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Pigment Epithelium-Derived Factor (PEDF) Prevents Hepatic Fat Storage, Inflammation, and Fibrosis in Dietary Steatohepatitis of Mice

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Abstract

Background and Aims

Pigment epithelium-derived factor (PEDF) has been shown to be a potent inhibitor of inflammation through its anti-oxidative property. Since oxidative response is considered to play the pivotal role of the development and progression of nonalcoholic steatohepatitis (NASH), it is conceivable that PEDF may play a protective role against NASH. In this study, we examined whether administration of PEDF slowed the progression of NASH in mice models.

Methods

Mice were fed methionine- and choline-deficient (MCD) diet with or without intramuscular administration of adenovirus-expressing PEDF (Ad-PEDF). Effects of PEDF administration on NASH were histologically and biochemically evaluated.

Results

Administration of Ad-PEDF significantly decreased hepatic fat storage as well as serum levels of ALT in MCD diet-fed mice. Dihydroethidium staining showed that MCD diet-triggered oxidative stress was reduced in the liver of Ad-PEDF-administered mice compared to that of PBS- or Ad-LacZ-administered mice. Activation of Kupffer cells and hepatic fibrosis was also inhibited by Ad-PEDF administration. Quantitative real-time RT-PCR revealed that MCD diet up-regulated expressions of TNF-α, IL-1β, IL-6, TGF-β, collagen-1, and collagen-3 mRNA, which were also attenuated with Ad-PEDF administration, whereas MCD diet-induced down-regulation of expressions of PPAR-γ mRNA was restored with Ad-PEDF administration. Furthermore, immunoblotting analysis showed that MCD diet-induced up-regulation of NADPH oxidase components was significantly decreased in Ad-PEDF-administered mice.

Conclusions

The present results demonstrated for the first time that PEDF could slow the development and progression of steatohepatitis through the suppression of steatosis and inflammatory response in MCD diet-fed mice. Our study suggests that PEDF supplementation may be a novel therapeutic strategy for the treatment of NASH.

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References

  1. Green RM. NASH—hepatic metabolism and not simply the metabolic syndrome. Hepatology. 2003;38:14–17.

    Article  CAS  PubMed  Google Scholar 

  2. Fabbrini E, Sullivan S, Klein S. Obesity and nonalcoholic fatty liver disease: biochemical, metabolic, and clinical implications. Hepatology. 2010;51:679–689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Tilg H, Moschen AR. Evolution of inflammation in nonalcoholic fatty liver disease: the multiple parallel hits hypothesis. Hepatology. 2010;52:1836–1846.

    Article  CAS  PubMed  Google Scholar 

  4. Tombran-Tink J, Chader GG, Johnson LV. PEDF: a pigment epithelium-derived factor with potent neuronal differentiative activity. Exp Eye Res. 1991;53:411–414.

    Article  CAS  PubMed  Google Scholar 

  5. Dawson DW, Volpert OV, Gillis P, et al. Pigment epithelium-derived factor: a potent inhibitor of angiogenesis. Science. 1999;285:245–248.

    Article  CAS  PubMed  Google Scholar 

  6. Yamagishi S, Adachi H, Abe A, et al. Elevated serum levels of pigment epithelium-derived factor in the metabolic syndrome. J Clin Endocrinol Metab. 2006;91:2447–2450.

    Article  CAS  PubMed  Google Scholar 

  7. Tahara N, Yamagishi S, Tahara A, et al. Serum level of pigment epithelium-derived factor is a marker of atherosclerosis in humans. Atherosclerosis. 2011;219:311–315.

    Article  CAS  PubMed  Google Scholar 

  8. Yoshida T, Yamagishi S, Nakamura K, et al. Pigment epithelium-derived factor (PEDF) ameliorates advanced glycation end product (AGE)-induced hepatic insulin resistance in vitro by suppressing Rac-1 activation. Horm Metab Res. 2008;40:620–625.

    Article  CAS  PubMed  Google Scholar 

  9. Matsui T, Nishino Y, Ojima A, Maeda S, Tahara N, Yamagishi S. Pigment epithelium-derived factor improves metabolic derangements and ameliorates dysregulation of adipocytokines in obese type 2 diabetic rats. Am J Pathol. 2014;184:1094–1103.

