Journal of Gastroenterology

, Volume 46, Issue 1, pp 101–107 | Cite as

Efficacy of long-term ezetimibe therapy in patients with nonalcoholic fatty liver disease

  • Hyohun Park
  • Toshihide Shima
  • Kanji Yamaguchi
  • Hironori Mitsuyoshi
  • Masahito Minami
  • Kohichiroh Yasui
  • Yoshito Itoh
  • Toshikazu Yoshikawa
  • Michiaki Fukui
  • Goji Hasegawa
  • Naoto Nakamura
  • Mitsuhiro Ohta
  • Hiroshi Obayashi
  • Takeshi Okanoue
Original Article—Liver, Pancreas, and Biliary Tract

Abstract

Background

Hyperlipidemia, insulin resistance, and oxidative stress can heavily contribute to the initiation and progression of nonalcoholic fatty liver disease (NAFLD). Currently, there is no established treatment for this disease. Recently, several studies have shown that ezetimibe (EZ), a lipid-lowering drug, attenuates liver steatosis in an experimental NAFLD model. This study was designed to assess the efficacy of long-term EZ monotherapy in patients with NAFLD.

Methods

A total of 45 patients with newly diagnosed liver biopsy-proven NAFLD were treated with EZ (10 mg/day) for 24 months. NAFLD-related biochemical parameters, imaging by computerized tomography, and liver biopsy were studied before and after treatment.

Results

Ezetimibe therapy significantly improved NAFLD-related metabolic parameters including visceral fat area, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-R), triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-Ch), oxidative-LDL, the net electronegative charge modified-LDL, profiles of lipoprotein particle size and fatty acids component, and estimated desaturase activity. EZ therapy also significantly lowered serum alanine aminotransferase and high-sensitivity C-reactive protein levels, whereas no significant changes were found in serum type IV collagen 7S, adiponectin, leptin, and resistin levels. Histological features of steatosis grade (P = 0.0003), necroinflammatory grade (P = 0.0456), ballooning score (P = 0.0253), and NAFLD activity score (NAS) (P = 0.0007) were significantly improved from baseline. However, the fibrosis stage was not significantly (P = 0.6547) changed.

Conclusion

The results in this study suggest that the long-term EZ therapy can lead to improvement in metabolic, biochemical, and histological abnormalities of NAFLD. Therefore, EZ may be a promising agent for treatment of NAFLD.

