The dual PPAR-α/γ agonist saroglitazar ameliorates thioacetamide-induced liver fibrosis in rats through regulating leptin
- 157 Downloads
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.
KeywordsSaroglitazar (SGZ) Liver fibrosis Leptin TGF-β1 PDGF-BB TIMP-1
Peroxisome proliferator-activated receptor
Transforming growth factor-β1
Alpha-smooth muscle actin
Platelet-derived growth factor-BB
Tissue inhibitor of metalloproteinases-1
The authors acknowledge Dr. Walied Abdo, Associate Prof. of Veterinary Pathology, Kafr El Sheikh University, Egypt, for aiding in the histopathological examination.
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.
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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
- 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