miR‐33 controls the expression of biliary transporters, and mediates statin‐ and diet‐induced hepatotoxicity

Abstract

Bile secretion is essential for whole body sterol homeostasis. Loss-of-function mutations in specific canalicular transporters in the hepatocyte disrupt bile flow and result in cholestasis. We show that two of these transporters, ABCB11 and ATP8B1, are functional targets of miR-33, a micro-RNA that is expressed from within an intron of SREBP-2. Consequently, manipulation of miR-33 levels in vivo with adenovirus or with antisense oligonucleotides results in changes in bile secretion and bile recovery from the gallbladder. Using radiolabelled cholesterol, we show that systemic silencing of miR-33 leads to increased sterols in bile and enhanced reverse cholesterol transport in vivo. Finally, we report that simvastatin causes, in a dose-dependent manner, profound hepatotoxicity and lethality in mice fed a lithogenic diet. These latter results are reminiscent of the recurrent cholestasis found in some patients prescribed statins. Importantly, pretreatment of mice with anti-miR-33 oligonucleotides rescues the hepatotoxic phenotype. Therefore, we conclude that miR-33 mediates some of the undesired, hepatotoxic effects of statins.

Shown for reading. Its publisher allows quoting it, not republishing it.

References 66

1. 1.

   Abu Rajab M, Kaplan MM. Statins in primary biliary cirrhosis: are they safe. Dig Dis Sci. 2010;55:2086-2088.

   Not in our library10.1007/s10620-009-0988-9

2. 2.

   Alvarez L, Jara P, Sanchez-Sabate E, Hierro L, Larrauri J, Diaz MC, Camarena C, De La Vega A, Frauca E, Lopez-Collazo E, et al. Reduced hepatic expression of Farnesoid X Receptor in hereditary cholestasis associated to mutation in ATP8B1. Hum Mol Genet. 2004;13:2451-2460.

   Not in our library10.1093/hmg/ddh261

3. 3.

   Annema W, Dikkers A, Freark de Boer J, Gautier T, Rensen PC, Rader DJ, Tietge UJ. ApoE promotes hepatic selective uptake but not RCT due to increased ABCA1-mediated cholesterol efflux to plasma. J Lipid Res. 2012;53:929-940.

   Not in our library10.1194/jlr.m020743

4. 4.

   Batey RG, Harvey M. Cholestasis associated with the use of pravastatin sodium. Med J Aust. 2002;176:561.

   Not in our library10.5694/j.1326-5377.2002.tb04559.x

5. 5.

   Bennett MK, Seo YK, Datta S, Shin DJ, Osborne TF. Selective binding of sterol regulatory element-binding protein isoforms and co-regulatory proteins to promoters for lipid metabolic genes in liver. J Biol Chem. 2008;283:15628-15637.

   Not in our library10.1074/jbc.m800391200

6. 6.

   Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Med Sci. 1959;37:911-917.

   Not in our library10.1139/o59-099

7. 7.

   Cai SY, Gautam S, Nguyen T, Soroka CJ, Rahner C, Boyer JL. ATP8B1 deficiency disrupts the bile canalicular membrane bilayer structure in hepatocytes, but FXR expression and activity are maintained. Gastroenterology. 2009;136:1060-1069.

   Not in our library10.1053/j.gastro.2008.10.025

8. 8.

   Chen F, Ananthanarayanan M, Emre S, Neimark E, Bull LN, Knisely AS, Strautnieks SS, Thompson RJ, Magid MS, Gordon R, et al. Progressive familial intrahepatic cholestasis, type 1, is associated with decreased farnesoid X receptor activity. Gastroenterology. 2004;126:756-764.

   Not in our library10.1053/j.gastro.2003.12.013

9. 9.

   Chen F, Ellis E, Strom SC, Shneider BL. ATPase Class I Type 8B Member 1 and protein kinase C zeta induce the expression of the canalicular bile salt export pump in human hepatocytes. Pediatr Res. 2010;67:183-187.

   Not in our library10.1203/pdr.0b013e3181c2df16

10. 10.

    Davalos A, Goedeke L, Smibert P, Ramirez CM, Warrier NP, Andreo U, Cirera-Salinas D, Rayner K, Suresh U, Pastor-Pareja JC, et al. miR-33a/b contribute to the regulation of fatty acid metabolism and insulin signaling. Proc Natl Acad Sci USA. 2011;108:9232-9237.

    Not in our library10.1073/pnas.1102281108

11. 11.

