G8-independent pathway for cholesterol elimination

Journal of Lipid Research

Volumn 56, Issue 4, 2015, Pages 810-820

  Wang, Yuhuan ^a   Liu, Xiaoxi ^a   Pijut, Sonja S ^a   Li, Jianing ^b   Horn, Jamie ^a   Bradford, Emily M ^a   Leggas, Markos ^a   Barrett, Terrence A ^a   Graf, Gregory A ^a,b  

^a UNIVERSITY OF KENTUCKY   (United States)

^b UNIVERSITY OF KENTUCKY   (United States)

Author keywords

ATP binding cassette transporter G5; ATP binding cassette transporter G8; Bile; Bile acids and salts biosynthesis; Biliary cholesterol secretion; Cholesterol 7 alpha hydroxylase; Cholesterol biosynthesis; High density lipoprotein; Nonalcoholic fatty liver disease; Reverse cholesterol transport; Ursodeoxycholic acid

Indexed keywords

ABC TRANSPORTER A1; ABC TRANSPORTER G5; EZETIMIBE; STEROL DERIVATIVE; URSODEOXYCHOLIC ACID; ABC TRANSPORTER; ABCG5 PROTEIN, MOUSE; ABCG8 PROTEIN, MOUSE; BILE ACID; CHOLESTEROL; LIPOPROTEIN;

ANIMAL EXPERIMENT; ANIMAL TISSUE; ARTICLE; BILE ACID SYNTHESIS; BILE SECRETION; CHOLESTEROL BLOOD LEVEL; CHOLESTEROL ELIMINATION; CHOLESTEROL LIVER LEVEL; COMBINATION CHEMOTHERAPY; CONTROLLED STUDY; DOSE RESPONSE; DRUG POTENTIATION; EXCRETION; FECES; FEMALE; GENOTYPE; MALE; MONOTHERAPY; MOUSE; NONHUMAN; PRIORITY JOURNAL; ANIMAL; BIOSYNTHESIS; CHEMISTRY; DEFICIENCY; DRUG EFFECTS; GENE INACTIVATION; GENETICS; HEPATOBILIARY SYSTEM; INTESTINE; METABOLISM; PROTEIN MULTIMERIZATION; PROTEIN QUATERNARY STRUCTURE; TRANSPORT AT THE CELLULAR LEVEL;

ANIMALS; ATP-BINDING CASSETTE TRANSPORTERS; BILE ACIDS AND SALTS; BILIARY TRACT; BIOLOGICAL TRANSPORT; CHOLESTEROL; DOSE-RESPONSE RELATIONSHIP, DRUG; DRUG SYNERGISM; EZETIMIBE; FECES; FEMALE; GENE KNOCKOUT TECHNIQUES; INTESTINES; LIPOPROTEINS; MALE; MICE; PROTEIN MULTIMERIZATION; PROTEIN STRUCTURE, QUATERNARY; URSODEOXYCHOLIC ACID;

EID: 84927667215     PISSN: 00222275     EISSN: 15397262     Source Type: Journal    
DOI: 10.1194/jlr.M053454     Document Type: Article

References (40)

