Skip to main content

Advertisement

SpringerLink
Log in

Increased serum liver X receptor ligand oxysterols in patients with non-alcoholic fatty liver disease

  • Original Article—Liver, Pancreas, and Biliary Tract
  • Published:
Journal of Gastroenterology Aims and scope Submit manuscript

Abstract

Background

This study is a post-hoc analysis of a subset of patients who participated in our multi-institutional case-control study that evaluated the effects of pitavastatin in patients with non-alcoholic fatty liver disease (NAFLD) with hypercholesterolemia.

Methods

Serum samples of fifteen patients with biopsy-proven NAFLD with dyslipidemia were investigated. Serum markers of lipid metabolism were quantified by liquid chromatography-mass spectrometry (LC–MS)/MS. These data were then compared with those of 36 sex- and age-matched healthy controls. In addition, changes in these markers produced by treatment with pitavastatin were evaluated.

Results

Serum non-cholesterol sterols, reflecting intestinal cholesterol absorption, were significantly lower in the NAFLD patients compared to the controls, and the cholesterol synthesis marker, the ratio of lathosterol to cholesterol, was not significantly different between the two groups. Serum proportions of liver X receptor α (LXRα) ligand oxysterols (ratios to cholesterol) were significantly elevated in the NAFLD patients compared to the controls. The sum of oxysterols relative to cholesterol and the homeostasis model assessment as an index of insulin resistance (HOMA-IR) were significantly correlated. The marker representing cholesterol synthesis was significantly suppressed by pitavastatin treatment, from 3 months after initiation of the treatment, and the suppression remained significant during the observation period. The markers representing cholesterol absorption were unchanged at 3 months, but had significantly increased at 12 months. Serum oxysterol levels relative to cholesterol maintained high values and did not change significantly during the 12-month period of treatment.

Conclusions:

We speculate that serum LXRα ligand oxysterol levels (relative to cholesterol) could be surrogate markers of insulin resistance, and that high oxysterol levels in the circulation may play an important role in the development of hepatic and peripheral insulin resistance followed by NAFLD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Neuschwander-Tetri BA, Caldwell SH. Nonalcoholic steatohepatitis: summary of an AASLD Single Topic Conference. Hepatology. 2003;37:1202–19.

    Article  PubMed  Google Scholar 

  2. Kotronen A, Westerbacka J, Bergholm R, Pietilainen KH, Yki-Jarvinen H. Liver fat in the metabolic syndrome. J Clin Endocrinol Metab. 2007;92:3490–7.

    Article  PubMed  CAS  Google Scholar 

  3. Seppala-Lindroos A, Vehkavaara S, Hakkinen AM, Goto T, Westerbacka J, Sovijarvi A, et al. Fat accumulation in the liver is associated with defects in insulin suppression of glucose production and serum free fatty acids independent of obesity in normal men. J Clin Endocrinol Metab. 2002;87:3023–8.

    Article  PubMed  CAS  Google Scholar 

  4. Ryysy L, Hakkinen AM, Goto T, Vehkavaara S, Westerbacka J, Halavaara J, et al. Hepatic fat content and insulin action on free fatty acids and glucose metabolism rather than insulin absorption are associated with insulin requirements during insulin therapy in type 2 diabetic patients. Diabetes. 2000;49:749–58.

    Article  PubMed  CAS  Google Scholar 

  5. Dzeletovic S, Breuer O, Lund E, Diczfalusy U. Determination of cholesterol oxidation products in human plasma by isotope dilution-mass spectrometry. Anal Biochem. 1995;225:73–80.

    Article  PubMed  CAS  Google Scholar 

  6. Gill S, Chow R, Brown AJ. Sterol regulators of cholesterol homeostasis and beyond: the oxysterol hypothesis revisited and revised. Prog Lipid Res. 2008;47:391–404.

    Article  PubMed  CAS  Google Scholar 

  7. Janowski BA, Willy PJ, Devi TR, Falck JR, Mangelsdorf DJ. An oxysterol signalling pathway mediated by the nuclear receptor LXR alpha. Nature. 1996;383:728–31.

    Article  PubMed  CAS  Google Scholar 

  8. Reschly EJ, Ai N, Welsh WJ, Ekins S, Hagey LR, Krasowski MD. Ligand specificity and evolution of liver X receptors. J Steroid Biochem Mol Biol. 2008;110:83–94.