    Article  CAS  PubMed  Google Scholar 

  10. Notari L, Baladron V, Aroca-Aguilar JD, et al. Identification of a lipase-linked cell membrane receptor for pigment epithelium-derived factor. J Biol Chem. 2006;281:38022–38037.

    Article  CAS  PubMed  Google Scholar 

  11. Chung C, Doll JA, Gattu AK, et al. Anti-angiogenic pigment epithelium-derived factor regulates hepatocyte triglyceride content through adipose triglyceride lipase (ATGL). J Hepatol. 2008;48:471–478.

    Article  CAS  PubMed  Google Scholar 

  12. Wu JW, Wang SP, Alvarez F, et al. Deficiency of liver adipose triglyceride lipase in mice causes progressive hepatic steatosis. Hepatology. 2011;54:122–132.

    Article  CAS  PubMed  Google Scholar 

  13. Nakamura K, Yamagishi S, Matsui T, et al. Pigment epithelium-derived factor inhibits neointimal hyperplasia after vascular injury by blocking NADPH oxidase-mediated reactive oxygen species generation. Am J Pathol. 2007;170:2159–2170.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Bligh EG, Dyer WJ. A rapid method of total lipid extraction and purification. Can J Biochem Physiol. 1959;37:911–917.

    Article  CAS  PubMed  Google Scholar 

  15. Hashimoto M, Tanabe Y, Fujii Y, Kikuta T, Shibata H, Shido O. Chronic administration of docosahexaenoic acid ameliorates the impairment of spatial cognition learning ability in amyloid beta-infused rats. J Nutr. 2005;135:549–555.

    CAS  PubMed  Google Scholar 

  16. Smirnova E, Goldberg EB, Makarova KS, Lin L, Brown WJ, Jackson CL. ATGL has a key role in lipid droplet/adiposome degradation in mammalian cells. EMBO Rep. 2006;7:106–113.

    Article  CAS  PubMed  Google Scholar 

  17. Paik YH, Brenner DA. NADPH oxidase mediated oxidative stress in hepatic fibrogenesis. Korean J Hepatol. 2011;17:251–257.

    Article  PubMed  PubMed Central  Google Scholar 

  18. De Minicis S, Seki E, Paik YH, et al. Role and cellular source of nicotinamide adenine dinucleotide phosphate oxidase in hepatic fibrosis. Hepatology. 2010;52:1420–1430.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Bettaieb A, Jiang JX, Sasaki Y, et al. Hepatocyte nicotinamide adenine dinucleotide phosphate reduced oxidase 4 regulates stress signaling, fibrosis, and insulin sensitivity during development of steatohepatitis in mice. Gastroenterology. 2015;149:468–480.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Yoshida T, Yamagishi S, Nakamura K, et al. Pigment epithelium-derived factor (PEDF) blocks the interleukin-6 signaling to C-reactive protein expression in Hep3B cells by suppressing Rac-1 activation. Life Sci. 2006;79:1981–1987.

    Article  CAS  PubMed  Google Scholar 

  21. Mejias M, Coch L, Berzigotti A, et al. Antiangiogenic and antifibrogenic activity of pigment epithelium-derived factor (PEDF) in bile duct-ligated portal hypertensive rats. Gut. 2015;64:657–666.

    Article  CAS  PubMed  Google Scholar 

  22. Cui W, Matsuno K, Iwata K, et al. NOX1/nicotinamide adenine dinucleotide phosphate, reduced form (NADPH) oxidase promotes proliferation of stellate cells and aggravates liver fibrosis induced by bile duct ligation. Hepatology. 2011;54:949–958.

    Article  CAS  PubMed  Google Scholar 

  23. Tanaka N, Takahashi S, Zhang Y, et al. Role of fibroblast growth factor 21 in the early stage of NASH induced by methionine- and choline-deficient diet. Biochem Biophys Acta. 2015;1852:1242–1252.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Takahashi Y, Soejima Y, Kumagai A, Watanabe M, Uozaki H, Fukusato T. Inhibitory effects of Japanese herbal medicines sho-saiko-to and juzen-taiho-to on nonalcoholic steatohepatitis in mice. PLoS ONE. 2014;9:e87279.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Tomita K, Teratani T, Suzuki T, et al. Free cholesterol accumulation in hepatic stellate cells: mechanism of liver fibrosis aggravation in nonalcoholic steatohepatitis in mice. Hepatology. 2014;59:154–169.