1. Savard, C., E. V. Tartaglione, R. Kuver, W. G. Haigh, G. C. Farrell, S. Subramanian, A. Chait, M. M. Yeh, L. S. Quinn, and G. N. Ioannou. 2013. Synergistic interaction of dietary cholesterol and dietary fat in inducing experimental steatohepatitis. Hepatology. 57: 81-92.
2. Subramanian, S., L. Goodspeed, S. Wang, J. Kim, L. Zeng, G. N. Ioannou, W. G. Haigh, M. M. Yeh, K. V. Kowdley, K. D. O'Brien, et al. 2011. Dietary cholesterol exacerbates hepatic steatosis and inflammation in obese LDL receptor-deficient mice. J. Lipid Res. 52: 1626-1635.
3. Van Rooyen, D. M., C. Z. Larter, W. G. Haigh, M. M. Yeh, G. Ioannou, R. Kuver, S. P. Lee, N. C. Teoh, and G. C. Farrell. 2011. Hepatic free cholesterol accumulates in obese, diabetic mice and causes non-alcoholic steatohepatitis. Gastroenterology. 141: 1393-1403.e5.
4. Sabeva, N. S., J. Liu, and G. A. Graf. 2009. The ABCG5 ABCG8 sterol transporter and phytosterols: implications for cardiometabolic disease. Curr. Opin. Endocrinol. Diabetes Obes. 16: 172-177.
5. Berge, K. E., H. Tian, G. A. Graf, L. Yu, N. V. Grishin, J. Schultz, P. Kwiterovich, B. Shan, R. Barnes, and H. H. Hobbs. 2000. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science. 290: 1771-1775.
6. Su, K., N. S. Sabeva, J. Liu, Y. Wang, S. Bhatnagar, D. R. van der Westhuyzen, and G. A. Graf. 2012. The ABCG5 ABCG8 sterol transporter opposes the development of fatty liver disease and loss of glycemic control independently of phytosterol accumulation. J. Biol. Chem. 287: 28564-28575.
7. Su, K., N. S. Sabeva, Y. Wang, X. Liu, J. D. Lester, J. Liu, S. Liang, and G. A. Graf. 2014. Acceleration of biliary cholesterol secretion restores glycemic control and alleviates hypertriglyceridemia in obese db/db mice. Arterioscler. Thromb. Vasc. Biol. 34: 26-33.
8. Davis, H. R., Jr., L. J. Zhu, L. M. Hoos, G. Tetzloff, M. Maguire, J. Liu, X. Yao, S. P. Iyer, M. H. Lam, E. G. Lund, et al. 2004. Niemann-Pick C1 Like 1 (NPC1L1) is the intestinal phytosterol and cholesterol transporter and a key modulator of whole-body cholesterol homeostasis. J. Biol. Chem. 279: 33586-33592.
9. Wilund, K. R., L. Yu, F. Xu, H. H. Hobbs, and J. C. Cohen. 2004. High-level expression of ABCG5 and ABCG8 attenuates diet-induced hypercholesterolemia and atherosclerosis in Ldlr-/- mice. J. Lipid Res. 45: 1429-1436.
10. Basso, F., L. A. Freeman, C. Ko, C. Joyce, M. J. Amar, R. D. Shamburek, T. Tansey, F. Thomas, J. Wu, B. Paigen, et al. 2007. Hepatic ABCG5/G8 overexpression reduces apoB-lipoproteins and atherosclerosis when cholesterol absorption is inhibited. J. Lipid Res. 48: 114-126.
11. Sabeva, N. S., E. J. Rouse, and G. A. Graf. 2007. Defects in the leptin axis reduce abundance of the ABCG5-ABCG8 sterol transporter in liver. J. Biol. Chem. 282: 22397-22405.
12. Tsuchida, T., M. Shiraishi, T. Ohta, K. Sakai, and S. Ishii. 2012. Ursodeoxycholic acid improves insulin sensitivity and hepatic steatosis by inducing the excretion of hepatic lipids in high-fat diet-fed KK-Ay mice. Metabolism. 61: 944-953.
13. Ozcan, U., E. Yilmaz, L. Ozcan, M. Furuhashi, E. Vaillancourt, R. O. Smith, C. Z. Gorgun, and G. S. Hotamisligil. 2006. Chemical chaperones reduce ER stress and restore glucose homeostasis in a mouse model of type 2 diabetes. Science. 313: 1137-1140.
14. Graf, G. A., L. Yu, W. P. Li, R. Gerard, P. L. Tuma, J. C. Cohen, and H. H. Hobbs. 2003. ABCG5 and ABCG8 are obligate heterodimers for protein trafficking and biliary cholesterol excretion. J. Biol. Chem. 278: 48275-48282.
15. Rayner, K. J., C. C. Esau, F. N. Hussain, A. L. McDaniel, S. M. Marshall, J. M. van Gils, T. D. Ray, F. J. Sheedy, L. Goedeke, X. Liu, et al. 2011. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature. 478: 404-407.
16. Yu, L., K. von Bergmann, D. Lutjohann, H. H. Hobbs, and J. C. Cohen. 2005. Ezetimibe normalizes metabolic defects in mice lacking ABCG5 and ABCG8. J. Lipid Res. 46: 1739-1744.
17. Cliffe, L. J., N. E. Humphreys, T. E. Lane, C. S. Potten, C. Booth, and R. K. Grencis. 2005. Accelerated intestinal epithelial cell turnover: a new mechanism of parasite expulsion. Science. 308: 1463-1465.
18. Talalay, P. 1960. Enzymic analysis of steroid hormones. Methods Biochem. Anal. 8: 119-143.
19. Yu, L., R. E. Hammer, J. Li-Hawkins, K. Von Bergmann, D. Lutjohann, J. C. Cohen, and H. H. Hobbs. 2002. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc. Natl. Acad. Sci. USA. 99: 16237-16242.