    Davit-Spraul A, Fabre M, Branchereau S, Baussan C, Gonzales E, Stieger B, Bernard O, Jacquemin E. ATP8B1 and ABCB11 analysis in 62 children with normal gamma-glutamyl transferase progressive familial intrahepatic cholestasis (PFIC): phenotypic differences between PFIC1 and PFIC2 and natural history. Hepatology. 2010;51:1645-1655.

    Not in our library10.1002/hep.23539

12. 12.

    de Castro ML, Hermo JA, Baz A, de Luaces C, Perez R, Clofent J. Acute cholestatic hepatitis after atorvastatin reintroduction. Gastroenterol Hepatol. 2006;29:21-24.

    Not in our library10.1157/13083248

13. 13.

    Emerick KM, Whitington PF. Partial external biliary diversion for intractable pruritus and xanthomas in Alagille syndrome. Hepatology. 2002;35:1501-1506.

    Not in our library10.1053/jhep.2002.33332

14. 14.

    Englert C, Grabhorn E, Burdelski M, Ganschow R. Liver transplantation in children with Alagille syndrome: indications and outcome. Pediatr Transplant. 2006;10:154-158.

    Not in our library10.1111/j.1399-3046.2005.00432.x

15. 15.

    Esteller A. Physiology of bile secretion. World J Gastroenterol. 2008;14:5641-5649.

    Not in our library10.3748/wjg.14.5641

16. 16.

    Ford DA, Monda JK, Brush RS, Anderson RE, Richards MJ, Fliesler SJ. Lipidomic analysis of the retina in a rat model of Smith–Lemli–Opitz syndrome: alterations in docosahexaenoic acid content of phospholipid molecular species. J Neurochem. 2008;105:1032-1047.

    Not in our library10.1111/j.1471-4159.2007.05203.x

17. 17.

    Frankenberg T, Miloh T, Chen FY, Ananthanarayanan M, Sun AQ, Balasubramaniyan N, Arias I, Setchell KD, Suchy FJ, Shneider BL. The membrane protein ATPase class I type 8B member 1 signals through protein kinase C zeta to activate the farnesoid X receptor. Hepatology. 2008;48:1896-1905.

    Not in our library10.1002/hep.22431

18. 18.

    Gadaleta RM, van Mil SW, Oldenburg B, Siersema PD, Klomp LW, van Erpecum KJ. Bile acids and their nuclear receptor FXR: relevance for hepatobiliary and gastrointestinal disease. Biochim Biophys Acta. 2010;1801:683-692.

    Not in our library10.1016/j.bbalip.2010.04.006

19. 19.

    Gerin I, Clerbaux LA, Haumont O, Lanthier N, Das AK, Burant CF, Leclercq IA, MacDougald OA, Bommer GT. Expression of miR-33 from an SREBP2 intron inhibits cholesterol export and fatty acid oxidation. J Biol Chem. 2010;285:33652-33661.

    Not in our library10.1074/jbc.m110.152090

20. 20.

    Han X, Gross RW. Quantitative analysis and molecular species fingerprinting of triacylglyceride molecular species directly from lipid extracts of biological samples by electrospray ionization tandem mass spectrometry. Anal Biochem. 2001;295:88-100.

    Not in our library10.1006/abio.2001.5178

21. 21.

    Han X, Gross RW. Shotgun lipidomics: electrospray ionization mass spectrometric analysis and quantitation of cellular lipidomes directly from crude extracts of biological samples. Mass Spectrom Rev. 2005;24:367-412.

    Not in our library10.1002/mas.20023

22. 22.

    Harris MJ, Le Couteur DG, Arias IM. Progressive familial intrahepatic cholestasis: genetic disorders of biliary transporters. J Gastroenterol Hepatol. 2005;20:807-817.

    Not in our library10.1111/j.1440-1746.2005.03743.x

23. 23.

    Hori T, Nguyen JH, Uemoto S. Progressive familial intrahepatic cholestasis. Hepatobiliary Pancreat Dis Int. 2010;9:570-578.

    Not in our library

24. 24.

    Horie T, Ono K, Horiguchi M, Nishi H, Nakamura T, Nagao K, Kinoshita M, Kuwabara Y, Marusawa H, Iwanaga Y, et al. MicroRNA-33 encoded by an intron of sterol regulatory element-binding protein 2 (Srebp2) regulates HDL in vivo. Proc Natl Acad Sci USA. 2010;107:17321-17326.

    Not in our library10.1073/pnas.1008499107

25. 25.

    Horton JD, Bashmakov Y, Shimomura I, Shimano H. Regulation of sterol regulatory element binding proteins in livers of fasted and refed mice. Proc Natl Acad Sci USA. 1998;95:5987-5992.

    Not in our library10.1073/pnas.95.11.5987

26. 26.

