Advertisement

Journal of Gastroenterology

, Volume 45, Issue 4, pp 426–434 | Cite as

Hepatic senescence marker protein-30 is involved in the progression of nonalcoholic fatty liver disease

  • Hyohun Park
  • Akihito Ishigami
  • Toshihide Shima
  • Masayuki Mizuno
  • Naoki Maruyama
  • 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

Both insulin resistance and increased oxidative stress in the liver are associated with the pathogenesis of nonalcoholic fatty liver disease (NAFLD). Senescence marker protein-30 (SMP30) was initially identified as a novel protein in the rat liver, and acts as an antioxidant and antiapoptotic protein. Our aim was to determine whether hepatic SMP30 levels are associated with the development and progression of NAFLD.

Methods

Liver biopsies and blood samples were obtained from patients with an NAFLD activity score (NAS) ≤ 2 (n = 18), NAS of 3–4 (n = 14), and NAS ≥ 5 (n = 66).

Results

Patients with NAS ≥ 5 had significantly lower hepatic SMP30 levels (12.5 ± 8.4 ng/mg protein) than patients with NAS ≤ 2 (30.5 ± 14.2 ng/mg protein) and patients with NAS = 3–4 (24.6 ± 12.2 ng/mg protein). Hepatic SMP30 decreased in a fibrosis stage-dependent manner. Hepatic SMP30 levels were correlated positively with the platelet count (r = 0.291) and negatively with the homeostasis model assessment of insulin resistance (r = −0.298), the net electronegative charge modified-low-density lipoprotein (r = −0.442), and type IV collagen 7S (r = −0.350). The immunostaining intensity levels of 4-hydroxynonenal in the liver were significantly and inversely correlated with hepatic SMP30 levels. Both serum large very low-density lipoprotein (VLDL) and very small low-density lipoprotein (LDL) levels in patients with NAS ≥ 5 were significantly higher than those seen in patients with NAS ≤ 2, and these lipoprotein fractions were significantly and inversely correlated with hepatic SMP30.

Conclusion

These results suggest that hepatic SMP30 is closely associated with the pathogenesis of NAFLD, although it is not known whether decreased hepatic SMP30 is a result or a cause of cirrhosis.

Keywords

SMP30 NAFLD NASH Insulin resistance Oxidative stress 

Notes

Acknowledgments

This study was supported by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (Goji Hasegawa), and a Grant-in-Aid from the Ministry of Health, Labour and Welfare (Takeshi Okanoue).

