Skip to main content

Advertisement

SpringerLink
Log in

Antifibrotic Effects of 1,25(OH)2D3 on Nonalcoholic Steatohepatitis in Female Mice

  • Original Article
  • Published:
Digestive Diseases and Sciences Aims and scope Submit manuscript

Abstract

Background

Postmenopausal women have a higher risk of nonalcoholic steatohepatitis (NASH) along with an increase in age, and vitamin D deficiency occurs in some patients with NASH.

Aim

We performed ovariectomy (OVX) surgery on female mice to mimic menopause, fed them a choline-deficient high-fat (CDHF) diet to induce NASH, and then investigated the effects of treatment with 1,25(OH)2D3.

Methods

Seven-week-old C57BL/6J female mice were separated into five experimental groups: SHAM, OVX, and OVX + intraperitoneal (i.p.) injection of 1,25(OH)2D3 (0.0008, 0.004, and 0.02 μg/kg). All groups were fed a CDHF diet for 8 weeks. Injections took place twice per week throughout the experimental period. Blood samples and liver tissue were collected for analyzing liver histological changes, serum biochemical indicators of hepatic function, and hepatic genes associated with fibrosis.

Results

Supplementation of 1,25(OH)2D3 in CDHF-diet mice showed decreased serum levels of ALT, AST, indicating the improvement in overall liver function, and suppressed histological NASH regarding fibrosis stage, lobular inflammation, and steatosis compared to the OVX group. Primary fibrotic markers of TGF-β, TIMP-1, α-SMA, and COL1A1 were significantly lower in the 1,25(OH)2D3 groups than in the OVX group. Furthermore, down-regulated levels of SMAD2 and SMAD3 were also observed in 1,25(OH)2D3 groups.

Conclusion

Supplementation of 1,25(OH)2D3 may ameliorate liver fibrosis and improve liver function in OVX mice with NASH induced by a CDHF diet, suggesting the therapeutic effects on postmenopause with NASH.

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
Fig. 4

Similar content being viewed by others

Abbreviations

NASH:

Nonalcoholic steatohepatitis

NAFLD:

Nonalcoholic fatty liver disease

CDHF:

Choline-deficient high-fat

CSHF:

Choline-sufficient high-fat

OVX:

Ovariectomized

VDR:

Vitamin D receptor

NAS:

NAFLD activity score

25(OH)D3 :

25-Hydroxyvitamin D

1,25(OH)2D3 :

1a,25-Dihydroxyvitamin D

HSC:

Hepatic stellate cell

COL1A1:

Type 1 collagen

TIMP-1:

Tissue inhibitor of the metalloproteinase-1

References

  1. Tanaka N, Takahashi S, Fang ZZ, et al. Role of white adipose lipolysis in the development of NASH induced by methionine- and choline-deficient diet. Biochim Biophys Acta. 2014;1841:1596–1607.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Fazel Y, Koenig AB, Sayiner M, Goodman ZD, Younossi ZM. Epidemiology and natural history of non-alcoholic fatty liver disease. Metabolism. 2016;65:1017–1025.

    Article  CAS  PubMed  Google Scholar 

  3. Lovejoy JC, Champagne CM, de Jonge L, Xie H, Smith SR. Increased visceral fat and decreased energy expenditure during the menopausal transition. Int J Obes (Lond). 2008;32:949–958.

    Article  CAS  Google Scholar 

  4. Kaunitz AM, Manson JE. Management of menopausal symptoms. Obstet Gynecol. 2015;126:859–876.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Chlebowski RT, Hendrix SL, Langer RD, et al. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women’s Health Initiative Randomized Trial. JAMA. 2003;289:3243–3253.

    Article  CAS  PubMed  Google Scholar 

  6. Shang Y. Molecular mechanisms of oestrogen and SERMs in endometrial carcinogenesis. Nat Rev Cancer. 2006;6:360.

    Article  CAS  PubMed  Google Scholar 

  7. Atsukawa M, Tsubota A, Shimada N, et al. Effect of native vitamin D3 supplementation on refractory chronic hepatitis C patients in simeprevir with pegylated interferon/ribavirin. Hepatol Res. 2016;46:450–458.

    Article  CAS  PubMed  Google Scholar 

  8. Kwok RM, Torres DM, Harrison SA. Vitamin D and nonalcoholic fatty liver disease (NAFLD): is it more than just an association? Hepatology. 2013;58:1166–1174.