    Article  PubMed  CAS  Google Scholar 

  9. DeBose-Boyd RA, Ou J, Goldstein JL, Brown MS. Expression of sterol regulatory element-binding protein 1c (SREBP-1c) mRNA in rat hepatoma cells requires endogenous LXR ligands. Proc Natl Acad Sci USA. 2001;98:1477–82.

    Article  PubMed  CAS  Google Scholar 

  10. Nakamuta M, Fujino T, Yada R, Yada M, Yasutake K, Yoshimoto T, et al. Impact of cholesterol metabolism and the LXRalpha-SREBP-1c pathway on nonalcoholic fatty liver disease. Int J Mol Med. 2009;23:603–8.

    PubMed  CAS  Google Scholar 

  11. Higuchi N, Kato M, Shundo Y, Tajiri H, Tanaka M, Yamashita N, et al. Liver X receptor in cooperation with SREBP-1c is a major lipid synthesis regulator in nonalcoholic fatty liver disease. Hepatol Res. 2008;38:1122–9.

    Article  PubMed  CAS  Google Scholar 

  12. Kotronen A, Seppanen-Laakso T, Westerbacka J, Kiviluoto T, Arola J, Ruskeepaa AL, et al. Hepatic stearoyl-CoA desaturase (SCD)-1 activity and diacylglycerol but not ceramide concentrations are increased in the nonalcoholic human fatty liver. Diabetes. 2009;58:203–8.

    Article  PubMed  CAS  Google Scholar 

  13. Matthan NR, Lichtenstein AH. Approaches to measuring cholesterol absorption in humans. Atherosclerosis. 2004;174:197–205.

    Article  PubMed  CAS  Google Scholar 

  14. Miettinen TA, Tilvis RS, Kesaniemi YA. Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population. Am J Epidemiol. 1990;131:20–31.

    PubMed  CAS  Google Scholar 

  15. Miettinen TA. Cholesterol production in obesity. Circulation. 1971;44:842–50.

    Article  PubMed  CAS  Google Scholar 

  16. Miettinen TA, Gylling H. Cholesterol absorption efficiency and sterol metabolism in obesity. Atherosclerosis. 2000;153:241–8.

    Article  PubMed  CAS  Google Scholar 

  17. Gylling H, Hallikainen M, Kolehmainen M, Toppinen L, Pihlajamaki J, Mykkanen H, et al. Cholesterol synthesis prevails over absorption in metabolic syndrome. Transl Res. 2007;149:310–6.

    Article  PubMed  CAS  Google Scholar 

  18. Bennion LJ, Grundy SM. Effects of diabetes mellitus on cholesterol metabolism in man. N Engl J Med. 1977;296:1365–71.

    Article  PubMed  CAS  Google Scholar 

  19. Simonen P, Kotronen A, Hallikainen M, Sevastianova K, Makkonen J, Hakkarainen A, et al. Cholesterol synthesis is increased and absorption decreased in non-alcoholic fatty liver disease independent of obesity. J Hepatol. 2011;54:153–9.

    Article  PubMed  CAS  Google Scholar 

  20. Gomez-Dominguez E, Gisbert JP, Moreno-Monteagudo JA, Garcia-Buey L, Moreno-Otero R. A pilot study of atorvastatin treatment in dyslipemid, non-alcoholic fatty liver patients. Aliment Pharmacol Ther. 2006;23:1643–7.

    Article  PubMed  CAS  Google Scholar 

  21. Hyogo H, Tazuma S, Arihiro K, Iwamoto K, Nabeshima Y, Inoue M, et al. Efficacy of atorvastatin for the treatment of nonalcoholic steatohepatitis with dyslipidemia. Metabolism. 2008;57:1711–8.

    Article  PubMed  CAS  Google Scholar 

  22. Nelson A, Torres DM, Morgan AE, Fincke C, Harrison SA. A pilot study using simvastatin in the treatment of nonalcoholic steatohepatitis: a randomized placebo-controlled trial. J Clin Gastroenterol. 2009;43:990–4.