    Hubacek JA, Berge KE, Cohen JC, Hobbs HH. Mutations in ATP-cassette binding proteins G5 (ABCG5) and G8 (ABCG8) causing sitosterolemia. Hum Mutat. 2001;18:359-360.

    Not in our library10.1002/humu.1206

27. 27.

    Khanuja B, Cheah YC, Hunt M, Nishina PM, Wang DQ, Chen HW, Billheimer JT, Carey MC, Paigen B. Lith1, a major gene affecting cholesterol gallstone formation among inbred strains of mice. Proc Natl Acad Sci USA. 1995;92:7729-7733.

    Not in our library10.1073/pnas.92.17.7729

28. 28.

    Khera AV, Rader DJ. Future therapeutic directions in reverse cholesterol transport. Curr Atheroscler Rep. 2010;12:73-81.

    Not in our library10.1007/s11883-009-0080-0

29. 29.

    Koh S, Takada T, Kukuu I, Suzuki H. FIC1-mediated stimulation of FXR activity is decreased with PFIC1 mutations in HepG2 cells. J Gastroenterol. 2009;44:592-600.

    Not in our library10.1007/s00535-009-0041-y

30. 30.

    Kubitz R, Keitel V, Haussinger D. Inborn errors of biliary canalicular transport systems. Methods Enzymol. 2005;400:558-569.

    Not in our library10.1016/s0076-6879(05)00031-5

31. 31.

    Lammert F, Wang DQ, Hillebrandt S, Geier A, Fickert P, Trauner M, Matern S, Paigen B, Carey MC. Spontaneous cholecysto- and hepatolithiasis in Mdr2-/- mice: a model for low phospholipid-associated cholelithiasis. Hepatology. 2004;39:117-128.

    Not in our library10.1002/hep.20022

32. 32.

    Marquart TJ, Allen RM, Ory DS, Baldan A. miR-33 links SREBP-2 induction to repression of sterol transporters. Proc Natl Acad Sci USA. 2010;107:12228-12232.

    Not in our library10.1073/pnas.1005191107

33. 33.

    Martinez-Fernandez P, Hierro L, Jara P, Alvarez L. Knockdown of ATP8B1 expression leads to specific downregulation of the bile acid sensor FXR in HepG2 cells: effect of the FXR agonist GW4064. Am J Physiol Gastrointest Liver Physiol. 2009;296:G1119-G1129.

    Not in our library10.1152/ajpgi.90371.2008

34. 34.

    Merli M, Bragazzi MC, Giubilo F, Callea F, Attili AF, Alvaro D. Atorvastatin-induced prolonged cholestasis with bile duct damage. Clin Drug Investig. 2010;30:205-209.

    Not in our library10.2165/11531660-000000000-00000

35. 35.

    Morotti RA, Suchy FJ, Magid MS. Progressive familial intrahepatic cholestasis (PFIC) type 1, 2, and 3: a review of the liver pathology findings. Semin Liver Dis. 2011;31:3-10.

    Not in our library10.1055/s-0031-1272831

36. 36.

    Moschetta A, Bookout AL, Mangelsdorf DJ. Prevention of cholesterol gallstone disease by FXR agonists in a mouse model. Nat Med. 2004;10:1352-1358.

    Not in our library10.1038/nm1138

37. 37.

    Najafi-Shoushtari SH, Kristo F, Li Y, Shioda T, Cohen DE, Gerszten RE, Naar AM. MicroRNA-33 and the SREBP host genes cooperate to control cholesterol homeostasis. Science. 2010;238:1566-1569.

    Not in our library10.1126/science.1189123

38. 38.

    Nijstad N, Wiersma H, Gautier T, van der Giet M, Maugeais C, Tietge UJ. Scavenger receptor BI-mediated selective uptake is required for the remodeling of high density lipoprotein by endothelial lipase. J Biol Chem. 2009;284:6093-6100.

    Not in our library10.1074/jbc.m807683200

39. 39.

    Nijstad N, Gautier T, Briand F, Rader DJ, Tietge UJ. Biliary sterol secretion is required for functional in vivo reverse cholesterol transport in mice. Gastroenterology. 2011;140:1043-1051.

    Not in our library10.1053/j.gastro.2010.11.055

40. 40.

    Paulusma CC, Groen A, Kunne C, Ho-Mok KS, Spijkerboer AL, Rudi de Waart D, Hoek FJ, Vreeling H, Hoeben KA, van Marle J, et al. Atp8b1 deficiency in mice reduces resistance of the canalicular membrane to hydrophobic bile salts and impairs bile salt transport. Hepatology. 2006;44:195-204.

    Not in our library10.1002/hep.21212

41. 41.

