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Naunyn-Schmiedeberg's Archives of Pharmacology

, Volume 392, Issue 12, pp 1569–1576 | Cite as

The dual PPAR-α/γ agonist saroglitazar ameliorates thioacetamide-induced liver fibrosis in rats through regulating leptin

  • Mirhan N. Makled
  • Maha H. SharawyEmail author
  • Mohammed S. El-Awady
Original Article
  • 157 Downloads

Abstract

Liver fibrosis is a challenging global health problem resulting from chronic liver injury with no treatment currently available. It has been shown that activators for different peroxisome proliferator-activated receptor (PPAR) isoforms (α, γ, and δ) can affect different pathways in liver fibrosis. To evaluate the effects of the dual PPAR-α/γ agonist saroglitazar (SGZ) against thioacetamide (TAA)-induced fibrosis in rats, SGZ was administered for 6 weeks together with TAA injection. Administration of SGZ ameliorated TAA-induced elevation in hepatic biomarkers. SGZ was able to inhibit periportal and intralobular fibrous connective tissue proliferation, to decrease hydroxyproline content, and to lower alpha smooth muscle actin (α-SMA) protein expression. To unearth the antifibrotic mechanism of SGZ, the role of several fibrotic markers was studied. SGZ possesses inhibitory effect on protein levels of leptin, transforming growth factor-beta 1 (TGF-β1) and platelet-derived growth factor-BB (PDGF-BB). Furthermore, SGZ rectified matrix degradation through decreasing tissue inhibitor of metalloproteinases-1 (TIMP-1). This study suggests that SGZ could have a possible antifibrotic effect via suppression of leptin that can repress TGF-β1 and PDFG-BB, with subsequent inhibition of TIMP-1.

Keywords

Saroglitazar (SGZ) Liver fibrosis Leptin TGF-β1 PDGF-BB TIMP-1 

Abbreviations

TAA

Thioacetamide

SGZ

Saroglitazar

PPAR

Peroxisome proliferator-activated receptor

TGF-β1

Transforming growth factor-β1

α-SMA

Alpha-smooth muscle actin

PDGF-BB

Platelet-derived growth factor-BB

TIMP-1

Tissue inhibitor of metalloproteinases-1

Notes

Acknowledgments

The authors acknowledge Dr. Walied Abdo, Associate Prof. of Veterinary Pathology, Kafr El Sheikh University, Egypt, for aiding in the histopathological examination.

Author contribution

All authors contributed equally. MM, MS, and ME conceived, designed the research, conducted the experiments, analyzed the data, and wrote the manuscript. All authors read and approved the manuscript.

Compliance with ethical standards

Animal welfare was ensured in accordance with the ethical standards of the “Research Ethics Committee” of the Faculty of Pharmacy, Mansoura University, Egypt, code number (2017-101/2019-20). These institutional standards are in line with “Principles of laboratory Animal Care” (NIH publication No. 85-23, revised 1985).