    Article  PubMed  CAS  Google Scholar 

  23. Hyogo H, Ikegami T, Tokushige K, Hashimoto E, Inui K, Matsuzaki Y, et al. Efficacy of pitavastatin for the treatment of non-alcoholic steatohepatitis with dyslipidemia: an open-label, pilot study. Hepatol Res. 2011;41:1057–65.

    Article  PubMed  CAS  Google Scholar 

  24. Honda A, Yamashita K, Miyazaki H, Shirai M, Ikegami T, Xu G, et al. Highly sensitive analysis of sterol profiles in human serum by LC–ESI–MS/MS. J Lipid Res. 2008;49:2063–73.

    Article  PubMed  CAS  Google Scholar 

  25. Honda A, Yamashita K, Hara T, Ikegami T, Miyazaki T, Shirai M, et al. Highly sensitive quantification of key regulatory oxysterols in biological samples by LC–ESI–MS/MS. J Lipid Res. 2009;50:350–7.

    Article  PubMed  CAS  Google Scholar 

  26. Honda A, Miyazaki T, Ikegami T, Iwamoto J, Yamashita K, Numazawa M, et al. Highly sensitive and specific analysis of sterol profiles in biological samples by HPLC–ESI–MS/MS. J Steroid Biochem Mol Biol. 2010;121:556–64.

    Article  PubMed  CAS  Google Scholar 

  27. Honda A, Yamashita K, Numazawa M, Ikegami T, Doy M, Matsuzaki Y, et al. Highly sensitive quantification of 7alpha-hydroxy-4-cholesten-3-one in human serum by LC–ESI–MS/MS. J Lipid Res. 2007;48:458–64.

    Article  PubMed  CAS  Google Scholar 

  28. Honda A, Yamashita K, Ikegami T, Hara T, Miyazaki T, Hirayama T, et al. Highly sensitive quantification of serum malonate, a possible marker for de novo lipogenesis, by LC–ESI–MS/MS. J Lipid Res. 2009;50(2124):30.

    Google Scholar 

  29. Ghoshal AK, Guo T, Soukhova N, Soldin SJ. Rapid measurement of plasma acylcarnitines by liquid chromatography-tandem mass spectrometry without derivatization. Clin Chim Acta. 2005;358:104–12.

    Article  PubMed  CAS  Google Scholar 

  30. Babiker A, Diczfalusy U. Transport of side-chain oxidized oxysterols in the human circulation. Biochim Biophys Acta. 1998;1392:333–9.

    Article  PubMed  CAS  Google Scholar 

  31. Honda A, Miyazaki T, Ikegami T, Iwamoto J, Maeda T, Hirayama T, et al. Cholesterol 25-hydroxylation activity of CYP3A. J Lipid Res. 2011;52:1509–16.

    Article  PubMed  CAS  Google Scholar 

  32. Cali JJ, Russell DW. Characterization of human sterol 27-hydroxylase. A mitochondrial cytochrome P-450 that catalyzes multiple oxidation reaction in bile acid biosynthesis. J Biol Chem. 1991;266:7774–8.

    PubMed  CAS  Google Scholar 

  33. Lund EG, Guileyardo JM, Russell DW. cDNA cloning of cholesterol 24-hydroxylase, a mediator of cholesterol homeostasis in the brain. Proc Natl Acad Sci USA. 1999;96:7238–43.

    Article  PubMed  CAS  Google Scholar 

  34. van der Veen JN, van Dijk TH, Vrins CL, van Meer H, Havinga R, Bijsterveld K, et al. Activation of the liver X receptor stimulates trans-intestinal excretion of plasma cholesterol. J Biol Chem. 2009;284:19211–9.

    Article  PubMed  Google Scholar 

  35. Altmann SW, Davis HR Jr, 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.

    Article  PubMed  CAS  Google Scholar 

  36. Berge KE, Tian H, Graf GA, Yu L, Grishin NV, Schultz J, et al. Accumulation of dietary cholesterol in sitosterolemia caused by mutations in adjacent ABC transporters. Science. 2000;290:1771–5.

    Article  PubMed  CAS  Google Scholar 

  37. Lee MH, Lu K, Hazard S, Yu H, Shulenin S, Hidaka H, et al. Identification of a gene, ABCG5, important in the regulation of dietary cholesterol absorption. Nat Genet. 2001;27:79–83.