    Article  CAS  PubMed  Google Scholar 

  26. Wu CW, Chu ES, Lam CN, et al. PPARγ is essential for protection against nonalcoholic steatohepatitis. Gene Ther. 2010;17:790–798.

    Article  CAS  PubMed  Google Scholar 

  27. Yu J, Zhang S, Chu ES, et al. Peroxisome proliferator-activated receptors gamma reverses hepatic nutritional fibrosis in mice and suppresses activation of hepatic stellate cells in vitro. Int J Biochem Cell Biol. 2010;42:948–957.

    Article  CAS  PubMed  Google Scholar 

  28. Hirsch J, Johnson CL, Nelius T, Kennedy R, Riese W, Filleur S. PEDF inhibits IL8 production in prostate cancer cells through PEDF receptor/phospholipase A2 and regulation of NFκB and PPARγ. Cytokine. 2011;55:202–210.

    Article  CAS  PubMed  Google Scholar 

  29. Blanquicett C, Kang BY, Ritzenthaler JD, Jones DP, Hart CM. Oxidative stress modulates PPARγ in vascular endothelial cells. Free Radic Biol Med. 2010;48:1618–1625.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Ho TC, Chen SL, Yang YC, Liao CL, Cheng HC, Tsao YP. PEDF induces p53-mediated apoptosis through PPAR gamma signaling in human umbilical vein endothelial cells. Cardiovasc Res. 2007;76:213–223.

    Article  CAS  PubMed  Google Scholar 

  31. Ishibashi Y, Matsui T, Ohta K, et al. PEDF inhibits AGE-induced podocyte apoptosis via PPAR-gamma activation. Microvasc Res. 2013;85:54–58.

    Article  CAS  PubMed  Google Scholar 

  32. Nakamura K, Yamagishi S, Yoshida T, et al. Hydrogen peroxide stimulates pigment epithelium-derived factor gene and protein expression in the human hepatocyte cell line OUMS-29. J Int Med Res. 2007;35:427–432.

    Article  CAS  PubMed  Google Scholar 

  33. Hyogo H, Yamagishi S, Maeda S, Kimura Y, Ishitobi T, Chayama K. Serum levels of pigment epithelium-derived factor (PEDF) are independently associated with procollagen III N-terminal peptide levels in patients with nonalcoholic fatty liver disease. Clin Biochem. 2012;45:1554–1557.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

We thank Yasuko Imamura and Masako Hayakawa for excellent technical help and Taeko Narisawa for secretarial assistance. This work was supported by JSPS Grant-in-Aid for Scientific Research (C) Grant Number 16K09385 (TT).

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Authors and Affiliations

  1. Division of Gastroenterology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan

    Takafumi Yoshida, Takao Hisamoto, Mitsuhiko Abe, Yu Ikezono, Fumitaka Wada, Hideki Iwamoto, Toru Nakamura, Hironori Koga & Takuji Torimura

  2. Liver Cancer Research Division, Research Center for Innovative Cancer Therapy, Kurume University School of Medicine, Kurume Clinical Pharmacology Clinic, 67 Asahi-Machi, Kurume, 830-0011, Japan

    Takafumi Yoshida, Takao Hisamoto, Mitsuhiko Abe, Yu Ikezono, Fumitaka Wada, Hideki Iwamoto, Toru Nakamura, Hironori Koga & Takuji Torimura

  3. Department of Pathophysiology and Therapeutics of Diabetic Vascular Complications, Kurume University School of Medicine, Kurume, Japan

    Takanori Matsui & Sho-ichi Yamagishi

  4. Department of Diagnostic Pathology, Kurume University School of Medicine, Kurume, Japan

    Jun Akiba

  5. Nakamura Clinic, Wakamatsu-ku, Kitakyushu, Japan

    Kazuo Nakamura

Authors
  1. Takafumi Yoshida
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  2. Jun Akiba
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  3. Takanori Matsui
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  5. Takao Hisamoto
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Correspondence to Takafumi Yoshida.

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Yoshida, T., Akiba, J., Matsui, T. et al. Pigment Epithelium-Derived Factor (PEDF) Prevents Hepatic Fat Storage, Inflammation, and Fibrosis in Dietary Steatohepatitis of Mice. Dig Dis Sci 62, 1527–1536 (2017). https://doi.org/10.1007/s10620-017-4550-x

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  • DOI: https://doi.org/10.1007/s10620-017-4550-x

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