    Paulusma CC, Folmer DE, Ho-Mok KS, de Waart DR, Hilarius PM, Verhoeven AJ, Oude Elferink RP. ATP8B1 requires an accessory protein for endoplasmic reticulum exit and plasma membrane lipid flippase activity. Hepatology. 2008;47:268-278.

    Not in our library10.1002/hep.21950

42. 42.

    Pawlikowska L, Groen A, Eppens EF, Kunne C, Ottenhoff R, Looije N, Knisely AS, Killeen NP, Bull LN, Elferink RP, et al. A mouse genetic model for familial cholestasis caused by ATP8B1 mutations reveals perturbed bile salt homeostasis but no impairment in bile secretion. Hum Mol Genet. 2004;13:881-892.

    Not in our library10.1093/hmg/ddh100

43. 43.

    Portincasa P, Palasciano G, Svelto M, Calamita G. Aquaporins in the hepatobiliary tract. Which, where and what they do in health and disease. Eur J Clin Invest. 2008;38:1-10.

    Not in our library10.1111/j.1365-2362.2007.01897.x

44. 44.

    Rader DJ, Alexander ET, Weibel GL, Billheimer J, Rothblat GH. The role of reverse cholesterol transport in animals and humans and relationship to atherosclerosis. J Lipid Res. 2009;50(Suppl):S189-S194.

    Not in our library10.1194/jlr.r800088-jlr200

45. 45.

    Rahier JF, Rahier J, Leclercq I, Geubel AP. Severe acute cholestatic hepatitis with prolonged cholestasis and bile-duct injury following atorvastatin therapy: a case report. Acta Gastroenterol Belg. 2008;71:318-320.

    Not in our library

46. 46.

    Rayner KJ, Suarez Y, Davalos A, Parathath S, Fitzgerald ML, Tamehiro N, Fisher EA, Moore KJ, Fernandez-Hernando C. miR-33 contributes to the regulation of cholesterol homeostasis. Science. 2010;238:1570-1573.

    Not in our library10.1126/science.1189862

47. 47.

    Rayner KJ, Esau CC, Hussain FN, McDaniel AL, Marshall SM, van Gils JM, Ray TD, Sheedy FJ, Goedeke L, Liu X, et al. Inhibition of miR-33a/b in non-human primates raises plasma HDL and lowers VLDL triglycerides. Nature. 2011a;478:404-407.

    Not in our library10.1038/nature10486

48. 48.

    Rayner KJ, Sheedy FJ, Esau CC, Hussain FN, Temel RE, Parathath S, van Gils JM, Rayner AJ, Chang AN, Suarez Y, et al. Antagonism of miR-33 in mice promotes reverse cholesterol transport and regression of atherosclerosis. J Clin Invest. 2011b;121:2921-2931.

    Not in our library10.1172/jci57275

49. 49.

    Ridruejo E, Mando OG. Acute cholestatic hepatitis after reinitiating treatment with atorvastatin. J Hepatol. 2002;37:165-166.

    Not in our library10.1016/s0168-8278(02)00092-2

50. 50.

    Shah S, Sanford UR, Vargas JC, Xu H, Groen A, Paulusma CC, Grenert JP, Pawlikowska L, Sen S, Elferink RP, et al. Strain background modifies phenotypes in the ATP8B1-deficient mouse. PLoS One. 2010;5:e8984.

    Not in our library10.1371/journal.pone.0008984

51. 51.

    Stanca CM, Bach N, Allina J, Bodian C, Bodenheimer H, Odin JA. Atorvastatin does not improve liver biochemistries or Mayo Risk Score in primary biliary cirrhosis. Dig Dis Sci. 2008;53:1988-1993.

    Not in our library10.1007/s10620-007-0003-2

52. 52.

    Stojakovic T, Putz-Bankuti C, Fauler G, Scharnagl H, Wagner M, Stadlbauer V, Gurakuqi G, Stauber RE, Marz W, Trauner M. Atorvastatin in patients with primary biliary cirrhosis and incomplete biochemical response to ursodeoxycholic acid. Hepatology. 2007;46:776-784.

    Not in our library10.1002/hep.21741

53. 53.

    Stojakovic T, Claudel T, Putz-Bankuti C, Fauler G, Scharnagl H, Wagner M, Sourij H, Stauber RE, Winkler K, Marz W, et al. Low-dose atorvastatin improves dyslipidemia and vascular function in patients with primary biliary cirrhosis after one year of treatment. Atherosclerosis. 2010;209:178-183.

    Not in our library10.1016/j.atherosclerosis.2009.08.052

54. 54.

