ORIGINAL ARTICLE The dual PPAR-α/γ agonist saroglitazar ameliorates thioacetamide-induced liver fibrosis in rats through regulating leptin Mirhan N. Makled 1 & Maha H. Sharawy 1 & Mohammed S. El-Awady 1 Received: 8 April 2019 /Accepted: 23 July 2019 # Springer-Verlag GmbH Germany, part of Springer Nature 2019 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 Introduction Liver fibrosis is a wound-healing reaction in the liver follow- ing numerous insults to the hepatocytes, in which extracellular matrix (ECM) proteins accumulate (Tsai et al. 2010). The activation of hepatic stellate cells (HSCs) and deposition of collagen result in hepatic fibrosis. In activated HSCs, the ex- pression of tissue inhibitor of metalloproteinases-1 (TIMP-1) is upregulated promoting the inhibition of matrix metallopeptidase (MMP) activity and consequent buildup of matrix proteins in the extracellular space (Hemmann et al. 2007). Besides, emerging evidences suggest that adipokines play a serious role in the pathogenesis of liver fibrosis special- ly leptin, a profibrogenic adipokine which is mediated mainly by activated HSCs and collagen I, and its counterregulatory adipokine adiponectin (Elinav et al. 2009). In this study, repeated i.p. injections of thioacetamide (TAA), a documented hepatotoxicant, was used to induce liver fibrosis that can highly resemble the fibrosis seen in humans (Li et al. 2002). The free radical thioacetamide-S-oxide is the metabolic intermediate of TAA that is accountable for the hepatotoxic effects by covalently binding to hepatic macro- molecules leading to cellular damage and centrilobular necro- sis (Takahashi and Fukusato 2017). Saroglitazar (SGZ), an aryl alkoxy propionic acid deriva- tive, is a novel prototype of glitazar class that has been ap- proved for the management of diabetic dyslipidemia and hypertriglyceridemia. SGZ targets more than one of the per- oxisome proliferator-activated receptor (PPAR) isoforms, * Maha H. Sharawy maha_sharawy@hotmail.com; maha_hesham@mans.edu.eg 1 Department of Pharmacology and Toxicology, Faculty of Pharmacy, Mansoura University, Mansoura 35516, Egypt Naunyn-Schmiedeberg's Archives of Pharmacology https://doi.org/10.1007/s00210-019-01703-5