Keywords

Ezetimibe NAFLD Insulin resistance Lipid metabolism Fatty acid metabolism 

References

  1. 1.
    Angulo P. Nonalcoholic fatty liver disease. N Engl J Med. 2002;18:1221–31.CrossRefGoogle Scholar
  2. 2.
    Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387–95.CrossRefPubMedGoogle Scholar
  3. 3.
    Farrell GC. Non-alcoholic steatohepatitis: what is it, and why is it important in the Asia-Pacific region? J Gastroenterol Hepatol. 2003;18:124–38.CrossRefPubMedGoogle Scholar
  4. 4.
    Chitturi S, Abeygunasekera S, Farrell GC, Holmes-Walker J, Hui JM, Fung C, et al. NASH and insulin resistance: insulin hypersecretion and specific association with the insulin resistance syndrome. Hepatology. 2002;35:373–9.CrossRefPubMedGoogle Scholar
  5. 5.
    Sanyal AJ, Campbell-Sargent C, Mirshahi F, Rizzo WB, Contos MJ, Sterling RK, et al. Nonalcoholic steatohepatitis: association of insulin resistance and mitochondrial abnormalities. Gastroenterology. 2001;120:1183–92.CrossRefPubMedGoogle Scholar
  6. 6.
    Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114:842–5.CrossRefPubMedGoogle Scholar
  7. 7.
    Marchesini G, Marzocchi R, Agostini F, Bugianesi E. Nonalcoholic fatty liver disease and the metabolic syndrome. Curr Opin Lipidol. 2005;16:421–7.CrossRefPubMedGoogle Scholar
  8. 8.
    Bugianesi E, Gentilcore E, Manini R, Natale S, Vanni E, Villanova N, et al. A randomized controlled trial of metformin versus vitamin E or prescriptive diet in nonalcoholic fatty liver disease. Am J Gastroenterol. 2005;100:1082–90.CrossRefPubMedGoogle Scholar
  9. 9.
    Nair S, Diehl AM, Wiseman M, Farr GH Jr, Perrillo RP. Metformin in the treatment of non-alcoholic steatohepatitis: a pilot open label trial. Aliment Pharmacol Ther. 2004;20:23–8.CrossRefPubMedGoogle Scholar
  10. 10.
    Schwimmer JB, Middleton MS, Deutsch R, Lavine JE. A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2005;21:871–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Promrat K, Lutchman G, Uwaifo GI, Freedman RJ, Soza A, Heller T, Doo E, et al. A pilot study of pioglitazone treatment for nonalcoholic steatohepatitis. Hepatology. 2004;39:188–96.CrossRefPubMedGoogle Scholar
  12. 12.
    Neuschwander-Tetri BA, Brunt EM, Wehmeier KR, Oliver D, Bacon BR. Improved nonalcoholic steatohepatitis after 48 weeks of treatment with the PPAR-gamma ligand rosiglitazone. Hepatology. 2003;38:1008–17.PubMedGoogle Scholar
  13. 13.
    Sanyal AJ, Mofrad PS, Contos MJ, Sargeant C, Luketic VA, Sterling RK, et al. A pilot study of vitamin E versus vitamin E and pioglitazone for the treatment of nonalcoholic steatohepatitis. Clin Gastroenterol Hepatol. 2004;2:1107–15.CrossRefPubMedGoogle Scholar
  14. 14.
    Belfort R, Harrison SA, Brown K, Darland C, Finch J, Hardies J, et al. A placebo-controlled trial of pioglitazone in subjects with nonalcoholic steatohepatitis. N Engl J Med. 2006;355:2297–307.CrossRefPubMedGoogle Scholar
  15. 15.
    Loomba R, Lutchman G, Kleiner DE, Ricks M, Feld JJ, Borg BB, et al. Pilot study of metformin for the treatment of nonalcoholic steatohepatitis. Aliment Pharmacol Ther. 2008;29:172–82.CrossRefPubMedGoogle Scholar
  16. 16.
    Idilman R, Mizrak D, Corapcioglu D, Bektas M, Doganay B, Sayki M, et al. Insulin-sensitizing agents may reduce consequences of insulin resistance in individuals with non-alcoholic steatohepatitis. Aliment Pharmacol Ther. 2008;28:200–8.CrossRefPubMedGoogle Scholar
  17. 17.
    Altmann SW, Davis HR, Zhu LJ, Yao X, Hoos LM, Tetzloff G, et al. Niemann–Pick C1 like 1 protein is critical for intestinal cholesterol absorption. Science. 2004;303:1201–4.CrossRefPubMedGoogle Scholar
  18. 18.