    Temel RE, Sawyer JK, Yu L, Lord C, Degirolamo C, McDaniel A, Marshall S, Wang N, Shah R, Rudel LL, et al. Biliary sterol secretion is not required for macrophage reverse cholesterol transport. Cell Metab. 2010;12:96-102.

    Not in our library10.1016/j.cmet.2010.05.011

55. 55.

    Tietge UJ, Nijstad N, Havinga R, Baller JF, van der Sluijs FH, Bloks VW, Gautier T, Kuipers F. Secretory phospholipase A2 increases SR-BI-mediated selective uptake from HDL but not biliary cholesterol secretion. J Lipid Res. 2008;49:563-571.

    Not in our library10.1194/jlr.m700276-jlr200

56. 56.

    Torres M, Sobrino J, Asensio C, Lopez D. Acute cholestatic hepatitis induced by cerivastatin. Med Clin. 2002;118:717.

    Not in our library10.1016/s0025-7753(02)72507-4

57. 57.

    Ujhazy P, Ortiz D, Misra S, Li S, Moseley J, Jones H, Arias IM. Familial intrahepatic cholestasis 1: studies of localization and function. Hepatology. 2001;34:768-775.

    Not in our library10.1053/jhep.2001.27663

58. 58.

    van der Woerd WL, van Mil SW, Stapelbroek JM, Klomp LW, van de Graaf SF, Houwen RH. Familial cholestasis: progressive familial intrahepatic cholestasis, benign recurrent intrahepatic cholestasis and intrahepatic cholestasis of pregnancy. Best Pract Res Clin Gastroenterol. 2010;24:541-553.

    Not in our library10.1016/j.bpg.2010.07.010

59. 59.

    Wang X, Rader DJ. Molecular regulation of macrophage reverse cholesterol transport. Curr Opin Cardiol. 2007;22:368-372.

    Not in our library10.1097/hco.0b013e3281ec5113

60. 60.

    Wang R, Lam P, Liu L, Forrest D, Yousef IM, Mignault D, Phillips MJ, Ling V. Severe cholestasis induced by cholic acid feeding in knockout mice of sister of P-glycoprotein. Hepatology. 2003;38:1489-1499.

    Not in our library10.1016/j.hep.2003.09.037

61. 61.

    Wang X, Collins HL, Ranalletta M, Fuki IV, Billheimer JT, Rothblat GH, Tall AR, Rader DJ. Macrophage ABCA1 and ABCG1, but not SR-BI, promote macrophage reverse cholesterol transport in vivo. J Clin Invest. 2007;117:2216-2224.

    Not in our library10.1172/jci32057

62. 62.

    Wiersma H, Gatti A, Nijstad N, Kuipers F, Tietge UJ. Hepatic SR-BI, not endothelial lipase, expression determines biliary cholesterol secretion in mice. J Lipid Res. 2009;50:1571-1580.

    Not in our library10.1194/jlr.m800434-jlr200

63. 63.

    Yu L, Hammer RE, Li-Hawkins J, Von Bergmann K, Lutjohann D, Cohen JC, Hobbs HH. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc Natl Acad Sci USA. 2002;99:16237-16242.

    Not in our library10.1073/pnas.252582399

64. 64.

    Yu L, Gupta S, Xu F, Liverman AD, Moschetta A, Mangelsdorf DJ, Repa JJ, Hobbs HH, Cohen JC. Expression of ABCG5 and ABCG8 is required for regulation of biliary cholesterol secretion. J Biol Chem. 2005;280:8742-8747.

    Not in our library10.1074/jbc.m411080200

65. 65.

    Zadelaar S, Kleemann R, Verschuren L, de Vries-Van der Weij J, van der Hoorn J, Princen HM, Kooistra T. Mouse models for atherosclerosis and pharmaceutical modifiers. Arterioscler Thromb Vasc Biol. 2007;27:1706-1721.

    Not in our library10.1161/atvbaha.107.142570

66. 66.

    Zhang Y, Edwards PA. FXR signaling in metabolic disease. FEBS Lett. 2008;582:10-18.

    Not in our library10.1016/j.febslet.2007.11.015

Cited by papers we hold 3

• Cholesterol attenuates cytoprotective effects of phosphatidylcholine against bile salts · 2017
  Not checked
• Long‐term therapeutic silencing of miR‐33 increases circulating triglyceride levels and hepatic lipid accumulation in mice · 2014
  No notice
• MicroRNA-33 regulates sterol regulatory element-binding protein 1 expression in mice · 2013
  No notice

Reads

A person counts once a day per paper. We keep no cookie and no address: a reader is a hash that changes every day. Any month under five reads shows no number.