    Article  PubMed  CAS  Google Scholar 

  38. Yu L, Hammer RE, Li-Hawkins J, Von Bergmann K, Lutjohann D, Cohen JC, et al. Disruption of Abcg5 and Abcg8 in mice reveals their crucial role in biliary cholesterol secretion. Proc Natl Acad Sci USA. 2002;99:16237–42.

    Article  PubMed  CAS  Google Scholar 

  39. Yu L, Li-Hawkins J, Hammer RE, Berge KE, Horton JD, Cohen JC, et al. Overexpression of ABCG5 and ABCG8 promotes biliary cholesterol secretion and reduces fractional absorption of dietary cholesterol. J Clin Invest. 2002;110:671–80.

    PubMed  CAS  Google Scholar 

  40. Hirayama T, Mizokami Y, Honda A, Homma Y, Ikegami T, Saito Y, et al. Serum concentration of 27-hydroxycholesterol predicts the effects of high-cholesterol diet on plasma LDL cholesterol level. Hepatol Res. 2009;39:149–56.

    Article  PubMed  CAS  Google Scholar 

  41. Biddinger SB, Haas JT, Yu BB, Bezy O, Jing E, Zhang W, et al. Hepatic insulin resistance directly promotes formation of cholesterol gallstones. Nat Med. 2008;14:778–82.

    Article  PubMed  CAS  Google Scholar 

  42. Schreuder TC, Marsman HA, Lenicek M, van Werven JR, Nederveen AJ, Jansen PL, et al. The hepatic response to FGF19 is impaired in patients with nonalcoholic fatty liver disease and insulin resistance. Am J Physiol Gastrointest Liver Physiol. 2010;298:G440–5.

    Article  PubMed  CAS  Google Scholar 

  43. Trauner M, Claudel T, Fickert P, Moustafa T, Wagner M. Bile acids as regulators of hepatic lipid and glucose metabolism. Dig Dis. 2010;28:220–4.

    Article  PubMed  Google Scholar 

  44. Yang ZX, Shen W, Sun H. Effects of nuclear receptor FXR on the regulation of liver lipid metabolism in patients with non-alcoholic fatty liver disease. Hepatol Int. 2010;4:741–8.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The present study was supported by grants from the Ministry of Education, Culture, Sports, Science and Technology of Japan. This work was presented, in part, at Digestive Disease Week 2011 was held at Chicago, IL, USA.

Conflict of interest

All authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Division of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, 3-20-1 Chuo, Ami-machi, Inashiki-gun, Ibaraki, 300-0395, Japan

    Tadashi Ikegami, Akira Honda & Yasushi Matsuzaki

  2. Center for Collaborative Research, Tokyo Medical University Ibaraki Medical Center, Inashiki-gun, Japan

    Akira Honda & Teruo Miyazaki

  3. Department of Medicine and Molecular Science, Graduate School of Biochemical Science, Hiroshima University, Hiroshima, Japan

    Hideyuki Hyogo

  4. Department of General Medicine, Graduate School of Biochemical Science, Hiroshima University, Hiroshima, Japan

    Susumu Tazuma

  5. Department of Development for Community Medicine, Tokyo Medical University, Tokyo, Japan

    Teruo Miyazaki & Yasushi Matsuzaki

  6. Department of Medicine and Gastroenterology, Tokyo Women’s Medical University, Tokyo, Japan

    Katsutoshi Tokushige & Etsuko Hashimoto

  7. Department of Internal Medicine, Fujita Health University School of Medicine, Toyoake, Japan

    Kazuo Inui

Authors
  1. Tadashi Ikegami
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hideyuki Hyogo
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Akira Honda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Teruo Miyazaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Katsutoshi Tokushige
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Etsuko Hashimoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Kazuo Inui
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Yasushi Matsuzaki
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Susumu Tazuma
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Yasushi Matsuzaki.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ikegami, T., Hyogo, H., Honda, A. et al. Increased serum liver X receptor ligand oxysterols in patients with non-alcoholic fatty liver disease. J Gastroenterol 47, 1257–1266 (2012). https://doi.org/10.1007/s00535-012-0585-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00535-012-0585-0

Keywords

Search

Navigation