    Article  CAS  PubMed  Google Scholar 

  9. Provvedini D, Tsoukas C, Deftos L, Manolagas S. 1,25-Dihydroxyvitamin D3 receptors in human leukocytes. Science. 1983;221:1181–1183.

    Article  CAS  PubMed  Google Scholar 

  10. Peterlik M, Cross HS. Vitamin D and calcium deficits predispose for multiple chronic diseases. Eur J Clin Invest. 2005;35:290–304.

    Article  CAS  PubMed  Google Scholar 

  11. Rodríguez-Rodríguez E, Navia B, López-Sobaler AM, Ortega RM. Vitamin D in overweight/obese women and its relationship with dietetic and anthropometric variables. Obesity. 2009;17:778–782.

    Article  CAS  PubMed  Google Scholar 

  12. Chacko SA, Song Y, Manson JE, et al. Serum 25-hydroxyvitamin D concentrations in relation to cardiometabolic risk factors and metabolic syndrome in postmenopausal women. Am J Clin Nutr. 2011;94:209–217.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. de Almeida JPS, Liberatti LS, Barros FEN, et al. Profile of oxidative stress markers is dependent on vitamin D levels in patients with chronic hepatitis C. Nutrition. 2016;32:362–367.

    Article  CAS  PubMed  Google Scholar 

  14. Mata-Granados JM, Cuenca-Acevedo JR, Luque de Castro MD, Holick MF, Quesada-Gomez JM. Vitamin D insufficiency together with high serum levels of vitamin A increases the risk for osteoporosis in postmenopausal women. Arch Osteoporos. 2013;8:124.

    Article  CAS  PubMed  Google Scholar 

  15. Han YP, Kong M, Zheng S, et al. Vitamin D in liver diseases: from mechanisms to clinical trials. J Gastroenterol Hepatol. 2013;28:49–55.

    Article  CAS  PubMed  Google Scholar 

  16. Meems LM, Cannon MV, Mahmud H, et al. The vitamin D receptor activator paricalcitol prevents fibrosis and diastolic dysfunction in a murine model of pressure overload. J Steroid Biochem Mol Biol. 2012;132:282–289.

    Article  CAS  PubMed  Google Scholar 

  17. Hochrath K, Stokes CS, Geisel J, et al. Vitamin D modulates biliary fibrosis in ABCB4-deficient mice. Hepatol Int. 2014;8:443–452.

    Article  PubMed  Google Scholar 

  18. Han H, Cui M, You X, Chen M, Piao X, Jin G. A role of 1,25(OH)2D3 supplementation in rats with nonalcoholic steatohepatitis induced by choline-deficient diet. Nutr Metab Cardiovasc Dis. 2015;25:556–561.

    Article  CAS  PubMed  Google Scholar 

  19. Kleiner DE, Brunt EM, Van Natta M, et al. Design and validation of a histological scoring system for nonalcoholic fatty liver disease. Hepatology. 2005;41:1313–1321.

    Article  PubMed  Google Scholar 

  20. 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;94:2467–2474.

    Article  CAS  PubMed  Google Scholar 

  21. Zumaraga MP, Medina PJ, Recto JM, et al. Targeted next generation sequencing of the entire vitamin D receptor gene reveals polymorphisms correlated with vitamin D deficiency among older Filipino women with and without fragility fracture. J Nutr Biochem. 2017;41:98–108.

    Article  CAS  PubMed  Google Scholar 

  22. Luo F, Ishigami M, Achiwa K, et al. Raloxifene ameliorates liver fibrosis of nonalcoholic steatohepatitis induced by choline-deficient high-fat diet in ovariectomized mice. Dig Dis Sci. 2015;60:2730–2739. https://doi.org/10.1007/s10620-015-3660-6.

    Article  CAS  PubMed  Google Scholar 

  23. Kim J, Lee H, Lim J, et al. The lemon balm extract ALS-L1023 inhibits obesity and nonalcoholic fatty liver disease in female ovariectomized mice. Food Chem Toxicol. 2017;106:292–305.

    Article  CAS  PubMed  Google Scholar 

  24. Yepuru M, Eswaraka J, Kearbey JD, et al. Estrogen receptor-β selective ligands alleviate high-fat diet-and ovariectomy-induced obesity in mice. J Biol Chem. 2010;285:31292–31303.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Su D, Nie Y, Zhu A, et al. Vitamin D signaling through induction of paneth cell defensins maintains gut microbiota and improves metabolic disorders and hepatic steatosis in animal models. Front Physiol. 2016;7:498.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Honda T, Ishigami M, Luo F, et al. Branched-chain amino acids alleviate hepatic steatosis and liver injury in choline-deficient high-fat diet induced NASH mice. Metabolism. 2017;69:177–187.