    Garcia-Calvo M, Lisnock J, Bull HG, Hawes BE, Burnett DA, Braun MP, et al. The target of ezetimibe is Niemann–Pick C1-like 1 (NPC1L1). Proc Natl Acad Sci U S A. 2005;102:8132–7.CrossRefPubMedGoogle Scholar
  19. 19.
    Davies JP, Scott C, Oishi K, Liapis A, Ioannou YA. Inactivation of NPC1L1 causes multiple lipid transport defects and protects against diet-induced hypercholesterolemia. J Biol Chem. 2005;280:12710–20.CrossRefPubMedGoogle Scholar
  20. 20.
    Deushi M, Nomura M, Kawakami A, Haraguchi M, Ito M, Okazaki M, et al. Ezetimibe improves liver steatosis and insulin resistance in obese rat model of metabolic syndrome. FEBS Lett. 2007;581:5664–70.CrossRefPubMedGoogle Scholar
  21. 21.
    Zheng S, Hoos L, Cook J, Tetzloff G, Davis H Jr, van Heek M, et al. Ezetimibe improves high fat and cholesterol diet-induced non-alcoholic fatty liver disease in mice. Eur J Pharmacol. 2008;584:118–24.CrossRefPubMedGoogle Scholar
  22. 22.
    Brunt EM, Janney CG, Di Bisceglie AM, Neuschwander-Tetri BA, Bacon BR. Nonalcoholic steatohepatitis: a proposal for grading and staging the histological lesions. Am J Gastroenterol. 1999;94:2467–74.CrossRefPubMedGoogle Scholar
  23. 23.
    Kleiner DE, Brunt EM, Van Natta M, Behling C, Contos MJ, Cummings OW, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–21.CrossRefPubMedGoogle Scholar
  24. 24.
    Tokunaga K, Matsuzawa Y, Ishikawa K, Tarui S. A novel technique for the determination of body fat by computed tomography. Int J Obes. 1983;7:437–45.PubMedGoogle Scholar
  25. 25.
    Okazaki M, Usui S, Ishigami M, Sakai N, Nakamura T, Matsuzawa Y, et al. Identification of unique lipoprotein subclasses for visceral obesity by component analysis of cholesterol profile in high-performance liquid chromatography. Arterioscler Thromb Vasc Biol. 2005;25:578–84.CrossRefPubMedGoogle Scholar
  26. 26.
    Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959;37:911–7.PubMedGoogle Scholar
  27. 27.
    Yoneda M, Fujita K, Nozaki Y, Endo H, Takahashi H, Hosono K, et al. Efficacy of ezetimibe for the treatment of non-alcoholic steatohepatitis: an open-label, pilot study. Hepatol Res. 2010;40:613–21Google Scholar
  28. 28.
    Garvey WT, Kwon S, Zheng D, Shaughnessy S, Wallace P, Hutto A, et al. Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance. Diabetes. 2003;52:453–62.CrossRefPubMedGoogle Scholar
  29. 29.
    Adiels M, Borén J, Caslake MJ, Stewart P, Soro A, Westerbacka J, et al. Overproduction of VLDL1 driven by hyperglycemia is a dominant feature of diabetic dyslipidemia. Arterioscler Thromb Vasc Biol. 2005;25:1697–703.CrossRefPubMedGoogle Scholar
  30. 30.
    Gill JM, Brown JC, Bedford D, Wright DM, Cooney J, Hughes DA, et al. Hepatic production of VLDL1 but not VLDL2 is related to insulin resistance in normoglycaemic middle-aged subjects. Atherosclerosis. 2004;176:49–56.CrossRefPubMedGoogle Scholar
  31. 31.
    Griffin BA, Packard CJ. Metabolism of VLDL and LDL subclasses. Curr Opin Lipidol. 1994;5:200–6.CrossRefPubMedGoogle Scholar
  32. 32.
    Adiels M, Taskinen MR, Packard C, Caslake MJ, Soro-Paavonen A, Westerbacka J, et al. Overproduction of large VLDL particles is driven by increased liver fat content in man. Diabetologia. 2006;49:755–65.CrossRefPubMedGoogle Scholar
  33. 33.
    Adiels M, Westerbacka J, Soro-Paavonen A, Häkkinen AM, Vehkavaara S, Caslake MJ, et al. Acute suppression of VLDL1 secretion rate by insulin is associated with hepatic fat content and insulin resistance. Diabetologia. 2007;50:2356–65.CrossRefPubMedGoogle Scholar
  34. 34.
    Labonté ED, Camarota LM, Rojas JC, Jandacek RJ, Gilham DE, Davies JP, et al. Reduced absorption of saturated fatty acids and resistance to diet-induced obesity and diabetes by ezetimibe-treated and Npc1l1−/− mice. Am J Physiol Gastrointest Liver Physiol. 2008;295:G776–83.CrossRefPubMedGoogle Scholar