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. Bergman I, Loxley R (1963) Two improved and simplified methods for the spectrophotometric determination of hydroxyproline. Anal Chem 35:1961–1965CrossRefGoogle Scholar
  2. Cao Q, Mak KM, Lieber CS (2006) DLPC and SAMe combined prevent leptin-stimulated TIMP-1 production in LX-2 human hepatic stellate cells by inhibiting HO-mediated signal transduction. Liver Int 26:221–231CrossRefGoogle Scholar
  3. Cong M, Liu T, Wang P, Fan X, Yang A, Bai Y, Peng Z, Wu P, Tong X, Chen J, Li H, Cong R, Tang S, Wang B, Jia J, You H (2013) Antifibrotic effects of a recombinant adeno-associated virus carrying small interfering RNA targeting TIMP-1 in rat liver fibrosis. Am J Pathol 182:1607–1616CrossRefGoogle Scholar
  4. Elinav E, Ali M, Bruck R, Brazowski E, Phillips A, Shapira Y, Katz M, Solomon G, Halpern Z, Gertler A (2009) Competitive inhibition of leptin signaling results in amelioration of liver fibrosis through modulation of stellate cell function. Hepatology (Baltimore, Md) 49:278–286CrossRefGoogle Scholar
  5. Fiorucci S, Rizzo G, Antonelli E, Renga B, Mencarelli A, Riccardi L, Morelli A, Pruzanski M, Pellicciari R (2005) Cross-talk between farnesoid-X-receptor (FXR) and peroxisome proliferator-activated receptor gamma contributes to the antifibrotic activity of FXR ligands in rodent models of liver cirrhosis. J Pharmacol Exp Ther 315:58–68CrossRefGoogle Scholar
  6. Galli A, Crabb D, Price D, Ceni E, Salzano R, Surrenti C, Casini A (2000) Peroxisome proliferator-activated receptor gamma transcriptional regulation is involved in platelet-derived growth factor-induced proliferation of human hepatic stellate cells. Hepatology (Baltimore, Md) 31:101–108CrossRefGoogle Scholar
  7. Gressner AM, Weiskirchen R (2006) Modern pathogenetic concepts of liver fibrosis suggest stellate cells and TGF-beta as major players and therapeutic targets. J Cell Mol Med 10:76–99CrossRefGoogle Scholar
  8. Hemmann S, Graf J, Roderfeld M, Roeb E (2007) Expression of MMPs and TIMPs in liver fibrosis - a systematic review with special emphasis on anti-fibrotic strategies. J Hepatol 46:955–975CrossRefGoogle Scholar
  9. Herbst H, Wege T, Milani S, Pellegrini G, Orzechowski HD, Bechstein WO, Neuhaus P, Gressner AM, Schuppan D (1997) Tissue inhibitor of metalloproteinase-1 and -2 RNA expression in rat and human liver fibrosis. Am J Pathol 150:1647–1659PubMedPubMedCentralGoogle Scholar
  10. Honda H, Ikejima K, Hirose M, Yoshikawa M, Lang T, Enomoto N, Kitamura T, Takei Y, Sato N (2002) Leptin is required for fibrogenic responses induced by thioacetamide in the murine liver. Hepatology (Baltimore, Md) 36:12–21CrossRefGoogle Scholar
  11. Jain MR, Giri SR, Bhoi B, Trivedi C, Rath A, Rathod R, Ranvir R, Kadam S, Patel H, Swain P, Roy SS, Das N, Karmakar E, Wahli W, Patel PR (2018) Dual PPARα/γ agonist saroglitazar improves liver histopathology and biochemistry in experimental NASH models. Liver Int: official journal of the International Association for the Study of the Liver 38:1084–1094CrossRefGoogle Scholar
  12. Jain MR, Giri SR, Trivedi C, Bhoi B, Rath A, Vanage G, Vyas P, Ranvir R, Patel PR (2015) Saroglitazar, a novel PPARalpha/gamma agonist with predominant PPARalpha activity, shows lipid-lowering and insulin-sensitizing effects in preclinical models. Pharmacol Res Perspect 3:e00136CrossRefGoogle Scholar
  13. Joshi SR (2015) Saroglitazar for the treatment of dyslipidemia in diabetic patients. Expert Opin Pharmacother 16:597–606CrossRefGoogle Scholar
  14. Kumar D, Goand UK, Gupta S, Shankar K, Varshney S, Rajan S, Srivastava A, Gupta A, Vishwakarma AL, Srivastava AK, Gaikwad AN (2018) Saroglitazar reduces obesity and associated inflammatory consequences in murine adipose tissue. Eur J Pharmacol 822:32–42CrossRefGoogle Scholar
  15. Lang T, Ikejima K, Yoshikawa M, Enomoto N, Iijima K, Kitamura T, Takei Y, Sato N (2004) Leptin facilitates proliferation of hepatic stellate cells through up-regulation of platelet-derived growth factor receptor. Biochem Biophys Res Commun 323:1091–1095CrossRefGoogle Scholar