20. Wang, J., M. A. Mitsche, D. Luetjohann, J. C. Cohen, X. S. Xie, and H. H. Hobbs. 2015. Relative roles of ABCG5/ABCG8 in liver and intestine. J. Lipid Res. 56: 319-330.
21. McDonald, J. G., D. D. Smith, A. R. Stiles, and D. W. Russell. 2012. A comprehensive method for extraction and quantitative analysis of sterols and secosteroids from human plasma. J. Lipid Res. 53: 1399-1409.
22. Honda, A., T. Miyazaki, T. Ikegami, J. Iwamoto, K. Yamashita, M. Numazawa, and Y. Matsuzaki. 2010. Highly sensitive and specific analysis of sterol profiles in biological samples by HPLC-ESI-MS/MS. J. Steroid Biochem. Mol. Biol. 121: 556-564.
23. Kempen, H. J., J. F. Glatz, J. A. Gevers Leuven, H. A. van der Voort, and M. B. Katan. 1988. Serum lathosterol concentration is an indicator of whole-body cholesterol synthesis in humans. J. Lipid Res. 29: 1149-1155.
24. van der Veen, J. N., T. H. van Dijk, C. L. Vrins, H. van Meer, R. Havinga, K. Bijsterveld, U. J. Tietge, A. K. Groen, and F. Kuipers. 2009. Activation of the liver X receptor stimulates trans-intestinal excretion of plasma cholesterol. J. Biol. Chem. 284: 19211-19219.
25. Brunham, L. R., J. K. Kruit, J. Iqbal, C. Fievet, J. M. Timmins, T. D. Pape, B. A. Coburn, N. Bissada, B. Staels, A. K. Groen, et al. 2006. Intestinal ABCA1 directly contributes to HDL biogenesis in vivo. J. Clin. Invest. 116: 1052-1062.
26. Glomset, J. A. 1968. The plasma lecithins:cholesterol acyltransferase reaction. J. Lipid Res. 9: 155-167.
27. Ohashi, R., H. Mu, X. Wang, Q. Yao, and C. Chen. 2005. Reverse cholesterol transport and cholesterol efflux in atherosclerosis. QJM. 98: 845-856.
28. Spady, D. K. 1999. Reverse cholesterol transport and atherosclerosis regression. Circulation. 100: 576-578.
29. Amaral, J. D., R. J. Viana, R. M. Ramalho, C. J. Steer, and C. M. Rodrigues. 2009. Bile acids: regulation of apoptosis by ursodeoxycholic acid. J. Lipid Res. 50: 1721-1734.
30. Angulo, P. 2002. Use of ursodeoxycholic acid in patients with liver disease. Curr. Gastroenterol. Rep. 4: 37-44.
31. Lindor, K. D., K. V. Kowdley, E. J. Heathcote, M. E. Harrison, R. Jorgensen, P. Angulo, J. F. Lymp, L. Burgart, and P. Colin. 2004. Ursodeoxycholic acid for treatment of nonalcoholic steatohepatitis: results of a randomized trial. Hepatology. 39: 770-778.
32. Dufour, J. F., C. M. Oneta, J. J. Gonvers, F. Bihl, A. Cerny, J. M. Cereda, J. F. Zala, B. Helbling, M. Steuerwald, and A. Zimmermann. 2006. Randomized placebo-controlled trial of ursodeoxycholic acid with vitamin E in nonalcoholic steatohepatitis. Clin. Gastroenterol. Hepatol. 4: 1537-1543.
33. Ratziu, V., V. de Ledinghen, F. Oberti, P. Mathurin, C. Wartelle-Bladou, C. Renou, P. Sogni, M. Maynard, D. Larrey, L. Serfaty, et al. 2011. A randomized controlled trial of high-dose ursodesoxycholic acid for nonalcoholic steatohepatitis. J. Hepatol. 54: 1011-1019.
34. Adams, L. A., P. Angulo, J. Petz, J. Keach, and K. D. Lindor. 2010. A pilot trial of high-dose ursodeoxycholic acid in nonalcoholic steatohepatitis. Hepatol. Int. 4: 628-633.
35. Yoneda, M., K. Fujita, Y. Nozaki, H. Endo, H. Takahashi, K. Hosono, K. Suzuki, H. Mawatari, H. Kirikoshi, M. Inamori, et al. 2010. Efficacy of ezetimibe for the treatment of non-alcoholic steatohepatitis: an open-label, pilot study. Hepatol. Res. 40: 566-573.
36. Park, H., T. Shima, K. Yamaguchi, H. Mitsuyoshi, M. Minami, K. Yasui, Y. Itoh, T. Yoshikawa, M. Fukui, G. Hasegawa, et al. 2011. Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease. J. Gastroenterol. 46: 101-107.
37. Potthoff, M. J., S. A. Kliewer, and D. J. Mangelsdorf. 2012. Endocrine fibroblast growth factors 15/19 and 21: from feast to famine. Genes Dev. 26: 312-324.
38. Kir, S., S. A. Beddow, V. T. Samuel, P. Miller, S. F. Previs, K. Suino-Powell, H. E. Xu, G. I. Shulman, S. A. Kliewer, and D. J. Mangelsdorf. 2011. FGF19 as a postprandial, insulin-independent activator of hepatic protein and glycogen synthesis. Science. 331: 1621-1624.
39. Beuers, U. 2013. beta1 integrin is a long-sought sensor for tauroursodeoxycholic acid. Hepatology. 57: 867-869.
40. Gohlke, H., B. Schmitz, A. Sommerfeld, R. Reinehr, and D. Haussinger. 2013. α5 β1-integrins are sensors for tauroursodeoxycholic acid in hepatocytes. Hepatology. 57: 1117-1129.