  35. 35.
    Joshi-Barve S, Barve SS, Amancherla K, Gobejishvili L, Hill D, Cave M, et al. Palmitic acid induces production of proinflammatory cytokine interleukin-8 from hepatocytes. Hepatology. 2007;46:823–30.CrossRefPubMedGoogle Scholar
  36. 36.
    Wei Y, Wang D, Topczewski F, Pagliassotti MJ. Saturated fatty acids induce endoplasmic reticulum stress and apoptosis independently of ceramide in liver cells. Am J Physiol Endocrinol Metab. 2006;291:E275–81.CrossRefPubMedGoogle Scholar
  37. 37.
    Pagliassotti MJ, Wei Y, Wang D. Insulin protects liver cells from saturated fatty acid-induced apoptosis via inhibition of c-Jun NH2 terminal kinase activity. Endocrinology. 2007;148:3338–45.CrossRefPubMedGoogle Scholar
  38. 38.
    Malhi H, Bronk SF, Werneburg NW, Gores GJ. Free fatty acids induce JNK-dependent hepatocyte lipoapoptosis. J Biol Chem. 2006;281:12093–101.CrossRefPubMedGoogle Scholar
  39. 39.
    Miyazaki M, Kim YC, Gray-Keller MP, Attie AD, Ntambi JM. The biosynthesis of hepatic cholesterol esters and triglycerides is impaired in mice with a disruption of the gene for stearoyl-CoA desaturase 1. J Biol Chem. 2000;275:30132–8.CrossRefPubMedGoogle Scholar
  40. 40.
    Attie AD, Krauss RM, Gray-Keller MP, Brownlie A, Miyazaki M, Kastelein JJ, et al. Relationship between stearoyl-CoA desaturase activity and plasma triglycerides in human and mouse hypertriglyceridemia. J Lipid Res. 2002;43:1899–907.CrossRefPubMedGoogle Scholar
  41. 41.
    Borkman M, Storlien LH, Pan DA, Jenkins AB, Chisholm DJ, Campbell LV. The relation between insulin sensitivity and the fatty acid composition of skeletal-muscle phospholipids. N Engl J Med. 1993;328:238–44.CrossRefPubMedGoogle Scholar
  42. 42.
    Pan DA, Lillioja S, Milner MR, Kriketos AD, Baur LA, Bogardus C, et al. Skeletal muscle membrane lipid composition is related to adiposity and insulin action. J Clin Invest. 1995;96:2802–8.CrossRefPubMedGoogle Scholar
  43. 43.
    Wahl HG, Kausch C, Machicao F, Rett K, Stumvoll M, Häring HU. Troglitazone downregulates delta-6 desaturase gene expression in human skeletal muscle cell cultures. Diabetes. 2002;51:1060–5.CrossRefPubMedGoogle Scholar
  44. 44.
    Adams LA, Sanderson S, Lindor KD, Angulo P. The histological course of nonalcoholic fatty liver disease: a longitudinal study of 103 patients with sequential liver biopsies. J Hepatol. 2005;42:132–8.CrossRefPubMedGoogle Scholar
  45. 45.
    Argo CK, Northup PG, Al-Osaimi AM, Caldwell SH. Systematic review of risk factors for fibrosis progression in non-alcoholic steatohepatitis. J Hepatol. 2009;51:371–9.CrossRefPubMedGoogle Scholar

Copyright information

© Springer 2010

Authors and Affiliations

  • Hyohun Park
    • 1
    • 2
  • Toshihide Shima
    • 1
  • Kanji Yamaguchi
    • 2
  • Hironori Mitsuyoshi
    • 2
  • Masahito Minami
    • 2
  • Kohichiroh Yasui
    • 2
  • Yoshito Itoh
    • 2
  • Toshikazu Yoshikawa
    • 2
  • Michiaki Fukui
    • 3
  • Goji Hasegawa
    • 3
  • Naoto Nakamura
    • 3
  • Mitsuhiro Ohta
    • 4
  • Hiroshi Obayashi
    • 5
  • Takeshi Okanoue
    • 1
    • 2
  1. 1.Department of Gastroenterology and HepatologySaiseikai Suita HospitalSuitaJapan
  2. 2.Department of Molecular Gastroenterology and Hepatology, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
  3. 3.Department of Endocrinology and Metabolism, Graduate School of Medical ScienceKyoto Prefectural University of MedicineKyotoJapan
  4. 4.Department of Medical BiochemistryKobe Pharmaceutical UniversityKobeJapan
  5. 5.Department of Molecular BiochemistryInstitute of Bio-Response InformaticsKyotoJapan

Personalised recommendations