    Article  CAS  PubMed  Google Scholar 

  27. Raubenheimer PJ, Nyirenda MJ, Walker BR. A choline-deficient diet exacerbates fatty liver but attenuates insulin resistance and glucose intolerance in mice fed a high-fat diet. Diabetes. 2006;55:2015–2020.

    Article  CAS  PubMed  Google Scholar 

  28. Hemmann S, Graf J, Roderfeld M, Roeb E. Expression of MMPs and TIMPs in liver fibrosis—a systematic review with special emphasis on anti-fibrotic strategies. J Hepatol. 2007;46:955–975.

    Article  CAS  PubMed  Google Scholar 

  29. Inagaki Y, Okazaki I. Emerging insights into transforming growth factor beta Smad signal in hepatic fibrogenesis. Gut. 2007;56:284–292.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. McCawley LJ, Matrisian LM. Matrix metalloproteinases: they’re not just for matrix anymore! Curr Opin Cell Biol. 2001;13:534–540.

    Article  CAS  PubMed  Google Scholar 

  31. Heldin CH, Miyazono K, ten Dijke P. TGF-beta signalling from cell membrane to nucleus through SMAD proteins. Nature. 1997;4:465–471.

    Article  CAS  Google Scholar 

  32. Chen Y, Lebrun JJ, Vale W. Regulation of transforming growth factor beta- and activin-induced transcription by mammalian Mad proteins. Proc Natl Acad Sci USA. 1996;93:12992–12997.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Elangovan H, Chahal S, Gunton JE. Vitamin D in liver disease: current evidence and potential directions. Biochim Biophys Acta. 2017;1863:907–916.

    Article  CAS  Google Scholar 

  34. Nagpal S, Na S, Rathnachalam R. Noncalcemic actions of vitamin D receptor ligands. Endocr Rev. 2005;26:662–687.

    Article  CAS  PubMed  Google Scholar 

  35. Ding N, Yu RT, Subramaniam N, et al. A vitamin D receptor/SMAD genomic circuit gates hepatic fibrotic response. Cell. 2013;153:601–613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Abramovitch S, Dahan-Bachar L, Sharvit E, et al. Vitamin D inhibits proliferation and profibrotic marker expression in hepatic stellate cells and decreases thioacetamide-induced liver fibrosis in rats. Gut. 2011;60:1728–1737.

    Article  CAS  PubMed  Google Scholar 

  37. Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008;22:659–661.

    Article  CAS  PubMed  Google Scholar 

  38. Shin J-W, Seol I-C, Son C-G. Interpretation of animal dose and human equivalent dose for drug development. J Korean Orient Med. 2010;31:1–7.

    Google Scholar 

  39. Vieth R. Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr. 1999;69:842–856.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by a Grant-in-Aid for Scientific Research (C) from the Japan Society for the Promotion of Science (JSPS) (Grant number 17K09418).

Author information

Authors and Affiliations

  1. Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya, 466-8550, Japan

    Lingyun Ma, Masatoshi Ishigami, Takashi Honda, Shinya Yokoyama, Kenta Yamamoto, Yoji Ishizu, Teiji Kuzuya, Kazuhiko Hayashi, Yoshiki Hirooka & Hidemi Goto

Authors
  1. Lingyun Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Masatoshi Ishigami
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takashi Honda
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Shinya Yokoyama
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Kenta Yamamoto
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Yoji Ishizu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Teiji Kuzuya
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Kazuhiko Hayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Yoshiki Hirooka
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Hidemi Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

TH and LYM designed the research. LYM, TH, YI, TK, and KH conducted the experiments. LYM, KY, and SY analyzed the data. LYM wrote the article, TH, MI, YH, and HG reviewed the manuscript. MI had primary responsibility for the final content. All authors have read and approved the final manuscript.

Corresponding author

Correspondence to Masatoshi Ishigami.

Ethics declarations

Conflict of interest

All authors declare that they have no conflict of interest in regard to the paper.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 89 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Ma, L., Ishigami, M., Honda, T. et al. Antifibrotic Effects of 1,25(OH)2D3 on Nonalcoholic Steatohepatitis in Female Mice. Dig Dis Sci 64, 2581–2590 (2019). https://doi.org/10.1007/s10620-019-05560-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10620-019-05560-3

Keywords

Search

Navigation