  16. Li X, Benjamin IS, Alexander B (2002) Reproducible production of thioacetamide-induced macronodular cirrhosis in the rat with no mortality. J Hepatol 36:488–493CrossRefGoogle Scholar
  17. Liedtke C, Luedde T, Sauerbruch T, Scholten D, Streetz K, Tacke F, Tolba R, Trautwein C, Trebicka J, Weiskirchen R (2013) Experimental liver fibrosis research: update on animal models, legal issues and translational aspects. Fibrogenesis Tissue Repair 6:19CrossRefGoogle Scholar
  18. Liu T, Wang X, Karsdal MA, Leeming DJ, Genovese F (2012) Molecular serum markers of liver fibrosis. Biomark Insights 7:105–117CrossRefGoogle Scholar
  19. Otte C, Otte JM, Strodthoff D, Bornstein SR, Folsch UR, Monig H, Kloehn S (2004) Expression of leptin and leptin receptor during the development of liver fibrosis and cirrhosis. Exp Clin Endocrinol Diab: official journal, German Society of Endocrinology [and] German Diabetes Association 112:10–17CrossRefGoogle Scholar
  20. Pawlak M, Lefebvre P, Staels B (2015) Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol 62:720–733CrossRefGoogle Scholar
  21. Qureshi Z (2016) Saroglitazar: the revolution in India. J Indian Coll Cardiol 6:105–108CrossRefGoogle Scholar
  22. Reddy GK, Enwemeka CS (1996) A simplified method for the analysis of hydroxyproline in biological tissues. Clin Biochem 29:225–229CrossRefGoogle Scholar
  23. Singh KP, Gerard HC, Hudson AP, Boros DL (2004) Dynamics of collagen, MMP and TIMP gene expression during the granulomatous, fibrotic process induced by Schistosoma mansoni eggs. Ann Trop Med Parasitol 98:581–593CrossRefGoogle Scholar
  24. Takahashi Y, Fukusato T (2017) Chapter 13 - animal models of liver diseases. In: Conn PM (ed.) Animal models for the study of human disease (2nd Edition). Academic Press, pp. 313–339Google Scholar
  25. Tsai MK, Lin YL, Huang YT (2010) Effects of salvianolic acids on oxidative stress and hepatic fibrosis in rats. Toxicol Appl Pharmacol 242:155–164CrossRefGoogle Scholar
  26. Tsuchida A, Yamauchi T, Takekawa S, Hada Y, Ito Y, Maki T, Kadowaki T (2005) Peroxisome proliferator-activated receptor (PPAR)alpha activation increases adiponectin receptors and reduces obesity-related inflammation in adipose tissue: comparison of activation of PPARalpha, PPARgamma, and their combination. Diabetes 54:3358–3370CrossRefGoogle Scholar
  27. Wang H, Lafdil F, Wang L, Yin S, Feng D, Gao B (2011) Tissue inhibitor of metalloproteinase 1 (TIMP-1) deficiency exacerbates carbon tetrachloride-induced liver injury and fibrosis in mice: involvement of hepatocyte STAT3 in TIMP-1 production. Cell Biosci 1:14CrossRefGoogle Scholar
  28. Wang J, Leclercq I, Brymora JM, Xu N, Ramezani-Moghadam M, London RM, Brigstock D, George J (2009) Kupffer cells mediate leptin-induced liver fibrosis. Gastroenterology 137:713–723CrossRefGoogle Scholar
  29. Yoshihara D, Kurahashi H, Morita M, Kugita M, Hiki Y, Aukema HM, Yamaguchi T, Calvet JP, Wallace DP, Nagao S (2011) PPAR-gamma agonist ameliorates kidney and liver disease in an orthologous rat model of human autosomal recessive polycystic kidney disease. Am J Physiol Ren Physiol 300:F465–F474CrossRefGoogle Scholar
  30. Zardi EM, Navarini L, Sambataro G, Piccinni P, Sambataro FM, Spina C, Dobrina A (2013) Hepatic PPARs: their role in liver physiology, fibrosis and treatment. Curr Med Chem 20:3370–3396CrossRefGoogle Scholar
  31. Zhang BB, Cai WM, Weng HL, Hu ZR, Lu J, Zheng M, Liu RH (2003) Diagnostic value of platelet derived growth factor-BB, transforming growth factor-beta1, matrix metalloproteinase-1, and tissue inhibitor of matrix metalloproteinase-1 in serum and peripheral blood mononuclear cells for hepatic fibrosis. World J Gastroenterol 9:2490–2496CrossRefGoogle Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Pharmacology and Toxicology, Faculty of PharmacyMansoura UniversityMansouraEgypt

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