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.
    Ludwig J, Viggiano TR, McGill DB, Oh BJ. Nonalcoholic steatohepatitis: Mayo Clinic experiences with a hitherto unnamed disease. Mayo Clin Proc. 1980;55:434–8.PubMedGoogle Scholar
  5. 5.
    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
  6. 6.
    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
  7. 7.
    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
  8. 8.
    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
  9. 9.
    Day CP, James OF. Steatohepatitis: a tale of two “hits”? Gastroenterology. 1998;114:842–5.CrossRefPubMedGoogle Scholar
  10. 10.
    Fujita T, Uchida K, Maruyama N. Purification of senescence marker protein-30 (SMP30) and its androgen-independent decrease with age in the rat liver. Biochim Biophys Acta. 1992;1116:122–8.PubMedGoogle Scholar
  11. 11.
    Ishigami A, Maruyama N. Significance of SMP30 in gerontology. Geriatr Gerontol Int. 2007;7:316–25.CrossRefGoogle Scholar
  12. 12.
    Fujita T, Inoue H, Kitamura T, Sato N, Shimosawa T, Maruyama N. Senescence marker protein-30 (SMP30) rescues cell death by enhancing plasma membrane Ca(2+)-pumping activity in Hep G2 cells. Biochem Biophys Res Commun. 1998;250:374–80.CrossRefPubMedGoogle Scholar
  13. 13.
    Inoue H, Fujita T, Kitamura T, Shimosawa T, Nagasawa R, Inoue R, et al. Senescence marker protein-30 (SMP30) enhances the calcium efflux from renal tubular epithelial cells. Clin Exp Nephrol. 1999;3:261–7.CrossRefGoogle Scholar
  14. 14.
    Kondo Y, Inai Y, Sato Y, Handa S, Kubo S, Shimokado K, et al. Senescence marker protein 30 functions as gluconolactonase in l-ascorbic acid biosynthesis, and its knockout mice are prone to scurvy. Proc Natl Acad Sci USA. 2006;103:5723–8.CrossRefPubMedGoogle Scholar
  15. 15.
    Ishigami A, Fujita T, Handa S, Shirasawa T, Koseki H, Kitamura T, et al. Senescence marker protein-30 knockout mouse liver is highly susceptible to tumor necrosis factor-alpha- and Fas-mediated apoptosis. Am J Pathol. 2002;161:1273–81.PubMedGoogle Scholar
  16. 16.
    Ishigami A, Kondo Y, Nanba R, Ohsawa T, Handa S, Kubo S, et al. SMP30 deficiency in mice causes an accumulation of neutral lipids and phospholipids in the liver and shortens the life span. Biochem Biophys Res Commun. 2004;315:575–80.CrossRefPubMedGoogle Scholar
  17. 17.
    Sato T, Seyama K, Sato Y, Mori H, Souma S, Akiyoshi T, et al. Senescence marker protein-30 protects mice lungs from oxidative stress, aging, and smoking. Am J Respir Crit Care Med. 2006;174:530–7.CrossRefPubMedGoogle Scholar
  18. 18.
    Son TG, Zou Y, Jung KJ, Yu BP, Ishigami A, Maruyama N, et al. SMP30 deficiency causes increased oxidative stress in brain. Mech Ageing Dev. 2006;127:451–7.PubMedGoogle Scholar
  19. 19.
    Kondo Y, Sasaki T, Sato Y, Amano A, Aizawa S, Iwama M, et al. Vitamin C depletion increases superoxide generation in brains of SMP30/GNL knockout mice. Biochem Biophys Res Commun. 2008;377:291–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Sato Y, Kajiyama S, Amano A, Kondo Y, Sasaki T, Handa S, et al. Hydrogen-rich pure water prevents superoxide formation in brain slices of vitamin C-depleted SMP30/GNL knockout mice. Biochem Biophys Res Commun. 2008;375:346–50.CrossRefPubMedGoogle Scholar
  21. 21.
    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
  22. 22.
    Okazaki M, Usui S, Fukui A, Kubota I, Tomoike H. Component analysis of HPLC profiles of unique lipoprotein subclass cholesterols for detection of coronary artery disease. Clin Chem. 2006;52:2049–53.CrossRefPubMedGoogle Scholar
  23. 23.
    Poli G. Pathogenesis of liver fibrosis: role of oxidative stress. Mol Aspects Med. 2000;21:49–98.CrossRefPubMedGoogle Scholar
  24. 24.
    Matsuoka M, Tsukamoto H. Stimulation of hepatic lipocyte collagen production by Kupffer cell-derived transforming growth factor beta: implication for a pathogenetic role in alcoholic liver fibrogenesis. Hepatology. 1990;11:599–605.CrossRefPubMedGoogle Scholar
  25. 25.
    Tomita K, Oike Y, Teratani T, Taguchi T, Noguchi M, Suzuki T, et al. Hepatic AdipoR2 signaling plays a protective role against progression of nonalcoholic steatohepatitis in mice. Hepatology. 2008;48:458–73.CrossRefPubMedGoogle Scholar
  26. 26.
    Parola M, Pinzani M, Casini A, Albano E, Poli G, Gentilini A, et al. Stimulation of lipid peroxidation or 4-hydroxynonenal treatment increases procollagen alpha 1 (I) gene expression in human liver fat-storing cells. Biochem Biophys Res Commun. 1993;194:1044–50.CrossRefPubMedGoogle Scholar
  27. 27.
    Parola M, Pinzani M, Casini A, Leonarduzzi G, Marra F, Caligiuri A, et al. Induction of procollagen type I gene expression and synthesis in human hepatic stellate cells by 4-hydroxy-2,3-nonenal and other 4-hydroxy-2,3-alkenals is related to their molecular structure. Biochem Biophys Res Commun. 1996;222:261–4.CrossRefPubMedGoogle Scholar
  28. 28.
    Park JK, Jeong DH, Park HY, Son KH, Shin DH, Do SH, et al. Hepatoprotective effect of Arazyme on CCl4-induced acute hepatic injury in SMP30 knock-out mice. Toxicology. 2008;246:132–42.CrossRefPubMedGoogle Scholar
  29. 29.
    Jeong DH, Goo MJ, Hong IH, Yang HJ, Ki MR, Do SH, et al. Inhibition of radiation-induced apoptosis via overexpression of SMP30 in Smad3-knockout mice liver. J Radiat Res (Tokyo). 2008;49:653–60.CrossRefGoogle Scholar
  30. 30.
    Griffin BA, Packard CJ. Metabolism of VLDL and LDL subclasses. Curr Opin Lipidol. 1994;5:200–6.CrossRefPubMedGoogle Scholar
  31. 31.
    Packard CJ. Triacylglycerol-rich lipoproteins and the generation of small, dense low-density lipoprotein. Biochem Soc Trans. 2003;31(Pt 5):1066–9.CrossRefPubMedGoogle Scholar
  32. 32.
    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
  33. 33.
    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

Copyright information

© Springer 2009

Authors and Affiliations

  • Hyohun Park
    • 1
    • 4
  • Akihito Ishigami
    • 2
    • 3
  • Toshihide Shima
    • 1
  • Masayuki Mizuno
    • 1
  • Naoki Maruyama
    • 3
  • Kanji Yamaguchi
    • 4
  • Hironori Mitsuyoshi
    • 4
  • Masahito Minami
    • 4
  • Kohichiroh Yasui
    • 4
  • Yoshito Itoh
    • 4
  • Toshikazu Yoshikawa
    • 4
  • Michiaki Fukui
    • 5
  • Goji Hasegawa
    • 5
  • Naoto Nakamura
    • 5
  • Mitsuhiro Ohta
    • 6
  • Hiroshi Obayashi
    • 7
  • Takeshi Okanoue
    • 1
    • 4
  1. 1.Department of Gastroenterology and HepatologySaiseikai Suita HospitalSuitaJapan
  2. 2.Department of Biochemistry, Faculty of Pharmaceutical ScienceToho UniversityChibaJapan
  3. 3.Aging RegulationTokyo Metropolitan Institute of GerontologyTokyoJapan
  4. 4.Department of Molecular Gastroenterology and HepatologyKyoto Prefectural University of Medicine, Graduate School of Medical ScienceKyotoJapan
  5. 5.Department of Endocrinology and MetabolismKyoto Prefectural University of Medicine, Graduate School of Medical ScienceKyotoJapan
  6. 6.Department of Medical BiochemistryKobe Pharmaceutical UniversityKobeJapan
  7. 7.Institute of Bio-Response InformaticsKyotoJapan

Personalised recommendations